Matching entries: 0
First Author Senior Author All Authors Title Year Journal Pmid Impactfactor #Citations
Beaumont, R.N. Freathy, R.M. Genome-wide association study of offspring birth weight in 86,577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics. 2018 Hum Mol Genet 29309628 5,340 0
Authors: Beaumont, R.N., Warrington, N.M., Cavadino, A., Tyrrell, J., Nodzenski, M., Horikoshi, M., Geller, F., Myhre, R., Richmond, R.C., Paternoster, L., Bradfield, J.P., Kreiner-Møller, E., Huikari, V., Metrustry, S., Lunetta, K.L., Painter, J.N., Hottenga, J.-J., Allard, C., Barton, S.J., Espinosa, A., Marsh, J.A., Potter, C., Zhang, G., Ang, W., Berry, D.J., Bouchard, L., Das, S., , E.G.G.(E.G.G.C., Hakonarson, H., Heikkinen, J., Helgeland, Ø., Hocher, B., Hofman, A., Inskip, H.M., Jones, S.E., Kogevinas, M., Lind, P.A., Marullo, L., Medland, S.E., Murray, A., Murray, J.C., Njølstad, P.R., Nohr, E.A., Reichetzeder, C., Ring, S.M., Ruth, K.S., Santa-Marina, L., Scholtens, D.M., Sebert, S., Sengpiel, V., Tuke, M.A., Vaudel, M., Weedon, M.N., Willemsen, G., Wood, A.R., Yaghootkar, H., Muglia, L.J., Bartels, M., Relton, C.L., Pennell, C.E., Chatzi, L., Estivill, X., Holloway, J.W., Boomsma, D.I., Montgomery, G.W., Murabito, J.M., Spector, T.D., Power, C., Järvelin, M.-R., Bisgaard, H., Grant, S.F., Sørensen, T.I., Jaddoe, V.W., Jacobsson, B., Melbye, M., McCarthy, M.I., Hattersley, A.T., Hayes, M.G., Frayling, T.M., Hivert, M.-F., Felix, J.F., Hyppönen, E., Lowe Jr, W.L., Evans, D.M., Lawlor, D.A., Feenstra, B. and Freathy, R.M.
Abstract: Genome-wide association studies (GWAS) of birth weight have focused on fetal genetics, while relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86,577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P<5x10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.
BibTeX:
@article{,
  author = {Beaumont, Robin N. and Warrington, Nicole M. and Cavadino, Alana and Tyrrell, Jessica and Nodzenski, Michael and Horikoshi, Momoko and Geller, Frank and Myhre, Ronny and Richmond, Rebecca C. and Paternoster, Lavinia and Bradfield, Jonathan P. and Kreiner-Møller, Eskil and Huikari, Ville and Metrustry, Sarah and Lunetta, Kathryn L. and Painter, Jodie N. and Hottenga, Jouke-Jan and Allard, Catherine and Barton, Sheila J. and Espinosa, Ana and Marsh, Julie A. and Potter, Catherine and Zhang, Ge and Ang, Wei and Berry, Diane J. and Bouchard, Luigi and Das, Shikta and , Early Growth Genetics (E. G. G) Consortium and Hakonarson, Hakon and Heikkinen, Jani and Helgeland, Øyvind and Hocher, Berthold and Hofman, Albert and Inskip, Hazel M. and Jones, Samuel E. and Kogevinas, Manolis and Lind, Penelope A. and Marullo, Letizia and Medland, Sarah E. and Murray, Anna and Murray, Jeffrey C. and Njølstad, Pål R. and Nohr, Ellen A. and Reichetzeder, Christoph and Ring, Susan M. and Ruth, Katherine S. and Santa-Marina, Loreto and Scholtens, Denise M. and Sebert, Sylvain and Sengpiel, Verena and Tuke, Marcus A. and Vaudel, Marc and Weedon, Michael N. and Willemsen, Gonneke and Wood, Andrew R. and Yaghootkar, Hanieh and Muglia, Louis J. and Bartels, Meike and Relton, Caroline L. and Pennell, Craig E. and Chatzi, Leda and Estivill, Xavier and Holloway, John W. and Boomsma, Dorret I. and Montgomery, Grant W. and Murabito, Joanne M. and Spector, Tim D. and Power, Christine and Järvelin, Marjo-Ritta and Bisgaard, Hans and Grant, Struan Fa and Sørensen, Thorkild Ia and Jaddoe, Vincent W. and Jacobsson, Bo and Melbye, Mads and McCarthy, Mark I. and Hattersley, Andrew T. and Hayes, M Geoffrey and Frayling, Timothy M. and Hivert, Marie-France and Felix, Janine F. and Hyppönen, Elina and Lowe, Jr, William L and Evans, David M. and Lawlor, Debbie A. and Feenstra, Bjarke and Freathy, Rachel M.},
  title = {Genome-wide association study of offspring birth weight in 86,577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.},
  journal = {Hum Mol Genet},
  school = {Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Oakfield Grove Bristol, BS8 2BN, UK.},
  year = {2018},
  url = {http://dx.doi.org/10.1093/hmg/ddx429},
  doi = {https://doi.org/10.1093/hmg/ddx429}
}
Stokholm, J. Bisgaard, H. Maturation of the gut microbiome and risk of asthma in childhood. 2018 Nat Commun
29321519 12,124 0
Authors: Stokholm, J., Blaser, M.J., Thorsen, J., Rasmussen, M.A., Waage, J., Vinding, R.K., Schoos, A.-M.M., Kunøe, A., Fink, N.R., Chawes, B.L., Bønnelykke, K., Brejnrod, A.D., Mortensen, M.S., Al-Soud, W.A., Sørensen, SJ., Bisgaard, H.
Abstract: The composition of the human gut microbiome matures within the first years of life. It has been hypothesized that microbial compositions in this period can cause immune dysregulations and potentially cause asthma. Here we show, by associating gut microbial composition from 16S rRNA gene amplicon sequencing during the first year of life with subsequent risk of asthma in 690 participants, that 1-year-old children with an immature microbial composition have an increased risk of asthma at age 5 years. This association is only apparent among children born to asthmatic mothers, suggesting that lacking microbial stimulation during the first year of life can trigger their inherited asthma risk. Conversely, adequate maturation of the gut microbiome in this period may protect these pre-disposed children.
BibTeX:
@article{,
  author = {Stokholm, Jakob and Blaser, Martin J. and Thorsen, Jonathan and Rasmussen, Morten A. and Waage, Johannes and Vinding, Rebecca K. and Schoos, Ann-Marie M. and Kunøe, Asja and Fink, Nadia R. and Chawes, Bo L. and Bønnelykke, Klaus and Brejnrod, Asker D. and Mortensen, Martin S. and Al-Soud, Waleed Abu and Sørensen, Søren J. and Bisgaard, Hans},
  title = {Maturation of the gut microbiome and risk of asthma in childhood.},
  journal = {Nat Commun},
  school = {COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Ledreborg Alle 34, 2820, Gentofte, Denmark. bisgaard@copsac.com.},
  year = {2018},
  volume = {9},
  number = {1},
  pages = {141},
  url = {http://dx.doi.org/10.1038/s41467-017-02573-2},
  doi = {https://doi.org/10.1038/s41467-017-02573-2}
}
Vrijlandt, E.J.L.E. Bisgaard, H. Safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms: a randomised, double-blind, placebo-controlled trial. 2018 Lancet Respir Med 29361462 19,287 2
Authors: Vrijlandt, E.J.L.E., El Azzi, G., Vandewalker, M., Rupp, N., Harper, T., Graham, L., Szefler, S.J., Moroni-Zentgraf, P., Sharma, A., Vulcu, S.D., Sigmund, R., Chawes, B., Engel, M. and Bisgaard, H.
Abstract: Few studies have assessed the safety and efficacy of potential asthma medications in children younger than 5 years. We descriptively assessed the safety and efficacy of tiotropium, a long-acting anticholinergic drug, in children aged 1-5 years with persistent asthmatic symptoms.This exploratory 12-week, randomised, double-blind, placebo-controlled, parallel-group, phase 2/3, regulatory multicentre trial was done at 32 hospitals, clinics, and clinical research units in 11 countries in Asia, Europe, and North America. Children aged 1-5 years with at least a 6-month history of persistent asthmatic symptoms and a need for inhaled corticosteroids were eligible. Patients were randomly allocated using an interactive voice or web-based response system to receive once-daily tiotropium 2·5 μg, tiotropium 5 μg, or placebo as an add-on to inhaled corticosteroids with or without additional controller medication. Patients and investigators were masked to study group assignment. Tiotropium was given via the Respimat inhaler once daily as two puffs of 1·25 μg in the 2·5 μg group, two puffs of 2·5 μg in the 5 μg group, or two puffs of placebo. The primary outcomes were safety, which was assessed by comparing adverse events between the tiotropium and placebo groups, and efficacy, which was measured as the change in weekly mean combined daytime asthma symptom score from baseline to week 12. Statistical analyses of treatment effects were exploratory; although endpoints were defined, they were used for descriptive analyses only. The safety and primary analyses were done in all patients who received at least one dose of their assigned treatment. This study is registered with ClinicalTrials.gov (NCT01634113), and is completed.Between July 26, 2012, and Dec 4, 2014, 102 children were randomly assigned to the three treatment groups (36 to receive tiotropium 2·5 μg, 32 to receive tiotropium 5 μg, and 34 to receive placebo). 101 children completed the study and were included in the analyses. The changes in adjusted weekly mean combined daytime asthma symptom scores between baseline and week 12 were not significantly different between any of the groups. The adjusted mean difference between the tiotropium 2·5 μg group and placebo group was -0·080 (95% CI -0·312 to 0·152) and the difference between tiotropium 5 μg and placebo group was -0·048 (-0·292 to 0·195). Adverse events were less frequent with tiotropium treatment than with placebo (20 [56 of 36 children with tiotropium 2·5 μg, 18 [58 of 31 with tiotropium 5 μg, and 25 [74 of 34 with placebo), although no formal statistical comparison between groups was performed. A greater proportion of children reported asthma exacerbations as adverse events in the placebo group (ten [29 of 34) than in the tiotropium groups (five [14 of 36 in the 2·5 μg group and two [6 of 31 in the 5 μg group). Serious adverse events were reported in three patients (all of whom received placebo); no adverse events led to discontinuation of treatment or death.To our knowledge, our small study is the first to assess the safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms. Tolerability of tiotropium was similar to that of placebo, which is consistent with previous findings in older populations. Although mean daytime asthma symptom scores were not significantly different between groups, tiotropium showed the potential to reduce asthma exacerbation risk compared with placebo. The findings of the study are limited by the small sample size and descriptive statistical analyses. Additional well powered trials are needed to further assess the safety and efficacy of tiotropium in young children.Boehringer Ingelheim.
BibTeX:
@article{,
  author = {Vrijlandt, Elianne J L E. and El Azzi, Georges and Vandewalker, Mark and Rupp, Ned and Harper, Thomas and Graham, LeRoy and Szefler, Stanley J. and Moroni-Zentgraf, Petra and Sharma, Ashish and Vulcu, Sebastian D. and Sigmund, Ralf and Chawes, Bo and Engel, Michael and Bisgaard, Hans},
  title = {Safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms: a randomised, double-blind, placebo-controlled trial.},
  journal = {Lancet Respir Med},
  school = {Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. Electronic address: bisgaard@copsac.com.},
  year = {2018},
  url = {http://dx.doi.org/10.1016/S2213-2600(18)30012-2},
  doi = {https://doi.org/10.1016/S2213-2600(18)30012-2}
}
Medina-Gomez, C. Rivadeneira, F. Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects. 2018 Am J Hum Genet
29304378 9,025 0
Authors: Medina-Gomez, C., Kemp, J.P., Trajanoska, K., Luan, J., Chesi, A., Ahluwalia, T.S., Mook-Kanamori, D.O., Ham, A., Hartwig, F.P., Evans, D.S., Joro, R., Nedeljkovic, I., Zheng, H.-F., Zhu, K., Atalay, M., Liu, C.-T., Nethander, M., Broer, L., Porleifsson, G., Mullin, B.H., Handelman, S.K., Nalls, M.A., Jessen, L.E., Heppe, D.H.M., Richards, J.B., Wang, C., Chawes, B., Schraut, K.E., Amin, N., Wareham, N., Karasik, D., Van der Velde, N., Ikram, M.A., Zemel, B.S., Zhou, Y., Carlsson, C.J., Liu, Y., McGuigan, F.E., Boer, C.G., Bønnelykke, K., Ralston, S.H., Robbins, J.A., Walsh, J.P., Zillikens, M.C., Langenberg, C., Li-Gao, R., Williams, F.M.K., Harris, T.B., Akesson, K., Jackson, R.D., Sigurdsson, G., den Heijer, M., van der Eerden, B.C.J., van de Peppel, J., Spector, T.D., Pennell, C., Horta, B.L., Felix, J.F., Zhao, J.H., Wilson, S.G., de Mutsert, R., Bisgaard, H., Styrkársdóttir, U., Jaddoe, V.W., Orwoll, E., Lakka, T.A., Scott, R., Grant, S.F.A., Lorentzon, M., van Duijn, C.M., Wilson, J.F., Stefansson, K., Psaty, B.M., Kiel, D.P., Ohlsson, C., Ntzani, E., van Wijnen, A.J., Forgetta, V., Ghanbari, M., Logan, J.G., Williams, G.R., Bassett, J.H.D., Croucher, P.I., Evangelou, E., Uitterlinden, A.G., Ackert-Bicknell, C.L., Tobias, J.H., Evans, D.M., Rivadeneira, F.
Abstract: Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.
BibTeX:
@article{,
  author = {Medina-Gomez, Carolina and Kemp, John P. and Trajanoska, Katerina and Luan, Jian'an and Chesi, Alessandra and Ahluwalia, Tarunveer S. and Mook-Kanamori, Dennis O. and Ham, Annelies and Hartwig, Fernando P. and Evans, Daniel S. and Joro, Raimo and Nedeljkovic, Ivana and Zheng, Hou-Feng and Zhu, Kun and Atalay, Mustafa and Liu, Ching-Ti and Nethander, Maria and Broer, Linda and Porleifsson, Gudmar and Mullin, Benjamin H. and Handelman, Samuel K. and Nalls, Mike A. and Jessen, Leon E. and Heppe, Denise H M. and Richards, J Brent and Wang, Carol and Chawes, Bo and Schraut, Katharina E. and Amin, Najaf and Wareham, Nick and Karasik, David and Van der Velde, Nathalie and Ikram, M Arfan and Zemel, Babette S. and Zhou, Yanhua and Carlsson, Christian J. and Liu, Yongmei and McGuigan, Fiona E. and Boer, Cindy G. and Bønnelykke, Klaus and Ralston, Stuart H. and Robbins, John A. and Walsh, John P. and Zillikens, M Carola and Langenberg, Claudia and Li-Gao, Ruifang and Williams, Frances M K. and Harris, Tamara B. and Akesson, Kristina and Jackson, Rebecca D. and Sigurdsson, Gunnar and den Heijer, Martin and van der Eerden, Bram C J. and van de Peppel, Jeroen and Spector, Timothy D. and Pennell, Craig and Horta, Bernardo L. and Felix, Janine F. and Zhao, Jing Hua and Wilson, Scott G. and de Mutsert, Renée and Bisgaard, Hans and Styrkársdóttir, Unnur and Jaddoe, Vincent W. and Orwoll, Eric and Lakka, Timo A. and Scott, Robert and Grant, Struan F A. and Lorentzon, Mattias and van Duijn, Cornelia M. and Wilson, James F. and Stefansson, Kari and Psaty, Bruce M. and Kiel, Douglas P. and Ohlsson, Claes and Ntzani, Evangelia and van Wijnen, Andre J. and Forgetta, Vincenzo and Ghanbari, Mohsen and Logan, John G. and Williams, Graham R. and Bassett, J H Duncan and Croucher, Peter I. and Evangelou, Evangelos and Uitterlinden, Andre G. and Ackert-Bicknell, Cheryl L. and Tobias, Jonathan H. and Evans, David M. and Rivadeneira, Fernando},
  title = {Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects.},
  journal = {Am J Hum Genet},
  school = {Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands; The Generation R Study Group, Erasmus MC, 3000 CA Rotterdam, the Netherlands; Department of Epidemiology, Erasmus MC, 3000 CA Rotterdam, the Netherlands. Electronic address: f.rivadeneira@erasmusmc.nl.},
  year = {2018},
  volume = {102},
  number = {1},
  pages = {88--102},
  url = {http://dx.doi.org/10.1016/j.ajhg.2017.12.005},
  doi = {https://doi.org/10.1016/j.ajhg.2017.12.005}
}
Jorup, C. Bisgaard, H. Budesonide/formoterol maintenance and reliever therapy in adolescent patients with asthma. 2018 Eur Respir J
29301922 10,569 0
Authors:Jorup, C., Lythgoe, D., Bisgaard, H.
Abstract: Asthma control is often suboptimal in adolescents, but few studies have evaluated asthma treatments in this population.This post hoc analysis assessed the efficacy and safety of budesonide/formoterol (BUD/FORM) maintenance and reliever therapy (MART) for treatment of persistent asthma in adolescent (age 12-17 years) subgroups within six randomised, double-blind trials. The primary end-point was time to first severe exacerbation. Secondary end-points included number of severe exacerbations, asthma-related symptoms, night-time awakenings, morning peak expiratory flow, forced expiratory volume in 1 s, as-needed medication use and five-item asthma control questionnaire scores.In adolescents (n=1847), BUD/FORM MART was similar to or more effective than comparators across each of the studies in reducing the risk of a first severe exacerbation (hazard ratios (HR) BUD/FORM MART versus comparators 0.15-1.01; pooled HR 0.49, 95% CI 0.34-0.70), with comparable outcomes to the adult subgroups (n=12 197). Similar treatment benefits for BUD/FORM MART were observed for secondary end-points. As-needed medication use was lower with BUD/FORM MART than comparators, and BUD/FORM as-needed use was lower in adolescents than adults. Treatment was well tolerated.This analysis supports the use of BUD/FORM MART in adolescents with persistent asthma, its efficacy and safety being consistent with that reported for adults.
BibTeX:
@article{,
  author = {Jorup, Carin and Lythgoe, Dan and Bisgaard, Hans},
  title = {Budesonide/formoterol maintenance and reliever therapy in adolescent patients with asthma.},
  journal = {Eur Respir J},
  year = {2018},
  volume = {51},
  number = {1},
  url = {http://dx.doi.org/10.1183/13993003.01688-2017},
  doi = {http://dx.doi.org/10.1183/13993003.01688-2017}
}
Demenais, F. Nicolae, D.L. Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks. 2018 Nat Genet
29273806 27,959 0
Authors: Demenais, F., Margaritte-Jeannin, P., Barnes, K.C., Cookson, W.O.C., Altmüller, J., Ang, W., Barr, R.G., Beaty, T.H., Becker, A.B., Beilby, J., Bisgaard, H., Bjornsdottir, U.S., Bleecker, E., Bønnelykke, K., Boomsma, D.I., Bouzigon, E., Brightling, C.E., Brossard, M., Brusselle, G.G., Burchard, E., Burkart, K.M., Bush, A., Chan-Yeung, M., Chung, K.F., Couto Alves, A., Curtin, J.A., Custovic, A., Daley, D., de Jongste, J.C., Del-Rio-Navarro, B.E., Donohue, K.M., Duijts, L., Eng, C., Eriksson, J.G., Farrall, M., Fedorova, Y., Feenstra, B., Ferreira, M.A., null, A.A.G.C.(A.A.G.C.c., Freidin, M.B., Gajdos, Z., Gauderman, J., Gehring, U., Geller, F., Genuneit, J., Gharib, S.A., Gilliland, F., Granell, R., Graves, P.E., Gudbjartsson, D.F., Haahtela, T., Heckbert, S.R., Heederik, D., Heinrich, J., Heliövaara, M., Henderson, J., Himes, B.E., Hirose, H., Hirschhorn, J.N., Hofman, A., Holt, P., Hottenga, J., Hudson, T.J., Hui, J., Imboden, M., Ivanov, V., Jaddoe, V.W.V., James, A., Janson, C., Jarvelin, M.-R., Jarvis, D., Jones, G., Jonsdottir, I., Jousilahti, P., Kabesch, M., Kähönen, M., Kantor, D.B., Karunas, A.S., Khusnutdinova, E., Koppelman, G.H., Kozyrskyj, A.L., Kreiner, E., Kubo, M., Kumar, R., Kumar, A., Kuokkanen, M., Lahousse, L., Laitinen, T., Laprise, C., Lathrop, M., Lau, S., Lee, Y.-A., Lehtimäki, T., Letort, Sé., Levin, A.M., Li, G., Liang, L., Loehr, L.R., London, S.J., Loth, D.W., Manichaikul, A., Marenholz, I., Martinez, F.J., Matheson, M.C., Mathias, R.A., Matsumoto, K., Mbarek, H., McArdle, W.L., Melbye, M., Melén, E., Meyers, D., Michel, S., Mohamdi, H., Musk, A.W., Myers, R.A., Nieuwenhuis, M.A.E., Noguchi, E., O'Connor, G.T., Ogorodova, L.M., Palmer, C.D., Palotie, A., Park, J.E., Pennell, C.E., Pershagen, Gö., Polonikov, A., Postma, D.S., Probst-Hensch, N., Puzyrev, V.P., Raby, B.A., Raitakari, O.T., Ramasamy, A., Rich, S.S., Robertson, C.F., Romieu, I., Salam, M.T., Salomaa, V., Schlünssen, V., Scott, R., Selivanova, P.A., Sigsgaard, T., Simpson, A., Siroux, V., Smith, L.J., Solodilova, M., Standl, M., Stefansson, K., Strachan, D.P., Stricker, B.H., Takahashi, A., Thompson, P.J., Thorleifsson, G., Thorsteinsdottir, U., Tiesler, C.M.T., Torgerson, D.G., Tsunoda, T., Uitterlinden, A.G., van der Valk, R.J.P., Vaysse, A., Vedantam, S., von Berg, A., von Mutius, E., Vonk, J.M., Waage, J., Wareham, N.J., Weiss, S.T., White, W.B., Wickman, M., Widén, E., Willemsen, G., Williams, L.K., Wouters, I.M., Yang, J.J., Zhao, J.H., Moffatt, M.F., Ober, C., Nicolae, D.L.
Abstract: We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.
BibTeX:
@article{,
  author = {Demenais, Florence and Margaritte-Jeannin, Patricia and Barnes, Kathleen C. and Cookson, William O C. and Altmüller, Janine and Ang, Wei and Barr, R Graham and Beaty, Terri H. and Becker, Allan B. and Beilby, John and Bisgaard, Hans and Bjornsdottir, Unnur Steina and Bleecker, Eugene and Bønnelykke, Klaus and Boomsma, Dorret I. and Bouzigon, Emmanuelle and Brightling, Christopher E. and Brossard, Myriam and Brusselle, Guy G. and Burchard, Esteban and Burkart, Kristin M. and Bush, Andrew and Chan-Yeung, Moira and Chung, Kian Fan and Couto Alves, Alexessander and Curtin, John A. and Custovic, Adnan and Daley, Denise and de Jongste, Johan C. and Del-Rio-Navarro, Blanca E. and Donohue, Kathleen M. and Duijts, Liesbeth and Eng, Celeste and Eriksson, Johan G. and Farrall, Martin and Fedorova, Yuliya and Feenstra, Bjarke and Ferreira, Manuel A. and , Australian Asthma Genetics Consortium (A. A. G. C) collaborators and Freidin, Maxim B. and Gajdos, Zofia and Gauderman, Jim and Gehring, Ulrike and Geller, Frank and Genuneit, Jon and Gharib, Sina A. and Gilliland, Frank and Granell, Raquel and Graves, Penelope E. and Gudbjartsson, Daniel F. and Haahtela, Tari and Heckbert, Susan R. and Heederik, Dick and Heinrich, Joachim and Heliövaara, Markku and Henderson, John and Himes, Blanca E. and Hirose, Hiroshi and Hirschhorn, Joel N. and Hofman, Albert and Holt, Patrick and Hottenga, Jouke and Hudson, Thomas J. and Hui, Jennie and Imboden, Medea and Ivanov, Vladimir and Jaddoe, Vincent W V. and James, Alan and Janson, Christer and Jarvelin, Marjo-Riitta and Jarvis, Deborah and Jones, Graham and Jonsdottir, Ingileif and Jousilahti, Pekka and Kabesch, Michael and Kähönen, Mika and Kantor, David B. and Karunas, Alexandra S. and Khusnutdinova, Elza and Koppelman, Gerard H. and Kozyrskyj, Anita L. and Kreiner, Eskil and Kubo, Michiaki and Kumar, Rajesh and Kumar, Ashish and Kuokkanen, Mikko and Lahousse, Lies and Laitinen, Tarja and Laprise, Catherine and Lathrop, Mark and Lau, Susanne and Lee, Young-Ae and Lehtimäki, Terho and Letort, Sébastien and Levin, Albert M. and Li, Guo and Liang, Liming and Loehr, Laura R. and London, Stephanie J. and Loth, Daan W. and Manichaikul, Ani and Marenholz, Ingo and Martinez, Fernando J. and Matheson, Melanie C. and Mathias, Rasika A. and Matsumoto, Kenji and Mbarek, Hamdi and McArdle, Wendy L. and Melbye, Mads and Melén, Erik and Meyers, Deborah and Michel, Sven and Mohamdi, Hamida and Musk, Arthur W. and Myers, Rachel A. and Nieuwenhuis, Maartje A E. and Noguchi, Emiko and O'Connor, George T. and Ogorodova, Ludmila M. and Palmer, Cameron D. and Palotie, Aarno and Park, Julie E. and Pennell, Craig E. and Pershagen, Göran and Polonikov, Alexey and Postma, Dirkje S. and Probst-Hensch, Nicole and Puzyrev, Valery P. and Raby, Benjamin A. and Raitakari, Olli T. and Ramasamy, Adaikalavan and Rich, Stephen S. and Robertson, Colin F. and Romieu, Isabelle and Salam, Muhammad T. and Salomaa, Veikko and Schlünssen, Vivi and Scott, Robert and Selivanova, Polina A. and Sigsgaard, Torben and Simpson, Angela and Siroux, Valérie and Smith, Lewis J. and Solodilova, Maria and Standl, Marie and Stefansson, Kari and Strachan, David P. and Stricker, Bruno H. and Takahashi, Atsushi and Thompson, Philip J. and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tiesler, Carla M T. and Torgerson, Dara G. and Tsunoda, Tatsuhiko and Uitterlinden, André G. and van der Valk, Ralf J P. and Vaysse, Amaury and Vedantam, Sailaja and von Berg, Andrea and von Mutius, Erika and Vonk, Judith M. and Waage, Johannes and Wareham, Nick J. and Weiss, Scott T. and White, Wendy B. and Wickman, Magnus and Widén, Elisabeth and Willemsen, Gonneke and Williams, L Keoki and Wouters, Inge M. and Yang, James J. and Zhao, Jing Hua and Moffatt, Miriam F. and Ober, Carole and Nicolae, Dan L.},
  title = {Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks.},
  journal = {Nat Genet},
  year = {2018},
  volume = {50},
  number = {1},
  pages = {42--53},
  url = {http://dx.doi.org/10.1038/s41588-017-0014-7},
  doi = {http://dx.doi.org/10.1038/s41588-017-0014-7}
}
Wolsk, H.M. Bisgaard, H. Noninvasive Sampling of Mucosal Lining Fluid for the Quantification of In Vivo Upper Airway Immune-mediator Levels. 2017 J Vis Exp(126) 28809842 1,325 0
Authors: Wolsk, H.M., Chawes, B.L., Thorsen, J., Stokholm, J., Bønnelykke, K., Brix, S. and Bisgaard, H.
Abstract: This protocol describes noninvasive sampling of undisturbed upper airway mucosal lining fluid. It also details the extraction procedure used prior to the analysis of immune mediators in fluid eluates for the study of the airway topical immune signature, without the need for stimulation procedures (often used by other techniques). The mucosal lining fluid is sampled on a strip of filter paper placed at the anterior part of the inferior turbinate and left for 2 min of absorption. Analytes are eluted from the filter papers, and the extracted protein-based eluates are analyzed by an electrochemiluminescence-based immunoassay, allowing for the high-sensitivity quantification of low- and high-level analytes in the same sample. We measured the in vivo levels of 20 preselected immune mediators related to specific immune signaling pathways in the upper airway mucosa, but the technique is not limited to that specific panel or sampling site. The technique was first implemented in 7-year-old children from the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) cohort with allergic rhinitis. It was thereafter used in the longitudinal COPSAC2010 birth cohort, sampled at 1 month, 2 years, and 6 years of age and at instances of acute respiratory symptoms. We successfully obtained and analyzed samples from 620 (89 of 700 1-month-old children; a few samples were below the assay detection limit (reported as the median (Inter-Quartile Range (IQR)). The number of samples below the detection limit (i.e. from 0 to the set point for the lower limit of detection) for each mediator was 29 (7.25 - 119.5). This technique enables the quantification of the in vivo airway mucosal immune profile from birth, can be applied longitudinally, and can be applied to studies on the effect of genetics and early-life environmental exposures, pathophysiology, endotyping, and monitoring of respiratory diseases, and development and evaluation of novel therapeutics.
BibTeX:
@article{,
  author = {Wolsk, Helene M. and Chawes, Bo L. and Thorsen, Jonathan and Stokholm, Jakob and Bønnelykke, Klaus and Brix, Susanne and Bisgaard, Hans},
  title = {Noninvasive Sampling of Mucosal Lining Fluid for the Quantification of In Vivo Upper Airway Immune-mediator Levels.},
  journal = {J Vis Exp},
  school = {Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen; bisgaard@copsac.com.},
  year = {2017},
  number = {126},
  url = {http://dx.doi.org/10.3791/55800},
  doi = {https://doi.org/10.3791/55800}
}
Wolsk, H.M. Weiss, S.T. Prenatal vitamin D supplementation reduces risk of asthma/recurrent wheeze in early childhood: A combined analysis of two randomized controlled trials. 2017 PLoS One 29077711 2,806 0
Authors: Wolsk, H.M., Chawes, B.L., Litonjua, A.A., Hollis, B.W., Waage, J., Stokholm, J., Bønnelykke, K., Bisgaard, H. and Weiss, S.T.
Abstract: We recently published two independent randomized controlled trials of vitamin D supplementation during pregnancy, both indicating a >20% reduced risk of asthma/recurrent wheeze in the offspring by 3 years of age. However, neither reached statistical significance.To perform a combined analysis of the two trials and investigate whether maternal 25-hydroxy-vitamin D (25(OH)D) level at trial entry modified the intervention effect.VDAART (N = 806) and COPSAC2010. (N = 581) randomized pregnant women to daily high-dose vitamin D3 (4,000 IU/d and 2,400 IU/d, respectively) or placebo. All women also received a prenatal vitamin containing 400 IU/d vitamin D3. The primary outcome was asthma/recurrent wheeze from 0-3yrs. Secondary end-points were specific IgE, total IgE, eczema and lower respiratory tract infections (LRTI). We conducted random effects combined analyses of the treatment effect, individual patient data (IPD) meta-analyses, and analyses stratified by 25(OH)D level at study entry.The analysis showed a 25% reduced risk of asthma/recurrent wheeze at 0-3yrs: adjusted odds ratio (aOR) = 0.74 (95% CI, 0.57-0.96), p = 0.02. The effect was strongest among women with 25(OH)D level ≥30ng/ml at study entry: aOR = 0.54 (0.33-0.88), p = 0.01, whereas no significant effect was observed among women with 25(OH)D level <30ng/ml at study entry: aOR = 0.84 (0.62-1.15), p = 0.25. The IPD meta-analyses showed similar results. There was no effect on the secondary end-points.This combined analysis shows that vitamin D supplementation during pregnancy results in a significant reduced risk of asthma/recurrent wheeze in the offspring, especially among women with 25(OH)D level ≥ 30 ng/ml at randomization, where the risk was almost halved. Future studies should examine the possibility of raising 25(OH)D levels to at least 30 ng/ml early in pregnancy or using higher doses than used in our studies.COPSAC2010: ClinicalTrials.gov NCT00856947; VDAART: ClinicalTrials.gov NCT00920621.
BibTeX:
@article{,
  author = {Wolsk, Helene M. and Chawes, Bo L. and Litonjua, Augusto A. and Hollis, Bruce W. and Waage, Johannes and Stokholm, Jakob and Bønnelykke, Klaus and Bisgaard, Hans and Weiss, Scott T.},
  title = {Prenatal vitamin D supplementation reduces risk of asthma/recurrent wheeze in early childhood: A combined analysis of two randomized controlled trials.},
  journal = {PLoS One},
  school = {Harvard Medical School, Boston, MA, United States of America.},
  year = {2017},
  volume = {12},
  number = {10},
  pages = {e0186657},
  url = {http://dx.doi.org/10.1371/journal.pone.0186657},
  doi = {https://doi.org/10.1371/journal.pone.0186657}
}
Stokholm, J. Bisgaard, H. Cat exposure in early life decreases asthma risk from the 17q21 high-risk variant. 2017 J Allergy Clin Immunol 29102067 13,081 0
Authors: Stokholm, J., Chawes, B.L., Vissing, N., Bønnelykke, K. and Bisgaard, H.
Abstract: Early-life exposure to cats and dogs has shown diverging associations with childhood asthma risk, and gene-environment interaction is one possible explanation.We investigated interactions between cat and dog exposure and single nucleotide polymorphism rs7216389 variants in the chromosome 17q21 locus, the strongest known genetic risk factor for childhood asthma.Genotyping was performed in 377 children from the at-risk Copenhagen Prospective Studies on Asthma in Childhood2000. The primary end point was the development of asthma until age 12 years. The secondary end point was the number of episodes with pneumonia and bronchiolitis from 0 to 3 years of age. Exposures included cat and dog ownership from birth and cat and dog allergen levels in bedding at age 1 year. Replication was performed in the unselected COPSAC2010 cohort with follow-up until 5 years of age.Cat and/or dog exposure from birth was associated with a lower prevalence of asthma among children with the rs7216389 high-risk TT genotype (adjusted hazard ratio, 0.16; 95% CI, 0.04-0.71; P = .015), with no effect in those with the CC/CT genotype (adjusted P = .283), demonstrating interaction between cat and dog exposure and the rs7216389 genotype (adjusted P = .044). Cat allergen levels were inversely associated with asthma development in children with the TT genotype (adjusted hazard ratio, 0.83; 95% CI, 0.71-0.97; P = .022), supporting the cat-rs7216389 genotype interaction (adjusted P = .008). Dog allergen exposure did not show such interaction. Furthermore, the TT genotype was associated with higher risk of pneumonia and bronchiolitis, and this increased risk was likewise decreased in children exposed to cat. Replication showed similar effects on asthma risk.The observed gene-environment interaction suggests a role of early-life exposure, especially to cat, for attenuating the risk of childhood asthma, pneumonia, and bronchiolitis in genetically susceptible subjects.
BibTeX:
@article{,
  author = {Stokholm, Jakob and Chawes, Bo L. and Vissing, Nadja and Bønnelykke, Klaus and Bisgaard, Hans},
  title = {Cat exposure in early life decreases asthma risk from the 17q21 high-risk variant.},
  journal = {J Allergy Clin Immunol},
  school = {COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. Electronic address: bisgaard@copsac.com.},
  year = {2017},
  url = {http://dx.doi.org/10.1016/j.jaci.2017.07.044},
  doi = {https://doi.org/10.1016/j.jaci.2017.07.044}
}
Wolsk, H.M. Bønnelykke, K. No evidence of intrauterine sensitization against inhalant allergens. 2017 J Allergy Clin Immunol 28040416 13,081 0
Authors: Wolsk, H.M., Andersen, M.R., Bisgaard, H. and Bønnelykke, K.
BibTeX:
@article{,
  author = {Wolsk, Helene Mygind and Andersen, Malene Rohr and Bisgaard, Hans and Bønnelykke, Klaus},
  title = {No evidence of intrauterine sensitization against inhalant allergens.},
  journal = {J Allergy Clin Immunol},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.},
  year = {2017},
  volume = {140},
  number = {1},
  pages = {286--288.e3},
  url = {http://dx.doi.org/10.1016/j.jaci.2016.10.048},
  doi = {https://doi.org/10.1016/j.jaci.2016.10.048}
}
Vinding, R.K. Stokholm, J. Cesarean Delivery and Body Mass Index at 6 Months and Into Childhood. 2017 Pediatrics 28814549 5,705 0
Authors: Vinding, R.K., Sejersen, T.S., Chawes, B.L., Bønnelykke, K., Buhl, T., Bisgaard, H. and Stokholm, J.
Abstract: The prevalence of cesarean delivery (CD) is rising worldwide, and so is childhood obesity. Studies have shown associations between these factors. We examined the development of BMI from birth through childhood to determine whether CDs were associated with differences in growth and obesity.Term children from the birth cohorts Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) and COPSAC2010 were included. Height, length, and weight measurements were collected prospectively until 5 years in COPSAC2010 and until 13 years in COPSAC2000. Dual-energy x-ray absorptiometry (DXA) scans were performed at 3.5 and 7 years. Information on relevant covariates were verified during clinical visits. Analyses were adjusted for covariates associating with CD.In COPSAC2010, 20% (N = 138/673) of the children were delivered by CD; 49% were girls. In COPSAC2000, 19% (N = 76/393) were delivered by CD; 51% were girls. Children delivered by CD had a higher mean BMI at 6 months compared with those delivered vaginally: COPSAC2010 β-coefficient, .41 (95% confidence interval [CI], .12 to .69), P = .01; COPSAC2000 β-coefficient, .16 (95% CI, -.11 to .68), P = .16; and meta-analysis β-coefficient, .37 (95% CI, .14 to .60), P = .002. There were no differences in BMI trajectory between the 2 groups by 5 and 13 years, nor cross-sectional BMI at 5 and 13 years, nor in fat percentages from DXA scans.Children delivered by CD had a higher BMI at 6 months of age, but this difference did not track into later childhood. Our study does not support the hypothesis that CD leads to later overweight.
BibTeX:
@article{,
  author = {Vinding, Rebecca Kofod and Sejersen, Tobias Steen and Chawes, Bo L. and Bønnelykke, Klaus and Buhl, Thora and Bisgaard, Hans and Stokholm, Jakob},
  title = {Cesarean Delivery and Body Mass Index at 6 Months and Into Childhood.},
  journal = {Pediatrics},
  school = {Department of Pediatrics, Naestved Hospital, Naestved, Denmark; and.},
  year = {2017},
  volume = {139},
  number = {6},
  url = {http://dx.doi.org/10.1542/peds.2016-4066},
  doi = {https://doi.org/10.1542/peds.2016-4066}
}
Smith, D. Stefansson, K. A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma. 2017 PLoS Genet 28273074 6,100 4
Authors: Smith, D., Helgason, H., Sulem, P., Bjornsdottir, U.S., Lim, A.C., Sveinbjornsson, G., Hasegawa, H., Brown, M., Ketchem, R.R., Gavala, M., Garrett, L., Jonasdottir, A., Jonasdottir, A., Sigurdsson, A., Magnusson, O.T., Eyjolfsson, G.I., Olafsson, I., Onundarson, P.T., Sigurdardottir, O., Gislason, D., Gislason, T., Ludviksson, B.R., Ludviksdottir, D., Boezen, H.M., Heinzmann, A., Krueger, M., Porsbjerg, C., Ahluwalia, T.S., Waage, J., Backer, V., Deichmann, K.A., Koppelman, G.H., Bønnelykke, K., Bisgaard, H., Masson, G., Thorsteinsdottir, U., Gudbjartsson, D.F., Johnston, J.A., Jonsdottir, I. and Stefansson, K.
Abstract: IL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM_001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65 that disrupts a canonical splice acceptor site before the last coding exon. It is also found at low frequency in European populations. rs146597587-C associates with lower eosinophil counts (β = -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids. The truncated IL-33 has normal intracellular localization but neither binds IL-33R/ST2 nor activates ST2-expressing cells. Together these data demonstrate that rs146597587-C is a loss of function mutation and support the hypothesis that IL-33 haploinsufficiency protects against asthma.
BibTeX:
@article{,
  author = {Smith, Dirk and Helgason, Hannes and Sulem, Patrick and Bjornsdottir, Unnur Steina and Lim, Ai Ching and Sveinbjornsson, Gardar and Hasegawa, Haruki and Brown, Michael and Ketchem, Randal R. and Gavala, Monica and Garrett, Logan and Jonasdottir, Adalbjorg and Jonasdottir, Aslaug and Sigurdsson, Asgeir and Magnusson, Olafur T. and Eyjolfsson, Gudmundur I. and Olafsson, Isleifur and Onundarson, Pall Torfi and Sigurdardottir, Olof and Gislason, David and Gislason, Thorarinn and Ludviksson, Bjorn Runar and Ludviksdottir, Dora and Boezen, H Marike and Heinzmann, Andrea and Krueger, Marcus and Porsbjerg, Celeste and Ahluwalia, Tarunveer S. and Waage, Johannes and Backer, Vibeke and Deichmann, Klaus A. and Koppelman, Gerard H. and Bønnelykke, Klaus and Bisgaard, Hans and Masson, Gisli and Thorsteinsdottir, Unnur and Gudbjartsson, Daniel F. and Johnston, James A. and Jonsdottir, Ingileif and Stefansson, Kari},
  title = {A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma.},
  journal = {PLoS Genet},
  school = {Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.},
  year = {2017},
  volume = {13},
  number = {3},
  pages = {e1006659},
  url = {http://dx.doi.org/10.1371/journal.pgen.1006659},
  doi = {https://doi.org/10.1371/journal.pgen.1006659}
}
Skaaby, T. Linneberg, A. Investigating the causal effect of smoking on hay fever and asthma: a Mendelian randomization meta-analysis in the CARTA consortium. 2017 Sci Rep 28533558 4,259 1
Authors: Skaaby, T., Taylor, A.E., Jacobsen, R.K., Paternoster, L., Thuesen, B.H., Ahluwalia, T.S., Larsen, S.C., Zhou, A., Wong, A., Gabrielsen, M.E., Bjørngaard, J.H., Flexeder, C., Männistö, S., Hardy, R., Kuh, D., Barry, S.J., Tang Møllehave, L., Cerqueira, C., Friedrich, N., Bonten, T.N., Noordam, R., Mook-Kanamori, D.O., Taube, C., Jessen, L.E., McConnachie, A., Sattar, N., Upton, M.N., McSharry, C., Bønnelykke, K., Bisgaard, H., Schulz, H., Strauch, K., Meitinger, T., Peters, A., Grallert, H., Nohr, E.A., Kivimaki, M., Kumari, M., Völker, U., Nauck, M., Völzke, H., Power, C., Hyppönen, E., Hansen, T., Jørgensen, T., Pedersen, O., Salomaa, V., Grarup, N., Langhammer, A., Romundstad, P.R., Skorpen, F., Kaprio, J., R Munafò, M. and Linneberg, A.
Abstract: Observational studies on smoking and risk of hay fever and asthma have shown inconsistent results. However, observational studies may be biased by confounding and reverse causation. Mendelian randomization uses genetic variants as markers of exposures to examine causal effects. We examined the causal effect of smoking on hay fever and asthma by using the smoking-associated single nucleotide polymorphism (SNP) rs16969968/rs1051730. We included 231,020 participants from 22 population-based studies. Observational analyses showed that current vs never smokers had lower risk of hay fever (odds ratio (OR) = 0·68, 95% confidence interval (CI): 0·61, 0·76; P < 0·001) and allergic sensitization (OR = 0·74, 95% CI: 0·64, 0·86; P < 0·001), but similar asthma risk (OR = 1·00, 95% CI: 0·91, 1·09; P = 0·967). Mendelian randomization analyses in current smokers showed a slightly lower risk of hay fever (OR = 0·958, 95% CI: 0·920, 0·998; P = 0·041), a lower risk of allergic sensitization (OR = 0·92, 95% CI: 0·84, 1·02; P = 0·117), but higher risk of asthma (OR = 1·06, 95% CI: 1·01, 1·11; P = 0·020) per smoking-increasing allele. Our results suggest that smoking may be causally related to a higher risk of asthma and a slightly lower risk of hay fever. However, the adverse events associated with smoking limit its clinical significance.
BibTeX:
@article{,
  author = {Skaaby, Tea and Taylor, Amy E. and Jacobsen, Rikke K. and Paternoster, Lavinia and Thuesen, Betina H. and Ahluwalia, Tarunveer S. and Larsen, Sofus C. and Zhou, Ang and Wong, Andrew and Gabrielsen, Maiken E. and Bjørngaard, Johan H. and Flexeder, Claudia and Männistö, Satu and Hardy, Rebecca and Kuh, Diana and Barry, Sarah J. and Tang Møllehave, Line and Cerqueira, Charlotte and Friedrich, Nele and Bonten, Tobias N. and Noordam, Raymond and Mook-Kanamori, Dennis O. and Taube, Christian and Jessen, Leon E. and McConnachie, Alex and Sattar, Naveed and Upton, Mark N. and McSharry, Charles and Bønnelykke, Klaus and Bisgaard, Hans and Schulz, Holger and Strauch, Konstantin and Meitinger, Thomas and Peters, Annette and Grallert, Harald and Nohr, Ellen A. and Kivimaki, Mika and Kumari, Meena and Völker, Uwe and Nauck, Matthias and Völzke, Henry and Power, Chris and Hyppönen, Elina and Hansen, Torben and Jørgensen, Torben and Pedersen, Oluf and Salomaa, Veikko and Grarup, Niels and Langhammer, Arnulf and Romundstad, Pål R. and Skorpen, Frank and Kaprio, Jaakko and R Munafò, Marcus and Linneberg, Allan},
  title = {Investigating the causal effect of smoking on hay fever and asthma: a Mendelian randomization meta-analysis in the CARTA consortium.},
  journal = {Sci Rep},
  school = {Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.},
  year = {2017},
  volume = {7},
  number = {1},
  pages = {2224},
  url = {http://dx.doi.org/10.1038/s41598-017-01977-w},
  doi = {https://doi.org/10.1038/s41598-017-01977-w}
}
Schoos, A.-M.M. Chawes, B.L. FeNO and Exercise Testing in Children at Risk of Asthma. 2017 J Allergy Clin Immunol Pract 29133224 5,317 0
Authors: Schoos, A.-M.M., Christiansen, C.F., Stokholm, J., Bønnelykke, K., Bisgaard, H. and Chawes, B.L.
Abstract: Exercise testing is the gold standard for diagnosing exercise-induced bronchoconstriction in children, but requires considerable cooperation and medical resources. Therefore, fraction of exhaled nitric oxide (FeNO) has been proposed as a tool to predict the need for exercise testing.The objective of this study was to investigate the relationship between FeNO, exercise test results, and a history of respiratory symptoms during exercise in children at risk of asthma.FeNO measurement, exercise testing, and interview about respiratory symptoms during exercise were completed in 224 seven-year-old children from the at-risk Copenhagen Prospective Studies on Asthma in Childhood2000 birth cohort. The associations between FeNO, exercise test results, and reported respiratory symptoms during exercise were analyzed adjusting for gender, respiratory infections, and inhaled corticosteroid treatment. The associations were also analyzed stratified by asthma and atopic status.Of the 224 children, 28 (13 had an established asthma diagnosis and 58 (26 had a positive exercise test (≥15% drop in forced expiratory volume in 1 second [FEV1] from baseline). FeNO and bronchial obstruction after exercise were linearly associated with a doubling of FeNO corresponding to a 2.4% drop in FEV1 (95% confidence interval, 0.8-4.1; P < .01). However, a receiver operating characteristic curve analysis showed that the best cutoff of FeNO for predicting exercise test outcome among children who reported respiratory symptoms during exercise was 17 ppb, which only had 74% negative predictive value. There was no association between FeNO and reported respiratory symptoms during exercise (odds ratio = 1.3 [0.8-1.9]; P = .29) or reported symptoms during exercise and exercise test results (odds ratio = 1.0 [1.0-1.1]; P = .12).A history of respiratory symptoms during exercise was not associated with either elevated FeNO or a positive exercise test in children at risk of asthma. FeNO and exercise test results were linearly associated traits, but FeNO could not reliably be used dichotomized to predict the need of exercise testing.
BibTeX:
@article{,
  author = {Schoos, Ann-Marie Malby and Christiansen, Christina Figgé and Stokholm, Jakob and Bønnelykke, Klaus and Bisgaard, Hans and Chawes, Bo Lund},
  title = {FeNO and Exercise Testing in Children at Risk of Asthma.},
  journal = {J Allergy Clin Immunol Pract},
  school = {COPSAC (Copenhagen Prospective Studies on Asthma in Childhood), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.},
  year = {2017},
  url = {http://dx.doi.org/10.1016/j.jaip.2017.10.014},
  doi = {https://doi.org/10.1016/j.jaip.2017.10.014}
}
Schoos, A.-M.M. Rasmussen, M.A. Sensitization trajectories in childhood revealed by using a cluster analysis. 2017 J Allergy Clin Immunol 28347735 13,081 0
Authors: Schoos, A.-M.M., Chawes, B.L., Melén, E., Bergström, A., Kull, I., Wickman, M., Bønnelykke, K., Bisgaard, H. and Rasmussen, M.A.
Abstract: Assessment of sensitization at a single time point during childhood provides limited clinical information. We hypothesized that sensitization develops as specific patterns with respect to age at debut, development over time, and involved allergens and that such patterns might be more biologically and clinically relevant.We sought to explore latent patterns of sensitization during the first 6 years of life and investigate whether such patterns associate with the development of asthma, rhinitis, and eczema.We investigated 398 children from the at-risk Copenhagen Prospective Studies on Asthma in Childhood 2000 (COPSAC2000) birth cohort with specific IgE against 13 common food and inhalant allergens at the ages of ½, 1½, 4, and 6 years. An unsupervised cluster analysis for 3-dimensional data (nonnegative sparse parallel factor analysis) was used to extract latent patterns explicitly characterizing temporal development of sensitization while clustering allergens and children. Subsequently, these patterns were investigated in relation to asthma, rhinitis, and eczema. Verification was sought in an independent unselected birth cohort (BAMSE) constituting 3051 children with specific IgE against the same allergens at 4 and 8 years of age.The nonnegative sparse parallel factor analysis indicated a complex latent structure involving 7 age- and allergen-specific patterns in the COPSAC2000 birth cohort data: (1) dog/cat/horse, (2) timothy grass/birch, (3) molds, (4) house dust mites, (5) peanut/wheat flour/mugwort, (6) peanut/soybean, and (7) egg/milk/wheat flour. Asthma was solely associated with pattern 1 (odds ratio [OR], 3.3; 95% CI, 1.5-7.2), rhinitis with patterns 1 to 4 and 6 (OR, 2.2-4.3), and eczema with patterns 1 to 3 and 5 to 7 (OR, 1.6-2.5). All 7 patterns were verified in the independent BAMSE cohort (R2 > 0.89).This study suggests the presence of specific sensitization patterns in early childhood differentially associated with development of clinical outcomes. Using such patterns in future research might provide more robust and clinically relevant results.
BibTeX:
@article{,
  author = {Schoos, Ann-Marie M. and Chawes, Bo L. and Melén, Erik and Bergström, Anna and Kull, Inger and Wickman, Magnus and Bønnelykke, Klaus and Bisgaard, Hans and Rasmussen, Morten A.},
  title = {Sensitization trajectories in childhood revealed by using a cluster analysis.},
  journal = {J Allergy Clin Immunol},
  school = {COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Food Science, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.},
  year = {2017},
  volume = {140},
  number = {6},
  pages = {1693--1699},
  url = {http://dx.doi.org/10.1016/j.jaci.2017.01.041},
  doi = {https://doi.org/10.1016/j.jaci.2017.01.041}
}
Schoos, A.-M.M. Kristensen, B. Precision allergy: Separate allergies to male and female dogs. 2017 J Allergy Clin Immunol Pract 28499775 5,317 0
Authors: Schoos, A.-M.M., Bønnelykke, K., Chawes, B.L., Stokholm, J., Bisgaard, H. and Kristensen, B.
BibTeX:
@article{,
  author = {Schoos, Ann-Marie Malby and Bønnelykke, Klaus and Chawes, Bo Lund and Stokholm, Jakob and Bisgaard, Hans and Kristensen, Bjarne},
  title = {Precision allergy: Separate allergies to male and female dogs.},
  journal = {J Allergy Clin Immunol Pract},
  school = {Biomedical Laboratory Scientist, Thermo Fisher Scientific, Allerød, Denmark.},
  year = {2017},
  volume = {5},
  number = {6},
  pages = {1754--1756},
  url = {http://dx.doi.org/10.1016/j.jaip.2017.03.028},
  doi = {https://doi.org/10.1016/j.jaip.2017.03.028}
}
Stokholm, J. Bisgaard, H. Preeclampsia Associates with Asthma, Allergy, and Eczema in Childhood. 2017 Am J Respir Crit Care Med 27626972 13,204 6
Authors: Stokholm, J., Sevelsted, A., Anderson, U.D. and Bisgaard, H.
Abstract: Preeclampsia reflects an unusual increase in systemic inflammation during pregnancy.We studied associations between preeclampsia and asthma, allergy, and eczema in Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) and in national registries.COPSAC2000 is a high-risk birth cohort of 411 Danish children. Asthma, allergy, and eczema were diagnosed prospectively, and lung function measured at age 1 month and 7 years. Sensitization was evaluated at age 6 months, 18 months, 4 years, and 6 years by skin prick tests and IgE measurements. The register-based cohort included 1.7 million children from Danish national registries in the 35-year period 1977-2012. Children born to mothers with preeclampsia were analyzed regarding risk of asthma, allergy, and eczema.In the COPSAC2000 cohort, 5.6% (n = 23) were diagnosed with preeclampsia. Preeclampsia was associated with increased risk of treatment with inhaled corticosteroids at age 7 years (adjusted odds ratio, 4.01 [95% confidence interval (CI), 1.11-14.43]; P = 0.0337), increased bronchial responsiveness to methacholine (adjusted β-coefficient log-μmol, -0.80 [95% CI, -1.55 to -0.06]; P = 0.0348), and allergic rhinitis (adjusted odds ratio, 4.83 [95% CI, 1.58-14.78]; P = 0.0057) in the 7-year-old children. Furthermore, the children had an increased risk of sensitization to both aeroallergens and food allergens, and increased amount of total IgE during childhood. In the registry-based cohort, 3.7% (n = 62,728) were born to mothers with preeclampsia. Preeclampsia was associated with increased risk of asthma, eczema, and aeroallergen and food allergy, especially pronounced after a duration of preeclampsia of 14 days or more. Maternal asthma increased the risk of preeclampsia.Preeclampsia is a shared prenatal risk factor for asthma, eczema, and allergy in childhood pointing toward in utero immune programming of the child.
BibTeX:
@article{,
  author = {Stokholm, Jakob and Sevelsted, Astrid and Anderson, Ulrik D. and Bisgaard, Hans},
  title = {Preeclampsia Associates with Asthma, Allergy, and Eczema in Childhood.},
  journal = {Am J Respir Crit Care Med},
  school = {1 Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.},
  year = {2017},
  volume = {195},
  number = {5},
  pages = {614--621},
  url = {http://dx.doi.org/10.1164/rccm.201604-0806OC},
  doi = {https://doi.org/10.1164/rccm.201604-0806OC}
}
Pedersen, T.M. Bisgaard, H. Antibiotics in Pregnancy Increase Children's Risk of Otitis Media and Ventilation Tubes. 2017 J Pediatr 28088397 3,874 0
Authors: Pedersen, T.M., Stokholm, J., Thorsen, J., Mora-Jensen, A.-R.C. and Bisgaard, H.
Abstract: To study the association between antibiotic intake in pregnancy and the development of otitis media and placement of ventilation tubes (VTs) in the offspring under the hypothesis that antibiotics in pregnancy may alter the offspring's propensity for disease.Data from the 700 children in the Copenhagen Prospective Studies on Asthma in Childhood 2010 unselected birth cohort study were used. Information on maternal antibiotic use and other exposures during pregnancy was collected prospectively from interviews and validated in national registries. Otitis media episodes were registered in a prospective diary for 3 years. Information regarding children's VTs was obtained from national registries.There were 514 children who had diary information and were included in the analysis regarding otitis media episodes. For VTs analysis, 699 children were included. Thirty-seven percent of the mothers received antibiotics during pregnancy, and this was associated with increased risk of otitis media (adjusted hazard ratio 1.30; 95% CI 1.04-1.63; P = .02). The risk of receiving VTs was especially associated with third trimester antibiotics (adjusted hazard ratio 1.60; 95% CI 1.08-2.36, P = .02). The risk of otitis media increased with increasing number of treatments (per-level adjusted hazard ratio 1.20; 95% CI 1.04-1.40; P = .02), but for VTs this association was not significant after adjustment.Maternal use of antibiotics during pregnancy is associated with an increased risk of otitis media and VT insertions in the offspring. Antibiotics late in pregnancy mainly contributed to these effects, pointing toward potential transmission of an unfavorable microbiome from mother to child.
BibTeX:
@article{,
  author = {Pedersen, Tine Marie and Stokholm, Jakob and Thorsen, Jonathan and Mora-Jensen, Anna-Rosa Cecilie and Bisgaard, Hans},
  title = {Antibiotics in Pregnancy Increase Children's Risk of Otitis Media and Ventilation Tubes.},
  journal = {J Pediatr},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. Electronic address: bisgaard@copsac.com.},
  year = {2017},
  volume = {183},
  pages = {153--158.e1},
  url = {http://dx.doi.org/10.1016/j.jpeds.2016.12.046},
  doi = {https://doi.org/10.1016/j.jpeds.2016.12.046}
}
Medina-Gomez, C. Rivadeneira, F. Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus. 2017 Nat Commun 28743860 12,124 0
Authors: Medina-Gomez, C., Kemp, J.P., Dimou, N.L., Kreiner, E., Chesi, A., Zemel, B.S., Bønnelykke, K., Boer, C.G., Ahluwalia, T.S., Bisgaard, H., Evangelou, E., Heppe, D.H.M., Bonewald, L.F., Gorski, J.P., Ghanbari, M., Demissie, S., Duque, G., Maurano, M.T., Kiel, D.P., Hsu, Y.-H., C J van der Eerden, B., Ackert-Bicknell, C., Reppe, S., Gautvik, K.M., Raastad, T., Karasik, D., van de Peppel, J., Jaddoe, V.W.V., Uitterlinden, A.G., Tobias, J.H., Grant, S.F.A., Bagos, P.G., Evans, D.M. and Rivadeneira, F.
Abstract: Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% (95% CI: 34-52 for TBLH-BMD, and 39% (95% CI: 30-48 for TB-LM, with a shared genetic component of 43% (95% CI: 29-56. We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5. Variants in the TOM1L2/SREBF1 locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that SREBF1 is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass.Bone mineral density and lean skeletal mass are heritable traits. Here, Medina-Gomez and colleagues perform bivariate GWAS analyses of total body lean mass and bone mass density in children, and show genetic loci with pleiotropic effects on both traits.
BibTeX:
@article{,
  author = {Medina-Gomez, Carolina and Kemp, John P. and Dimou, Niki L. and Kreiner, Eskil and Chesi, Alessandra and Zemel, Babette S. and Bønnelykke, Klaus and Boer, Cindy G. and Ahluwalia, Tarunveer S. and Bisgaard, Hans and Evangelou, Evangelos and Heppe, Denise H M. and Bonewald, Lynda F. and Gorski, Jeffrey P. and Ghanbari, Mohsen and Demissie, Serkalem and Duque, Gustavo and Maurano, Matthew T. and Kiel, Douglas P. and Hsu, Yi-Hsiang and C J van der Eerden, Bram and Ackert-Bicknell, Cheryl and Reppe, Sjur and Gautvik, Kaare M. and Raastad, Truls and Karasik, David and van de Peppel, Jeroen and Jaddoe, Vincent W V. and Uitterlinden, André G. and Tobias, Jonathan H. and Grant, Struan F A. and Bagos, Pantelis G. and Evans, David M. and Rivadeneira, Fernando},
  title = {Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus.},
  journal = {Nat Commun},
  school = {Department of Epidemiology, Erasmus Medical Center, Rotterdam, 3015GE, The Netherlands. f.rivadeneira@erasmusmc.nl.},
  year = {2017},
  volume = {8},
  number = {1},
  pages = {121},
  url = {http://dx.doi.org/10.1038/s41467-017-00108-3},
  doi = {https://doi.org/10.1038/s41467-017-00108-3}
}
Husby, A. Bønnelykke, K. CDHR3 gene variation and childhood bronchiolitis. 2017 J Allergy Clin Immunol 28782631 13,081 1
Authors: Husby, A., Pasanen, A., Waage, J., Sevelsted, A., Hodemaekers, H., Janssen, R., Karjalainen, M.K., Stokholm, J., Chawes, B.L., Korppi, M., Wennergren, G., Heinzmann, A., Bont, L., Bisgaard, H. and Bønnelykke, K.
BibTeX:
@article{,
  author = {Husby, Anders and Pasanen, Anu and Waage, Johannes and Sevelsted, Astrid and Hodemaekers, Hennie and Janssen, Riny and Karjalainen, Minna K. and Stokholm, Jakob and Chawes, Bo L. and Korppi, Matti and Wennergren, Göran and Heinzmann, Andrea and Bont, Louis and Bisgaard, Hans and Bønnelykke, Klaus},
  title = {CDHR3 gene variation and childhood bronchiolitis.},
  journal = {J Allergy Clin Immunol},
  school = { Danish Pediatric Asthma Center, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.},
  year = {2017},
  volume = {140},
  number = {5},
  pages = {1469--1471.e7},
  url = {http://dx.doi.org/10.1016/j.jaci.2017.06.044},
  doi = {https://doi.org/10.1016/j.jaci.2017.06.044}
}
Hekking, P.-P. Sterk, P.J. Pathway discovery using transcriptomic profiles in adult-onset severe asthma. 2017 J Allergy Clin Immunol 28756296 13,081 0
Authors: Hekking, P.-P., Loza, M.J., Pavlidis, S., de Meulder, B., Lefaudeux, D., Baribaud, F., Auffray, C., Wagener, A.H., Brinkman Ir, P., Lutter Ir, R., Bansal, A.T., Sousa, A.R., Bates, S.A., Pandis, Y., Fleming, L.J., Shaw, D.E., Fowler, S.J., Guo, Y., Meiser, A., Sun, K., Corfield, J., Howarth, P.H., Bel, E.H., Adcock, I.M., Chung, K.F., Djukanovic, R., Sterk, P.J., Bisgaard, H., and , U.-B.I.O.P.R.E.D.S.G.
Abstract: Adult-onset severe asthma is characterized by highly symptomatic disease despite high-intensity asthma treatments. Understanding of the underlying pathways of this heterogeneous disease is needed for the development of targeted treatments. Gene set variation analysis is a statistical technique used to identify gene profiles in heterogeneous samples.We sought to identify gene profiles associated with adult-onset severe asthma.This was a cross-sectional, observational study in which adult patients with adult-onset of asthma (defined as starting at age ≥18 years) as compared with childhood-onset severe asthma (<18 years) were selected from the U-BIOPRED cohort. Gene expression was assessed on the total RNA of induced sputum (n = 83), nasal brushings (n = 41), and endobronchial brushings (n = 65) and biopsies (n = 47) (Affymetrix HT HG-U133+ PM). Gene set variation analysis was used to identify differentially enriched predefined gene signatures of leukocyte lineage, inflammatory and induced lung injury pathways.Significant differentially enriched gene signatures in patients with adult-onset as compared with childhood-onset severe asthma were identified in nasal brushings (5 signatures), sputum (3 signatures), and endobronchial brushings (6 signatures). Signatures associated with eosinophilic airway inflammation, mast cells, and group 3 innate lymphoid cells were more enriched in adult-onset severe asthma, whereas signatures associated with induced lung injury were less enriched in adult-onset severe asthma.Adult-onset severe asthma is characterized by inflammatory pathways involving eosinophils, mast cells, and group 3 innate lymphoid cells. These pathways could represent useful targets for the treatment of adult-onset severe asthma.
BibTeX:
@article{,
  author = {Hekking, Pieter-Paul and Loza, Matt J. and Pavlidis, Stelios and de Meulder, Bertrand and Lefaudeux, Diane and Baribaud, Fred and Auffray, Charles and Wagener, Ariane H. and Brinkman, Ir, Paul and Lutter, Ir, Rene and Bansal, Aruna T. and Sousa, Ana R. and Bates, Steve A. and Pandis, Yannis and Fleming, Louise J. and Shaw, Dominique E. and Fowler, Stephen J. and Guo, Y. and Meiser, Andrea and Sun, Kai and Corfield, Julie and Howarth, Peter H. and Bel, Elisabeth H. and Adcock, Ian M. and Chung, Kian Fan and Djukanovic, Ratko and Sterk, Peter J. and , U-B. I. O. P. R. E. D Study Group},
  title = {Pathway discovery using transcriptomic profiles in adult-onset severe asthma.},
  journal = {J Allergy Clin Immunol},
  school = {Respiratory Medicine, Academic Medical Centre, Amsterdam, The Netherlands.},
  year = {2017},
  url = {http://dx.doi.org/10.1016/j.jaci.2017.06.037},
  doi = {https://doi.org/10.1016/j.jaci.2017.06.037}
}
Lefaudeux, D. Chung, K.F. U-BIOPRED clinical adult asthma clusters linked to a subset of sputum omics. 2017 J Allergy Clin Immunol 27773852 13,081 11
Authors: Lefaudeux, D., De Meulder, B., Loza, M.J., Peffer, N., Rowe, A., Baribaud, F., Bansal, A.T., Lutter, R., Sousa, A.R., Corfield, J., Pandis, I., Bakke, P.S., Caruso, M., Chanez, P., Dahlén, S.-E., Fleming, L.J., Fowler, S.J., Horvath, I., Krug, N., Montuschi, P., Sanak, M., Sandstrom, T., Shaw, D.E., Singer, F., Sterk, P.J., Roberts, G., Adcock, I.M., Djukanovic, R., Auffray, C., Chung, K.F. Bisgaard, H., and, U.-B.I.O.P.R.E.D.S.G.
Abstract: Asthma is a heterogeneous disease in which there is a differential response to asthma treatments. This heterogeneity needs to be evaluated so that a personalized management approach can be provided.We stratified patients with moderate-to-severe asthma based on clinicophysiologic parameters and performed an omics analysis of sputum.Partition-around-medoids clustering was applied to a training set of 266 asthmatic participants from the European Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes (U-BIOPRED) adult cohort using 8 prespecified clinic-physiologic variables. This was repeated in a separate validation set of 152 asthmatic patients. The clusters were compared based on sputum proteomics and transcriptomics data.Four reproducible and stable clusters of asthmatic patients were identified. The training set cluster T1 consists of patients with well-controlled moderate-to-severe asthma, whereas cluster T2 is a group of patients with late-onset severe asthma with a history of smoking and chronic airflow obstruction. Cluster T3 is similar to cluster T2 in terms of chronic airflow obstruction but is composed of nonsmokers. Cluster T4 is predominantly composed of obese female patients with uncontrolled severe asthma with increased exacerbations but with normal lung function. The validation set exhibited similar clusters, demonstrating reproducibility of the classification. There were significant differences in sputum proteomics and transcriptomics between the clusters. The severe asthma clusters (T2, T3, and T4) had higher sputum eosinophilia than cluster T1, with no differences in sputum neutrophil counts and exhaled nitric oxide and serum IgE levels.Clustering based on clinicophysiologic parameters yielded 4 stable and reproducible clusters that associate with different pathobiological pathways.
BibTeX:
@article{,
  author = {Lefaudeux, Diane and De Meulder, Bertrand and Loza, Matthew J. and Peffer, Nancy and Rowe, Anthony and Baribaud, Frédéric and Bansal, Aruna T. and Lutter, Rene and Sousa, Ana R. and Corfield, Julie and Pandis, Ioannis and Bakke, Per S. and Caruso, Massimo and Chanez, Pascal and Dahlén, Sven-Erik and Fleming, Louise J. and Fowler, Stephen J. and Horvath, Ildiko and Krug, Norbert and Montuschi, Paolo and Sanak, Marek and Sandstrom, Thomas and Shaw, Dominic E. and Singer, Florian and Sterk, Peter J. and Roberts, Graham and Adcock, Ian M. and Djukanovic, Ratko and Auffray, Charles and Chung, Kian Fan and , U-B. I. O. P. R. E. D Study Group},
  title = {U-BIOPRED clinical adult asthma clusters linked to a subset of sputum omics.},
  journal = {J Allergy Clin Immunol},
  school = { Harefield NHS Trust, London, United Kingdom. Electronic address: f.chung@imperial.ac.uk.},
  year = {2017},
  volume = {139},
  number = {6},
  pages = {1797--1807},
  url = {http://dx.doi.org/10.1016/j.jaci.2016.08.048},
  doi = {https://doi.org/10.1016/j.jaci.2016.08.048}
}
Kreiner, E. Bønnelykke, K. Shared genetic variants suggest common pathways in allergy and autoimmune diseases. 2017 J Allergy Clin Immunol 28188724 13,081 0
Authors: Kreiner, E., Waage, J., Standl, M., Brix, S., Pers, T.H., Couto Alves, A., Warrington, N.M., Tiesler, C.M.T., Fuertes, E., Franke, L., Hirschhorn, J.N., James, A., Simpson, A., Tung, J.Y., Koppelman, G.H., Postma, D.S., Pennell, C.E., Jarvelin, M.-R., Custovic, A., Timpson, N., Ferreira, M.A., Strachan, D.P., Henderson, J., Hinds, D., Bisgaard, H. and Bønnelykke, K.
Abstract: The relationship between allergy and autoimmune disorders is complex and poorly understood.We sought to investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms.We meta-analyzed 2 genome-wide association studies on self-reported allergy and sensitization comprising a total of 62,330 subjects. These results were used to calculate enrichment for single nucleotide polymorphisms (SNPs) previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites and characterized commonalities in variant burden on tissue-specific regulatory sites by calculating the enrichment of allergy SNPs falling in gene regulatory regions in various cells using Encode Roadmap DNase-hypersensitive site data. Finally, we compared the allergy data with those of all known diseases.Among 290 loci previously associated with 16 autoimmune diseases, we found a significant enrichment of loci also associated with allergy (P = 1.4e-17) encompassing 29 loci at a false discovery rate of less than 0.05. Such enrichment seemed to be a general characteristic for autoimmune diseases. Among the common loci, 48% had the same direction of effect for allergy and autoimmune diseases. Additionally, we observed an enrichment of allergy SNPs falling within immune pathways and regions of chromatin accessible in immune cells that was also represented in patients with autoimmune diseases but not those with other diseases.We identified shared susceptibility loci and commonalities in pathways between allergy and autoimmune diseases, suggesting shared disease mechanisms. Further studies of these shared genetic mechanisms might help in understanding the complex relationship between these diseases, including the parallel increase in disease prevalence.
BibTeX:
@article{,
  author = {Kreiner, Eskil and Waage, Johannes and Standl, Marie and Brix, Susanne and Pers, Tune H. and Couto Alves, Alexessander and Warrington, Nicole M. and Tiesler, Carla M T. and Fuertes, Elaine and Franke, Lude and Hirschhorn, Joel N. and James, Alan and Simpson, Angela and Tung, Joyce Y. and Koppelman, Gerard H. and Postma, Dirkje S. and Pennell, Craig E. and Jarvelin, Marjo-Riitta and Custovic, Adnan and Timpson, Nicholas and Ferreira, Manuel A. and Strachan, David P. and Henderson, John and Hinds, David and Bisgaard, Hans and Bønnelykke, Klaus},
  title = {Shared genetic variants suggest common pathways in allergy and autoimmune diseases.},
  journal = {J Allergy Clin Immunol},
  school = {COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.},
  year = {2017},
  volume = {140},
  number = {3},
  pages = {771--781},
  url = {http://dx.doi.org/10.1016/j.jaci.2016.10.055},
  doi = {https://doi.org/10.1016/j.jaci.2016.10.055}
}
Feng, H. He, K. In utero exposure to 25-hydroxyvitamin D and risk of childhood asthma, wheeze, and respiratory tract infections: A meta-analysis of birth cohort studies. 2017 J Allergy Clin Immunol 27639938 13,081 4
Authors: Feng, H., Xun, P., Pike, K., Wills, A.K., Chawes, B.L., Bisgaard, H., Cai, W., Wan, Y. and He, K.
Abstract: Studies of the associations between in utero 25-hydroxyvitamin D (25[OH]D) exposure and risk of childhood asthma, wheeze, and respiratory tract infections are inconsistent and inconclusive.We sought to assess associations between 25(OH)D levels in cord blood or maternal venous blood and risk of offspring's asthma, wheeze, and respiratory tract infections.Data were derived from PubMed, Embase, Google Scholar, references from relevant articles, and de novo results from published studies until December 2015. A random-effects meta-analysis was conducted among 16 birth cohort studies.Comparing the highest with the lowest category of 25(OH)D levels, the pooled odds ratios were 0.84 (95% CI, 0.70-1.01; P = .064) for asthma, 0.77 (95% CI, 0.58-1.03; P = .083) for wheeze, and 0.85 (95% CI, 0.66-1.09; P = .187) for respiratory tract infections. The observed inverse association for wheeze was more pronounced and became statistically significant in the studies that measured 25(OH)D levels in cord blood (0.43; 95% CI, 0.29-0.62; P < .001).Accumulated evidence generated from this meta-analysis suggests that increased in utero exposure to 25(OH)D is inversely associated with the risk of asthma and wheeze during childhood. These findings are in keeping with the results of 2 recently published randomized clinical trials of vitamin D supplementation during pregnancy.
BibTeX:
@article{,
  author = {Feng, Haixia and Xun, Pengcheng and Pike, Katharine and Wills, Andrew K. and Chawes, Bo L. and Bisgaard, Hans and Cai, Wei and Wan, Yanping and He, Ka},
  title = {In utero exposure to 25-hydroxyvitamin D and risk of childhood asthma, wheeze, and respiratory tract infections: A meta-analysis of birth cohort studies.},
  journal = {J Allergy Clin Immunol},
  school = {Department of Epidemiology and Biostatistics, School of Public Health-Bloomington, Indiana University, Bloomington, Ind. Electronic address: kahe@indiana.edu.},
  year = {2017},
  volume = {139},
  number = {5},
  pages = {1508--1517},
  url = {http://dx.doi.org/10.1016/j.jaci.2016.06.065},
  doi = {https://doi.org/10.1016/j.jaci.2016.06.065}
}
Farzan, N. Maitland-van der Zee, A.H. Rationale and design of the multiethnic Pharmacogenomics in Childhood Asthma consortium. 2017 Pharmacogenomics 28639505 2,350 1
Authors: Farzan, N., Vijverberg, S.J., Andiappan, A.K., Arianto, L., Berce, V., Blanca-López, N., Bisgaard, H., Bønnelykke, K., Burchard, E.G., Campo, P., Canino, G., Carleton, B., Celedón, J.C., Chew, F.T., Chiang, W.C., Cloutier, M.M., Daley, D., Den Dekker, H.T., Dijk, F.N., Duijts, L., Flores, C., Forno, E., Hawcutt, D.B., Hernandez-Pacheco, N., de Jongste, J.C., Kabesch, M., Koppelman, G.H., Manolopoulos, V.G., Melén, E., Mukhopadhyay, S., Nilsson, S., Palmer, C.N., Pino-Yanes, M., Pirmohamed, M., Potočnik, U., Raaijmakers, J.A., Repnik, K., Schieck, M., Sio, Y.Y., Smyth, R.L., Szalai, C., Tantisira, K.G., Turner, S., van der Schee, M.P., Verhamme, K.M. and Maitland-van der Zee, A.H.
Abstract: International collaboration is needed to enable large-scale pharmacogenomics studies in childhood asthma. Here, we describe the design of the Pharmacogenomics in Childhood Asthma (PiCA) consortium.Investigators of each study participating in PiCA provided data on the study characteristics by answering an online questionnaire.A total of 21 studies, including 14,227 children/young persons (58% male), from 12 different countries are currently enrolled in the PiCA consortium. Fifty six percent of the patients are Caucasians. In total, 7619 were inhaled corticosteroid users. Among patients from 13 studies with available data on asthma exacerbations, a third reported exacerbations despite inhaled corticosteroid use. In the future pharmacogenomics studies within the consortium, the pharmacogenomics analyses will be performed separately in each center and the results will be meta-analyzed.PiCA is a valuable platform to perform pharmacogenetics studies within a multiethnic pediatric asthma population.
BibTeX:
@article{,
  author = {Farzan, Niloufar and Vijverberg, Susanne J. and Andiappan, Anand K. and Arianto, Lambang and Berce, Vojko and Blanca-López, Natalia and Bisgaard, Hans and Bønnelykke, Klaus and Burchard, Esteban G. and Campo, Paloma and Canino, Glorisa and Carleton, Bruce and Celedón, Juan C. and Chew, Fook Tim and Chiang, Wen Chin and Cloutier, Michelle M. and Daley, Denis and Den Dekker, Herman T. and Dijk, F Nicole and Duijts, Liesbeth and Flores, Carlos and Forno, Erick and Hawcutt, Daniel B. and Hernandez-Pacheco, Natalia and de Jongste, Johan C. and Kabesch, Michael and Koppelman, Gerard H. and Manolopoulos, Vangelis G. and Melén, Erik and Mukhopadhyay, Somnath and Nilsson, Sara and Palmer, Colin N. and Pino-Yanes, Maria and Pirmohamed, Munir and Potočnik, Uros and Raaijmakers, Jan A. and Repnik, Katja and Schieck, Maximilian and Sio, Yang Yie and Smyth, Rosalind L. and Szalai, Csaba and Tantisira, Kelan G. and Turner, Steve and van der Schee, Marc P. and Verhamme, Katia M. and Maitland-van der Zee, Anke H.},
  title = {Rationale and design of the multiethnic Pharmacogenomics in Childhood Asthma consortium.},
  journal = {Pharmacogenomics},
  school = {Department of Respiratory Medicine, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.},
  year = {2017},
  volume = {18},
  number = {10},
  pages = {931--943},
  url = {http://dx.doi.org/10.2217/pgs-2017-0035},
  doi = {https://doi.org/10.2217/pgs-2017-0035}
}
Chinnaswamy, S. Kowalski, M.L. A functional IFN-λ4-generating DNA polymorphism could protect older asthmatic women from aeroallergen sensitization and associate with clinical features of asthma. 2017 Sci Rep 28874741 4,259 0
Authors: Chinnaswamy, S., Wardzynska, A., Pawelczyk, M., Makowska, J., Skaaby, T., Mercader, J.M., Ahluwalia, T.S., Grarup, N., Guindo-Martinez, M., Bisgaard, H., Torrents, D., Linneberg, A., Bønnelykke, K. and Kowalski, M.L.
Abstract: Lambda interferons (IFNLs) have immunomodulatory functions at epithelial barrier surfaces. IFN-λ4, a recent member of this family is expressed only in a subset of the population due to a frameshift-causing DNA polymorphism rs368234815. We examined the association of this polymorphism with atopy (aeroallergen sensitization) and asthma in a Polish hospital-based case-control cohort comprising of well-characterized adult asthmatics (n = 326) and healthy controls (n = 111). In the combined cohort, we saw no association of the polymorphism with asthma and/or atopy. However, the IFN-λ4-generating ΔG allele protected older asthmatic women (>50 yr of age) from atopic sensitization. Further, ΔG allele significantly associated with features of less-severe asthma including bronchodilator response and corticosteroid usage in older women in this Polish cohort. We tested the association of related IFNL locus polymorphisms (rs12979860 and rs8099917) with atopy, allergic rhinitis and presence/absence of asthma in three population-based cohorts from Europe, but saw no significant association of the polymorphisms with any of the phenotypes in older women. The polymorphisms associated marginally with lower occurrence of asthma in men/older men after meta-analysis of data from all cohorts. Functional and well-designed replication studies may reveal the true positive nature of these results.
BibTeX:
@article{,
  author = {Chinnaswamy, Sreedhar and Wardzynska, Aleksandra and Pawelczyk, Malgorzata and Makowska, Joanna and Skaaby, Tea and Mercader, Josep M. and Ahluwalia, Tarunveer S. and Grarup, Niels and Guindo-Martinez, Marta and Bisgaard, Hans and Torrents, David and Linneberg, Allan and Bønnelykke, Klaus and Kowalski, Marek L.},
  title = {A functional IFN-λ4-generating DNA polymorphism could protect older asthmatic women from aeroallergen sensitization and associate with clinical features of asthma.},
  journal = {Sci Rep},
  school = {Chair of Clinical Immunology and Microbiology, Healthy Aging Research Center, Medical University of Lodz, 251 Pomorska Str, 92-213, Lodz, Poland.},
  year = {2017},
  volume = {7},
  number = {1},
  pages = {10500},
  url = {http://dx.doi.org/10.1038/s41598-017-10467-y},
  doi = {https://doi.org/10.1038/s41598-017-10467-y}
}
Chawes, B.L. Bisgaard, H. Allergic sensitization at school age is a systemic low-grade inflammatory disorder. 2017 Allergy 27992959 7,361 2
Authors: Chawes, B.L., Stokholm, J., Schoos, A.-M.M., Fink, N.R., Brix, S. and Bisgaard, H.
Abstract: Systemic low-grade inflammation has been demonstrated in a range of the frequent noncommunicable diseases (NCDs) proposing a shared mechanism, but is largely unexplored in relation to allergic sensitization. We therefore aimed to investigate the possible association with childhood allergic sensitization.High-sensitivity C-reactive protein (hs-CRP), interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and chemokine (C-X-C motif) ligand 8 (CXCL8) were measured in plasma at age 6 months (N = 214) and 7 years (N = 277) in children from the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000 ) birth cohort. Allergic sensitization against common inhalant and food allergens was determined longitudinally at ages ½, 1½, 4 and 6 years by specific IgE assessments and skin prick tests. Associations between inflammatory biomarkers and sensitization phenotypes were tested with logistic regression and principal component analyses (PCAs).Adjusted for gender, recent infections, and a CRP genetic risk score, hs-CRP at 7 years was associated with concurrent elevated specific IgE against any allergen [adjusted OR (aOR) = 1.40; 95% CI, 1.14-1.72; P = 0.001], aeroallergens (aOR, 1.43; 1.15-1.77; P = 0.001), food allergens (aOR, 1.31; 95% CI, 1.02-1.67; P = 0.04), sensitization without any clinical allergy symptoms (aOR = 1.40; 1.06-1.85; P = 0.02), and with similar findings for skin prick tests. The other inflammatory markers were not univariately associated with sensitization, but multiparametric PCA suggested a specific inflammatory response among sensitized children. Inflammatory markers at age 6 months were not associated with subsequent development of sensitization phenotypes.Elevated hs-CRP is associated with allergic sensitization in school-aged children suggesting systemic low-grade inflammation as a phenotypic characteristic of this early-onset NCD.
BibTeX:
@article{,
  author = {Chawes, B. L. and Stokholm, J. and Schoos, A-M M. and Fink, N. R. and Brix, S. and Bisgaard, H.},
  title = {Allergic sensitization at school age is a systemic low-grade inflammatory disorder.},
  journal = {Allergy},
  school = {COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.},
  year = {2017},
  volume = {72},
  number = {7},
  pages = {1073--1080},
  url = {http://dx.doi.org/10.1111/all.13108},
  doi = {https://doi.org/10.1111/all.13108}
}
Chawes, B. Bisgaard, H. Knemometry is more sensitive to systemic effects of inhaled corticosteroids in children with asthma than 24-hour urine cortisol excretion. 2017 J Allergy Clin Immunol 28012663 13,081 1
Authors: Chawes, B., Nilsson, E., Nørgaard, S., Dossing, A., Mortensen, L. and Bisgaard, H.
Abstract: Pharmacodynamic assessment of the systemic effect of inhaled corticosteroids (ICSs) is often done by measuring 24-hour urine free cortisol (UFC) excretion. Knemometry assessing short-term lower-leg growth rate (LLGR) is a more rarely used alternative.The primary aim of this study was to compare the sensitivity of LLGR and 24-hour UFC excretion for evaluating systemic exposure to ICSs in prepubertal children with asthma. The secondary aim was to evaluate factors influencing the precision of LLGR calculated by the traditional 1 leg nonparametric method versus a new 2 leg parametric method.The study evaluated 60 children with mild asthma aged 5 to 12 years participating in a randomized controlled trial of ICSs with longitudinal concomitant assessments of LLGR and 24-hour UFC excretion. The sensitivity of the safety assessments was analyzed by comparing LLGR and 24-hour UFC in the placebo run-in period with values in the ICS treatment period by using paired t tests. Factors with a potential influence on LLGR were analyzed by means of ANOVA and the Levene test of homogeneity.The mean LLGR was significantly reduced during the ICS versus placebo run-in periods: 0.18 mm/wk (SD, 0.55 mm/wk) versus 0.45 mm/wk (SD, 0.39 mm/wk), with a mean difference of 0.27 mm/wk (95% CI, 0.05-0.48 mm/wk; P = .02). In contrast, there was no difference in 24-hour UFC excretion: 6.91 nmol/mmol (SD, 4.67 nmol/mmol) versus 7.58 nmol/mmol (SD, 6.17 nmol/mmol), with a mean difference of 0.67 nmol/mmol (95% CI, -1.13 to 2.48 nmol/mmol; P = .46). We observed no significant difference in parametric determined LLGR caused by the child's age or sex, investigator, or season of measurement, whereas some differences were observed for the nonparametric LLGR.These findings suggest that knemometry is a more sensitive pharmacodynamic measure of systemic effects of ICSs than 24-hour UFC excretion and that a parametric determination of LLGR increases the sensitivity of the method. These findings should be considered by legislative authorities in the future.
BibTeX:
@article{,
  author = {Chawes, Bo and Nilsson, Erik and Nørgaard, Sarah and Dossing, Anna and Mortensen, Li and Bisgaard, Hans},
  title = {Knemometry is more sensitive to systemic effects of inhaled corticosteroids in children with asthma than 24-hour urine cortisol excretion.},
  journal = {J Allergy Clin Immunol},
  school = {COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. Electronic address: bisgaard@copsac.com.},
  year = {2017},
  volume = {140},
  number = {2},
  pages = {431--436},
  url = {http://dx.doi.org/10.1016/j.jaci.2016.09.041},
  doi = {https://doi.org/10.1016/j.jaci.2016.09.041}
}
Bønnelykke, K. Bisgaard, H. CDHR3 Genetics and Rhinovirus C Respiratory Illnesses. 2017 Am J Respir Crit Care Med 29121479 13,204 0
Authors: Bønnelykke, K., Coleman, A.T., Evans, M.D., Thorsen, J., Waage, J., Vissing, N.H., Carlsson, C.J., Stokholm, J., Chawes, B.L., Jessen, L.E., Fischer, T.K., Bochkov, Y.A., Ober, C., Lemanske Jr, R.F., Jackson, D.J., Gern, J.E. and Bisgaard, H.
Abstract: Background Experimental evidence suggests that CDHR3 is a receptor for rhinovirus-C (RV-C), and a missense variant in this gene (rs6967330) is associated with childhood asthma with severe exacerbations. Objective To determine whether rs6967330 influences RV-C infections and illnesses in early childhood. Methods We studied associations between rs6967330 and respiratory infections and illnesses in the COPSAC2010 and COAST birth cohorts, where respiratory infections were monitored prospectively for the first 3 years of life. Nasal samples were collected during acute infections in both cohorts and during asymptomatic periods in COAST and analyzed for RV-A, RV-B and RV-C, and other common respiratory viruses. Results The CDHR3 asthma risk-allele (rs6967330-A) was associated with increased risk of respiratory tract illnesses (IRR 1.14 [1.05-1.23], P=0.003). Particularly, this variant was associated with risk of respiratory episodes with detection of RV-C in COPSAC2010 (IRR 1.89 [1.14-3.05], P=0.01) and in COAST (IRR 1.37 [1.02-1.82], P=0.03) children, and in a combined meta-analysis (IRR 1.51 [1.13-2.02], P=0.006). In contrast, the variant was not associated with illnesses related to other viruses (IRR 1.07 [0.92-1.25], P=0.37). Consistent with these observations, the CDHR3 variant was associated with increased detection of RV-C but not of other viruses during scheduled visits at specific ages. Conclusion The CDHR3 asthma risk allele is associated specifically with RV-C illnesses in two birth cohorts. This clinical evidence supports earlier molecular evidence indicating that CDHR3 functions as an RV-C receptor, and raises the possibility of preventing RV-C infections by targeting CDHR3.
BibTeX:
@article{,
  author = {Bønnelykke, Klaus and Coleman, Amaziah T. and Evans, Michael D. and Thorsen, Jonathan and Waage, Johannes and Vissing, Nadja H. and Carlsson, Christian J. and Stokholm, Jakob and Chawes, Bo L. and Jessen, Leon E. and Fischer, Thea K. and Bochkov, Yury A. and Ober, Carole and Lemanske, Jr, Robert F and Jackson, Daniel J. and Gern, James E. and Bisgaard, Hans},
  title = {CDHR3 Genetics and Rhinovirus C Respiratory Illnesses.},
  journal = {Am J Respir Crit Care Med},
  school = {COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark ; bisgaard@copsac.com.},
  year = {2017},
  url = {http://dx.doi.org/10.1164/rccm.201705-1021OC},
  doi = {https://doi.org/10.1164/rccm.201705-1021OC}
}
Barban, N. Mills, M.C. Genome-wide analysis identifies 12 loci influencing human reproductive behavior. 2016 Nat Genet 27798627 27,959 13
Authors: Barban, N., Jansen, R., de Vlaming, R., Vaez, A., Mandemakers, J.J., Tropf, F.C., Shen, X., Wilson, J.F., Chasman, D.I., Nolte, I.M., Tragante, V., van der Laan, S.W., Perry, J.R.B., Kong, A., , B.I.O.S.C., Ahluwalia, T.S., Albrecht, E., Yerges-Armstrong, L., Atzmon, G., Auro, K., Ayers, K., Bakshi, A., Ben-Avraham, D., Berger, K., Bergman, A., Bertram, L., Bielak, L.F., Bjornsdottir, G., Bonder, M.J., Broer, L., Bui, M., Barbieri, C., Cavadino, A., Chavarro, J.E., Turman, C., Concas, M.P., Cordell, H.J., Davies, G., Eibich, P., Eriksson, N., Esko, T., Eriksson, J., Falahi, F., Felix, J.F., Fontana, M.A., Franke, L., Gandin, I., Gaskins, A.J., Gieger, C., Gunderson, E.P., Guo, X., Hayward, C., He, C., Hofer, E., Huang, H., Joshi, P.K., Kanoni, S., Karlsson, R., Kiechl, S., Kifley, A., Kluttig, A., Kraft, P., Lagou, V., Lecoeur, C., Lahti, J., Li-Gao, R., Lind, P.A., Liu, T., Makalic, E., Mamasoula, C., Matteson, L., Mbarek, H., McArdle, P.F., McMahon, G., Meddens, S.F.W., Mihailov, E., Miller, M., Missmer, S.A., Monnereau, C., van der Most, P.J., Myhre, R., Nalls, M.A., Nutile, T., Kalafati, I.P., Porcu, E., Prokopenko, I., Rajan, K.B., Rich-Edwards, J., Rietveld, C.A., Robino, A., Rose, L.M., Rueedi, R., Ryan, K.A., Saba, Y., Schmidt, D., Smith, J.A., Stolk, L., Streeten, E., Tönjes, A., Thorleifsson, G., Ulivi, S., Wedenoja, J., Wellmann, J., Willeit, P., Yao, J., Yengo, L., Zhao, J.H., Zhao, W., Zhernakova, D.V., Amin, N., Andrews, H., Balkau, B., Barzilai, N., Bergmann, S., Biino, G., Bisgaard, H., Bønnelykke, K., Boomsma, D.I., Buring, J.E., Campbell, H., Cappellani, S., Ciullo, M., Cox, S.R., Cucca, F., Toniolo, D., Davey-Smith, G., Deary, I.J., Dedoussis, G., Deloukas, P., van Duijn, C.M., de Geus, E.J.C., Eriksson, J.G., Evans, D.A., Faul, J.D., Sala, C.F., Froguel, P., Gasparini, P., Girotto, G., Grabe, H.-J., Greiser, K.H., Groenen, P.J.F., de Haan, H.G., Haerting, J., Harris, T.B., Heath, A.C., Heikkilä, K., Hofman, A., Homuth, G., Holliday, E.G., Hopper, J., Hyppönen, E., Jacobsson, B., Jaddoe, V.W.V., Johannesson, M., Jugessur, A., Kähönen, M., Kajantie, E., Kardia, S.L.R., Keavney, B., Kolcic, I., Koponen, P., Kovacs, P., Kronenberg, F., Kutalik, Z., La Bianca, M., Lachance, G., Iacono, W.G., Lai, S., Lehtimäki, T., Liewald, D.C., , L.C.S., Lindgren, C.M., Liu, Y., Luben, R., Lucht, M., Luoto, R., Magnus, P., Magnusson, P.K.E., Martin, N.G., McGue, M., McQuillan, R., Medland, S.E., Meisinger, C., Mellström, D., Metspalu, A., Traglia, M., Milani, L., Mitchell, P., Montgomery, G.W., Mook-Kanamori, D., de Mutsert, R., Nohr, E.A., Ohlsson, C., Olsen, J., Ong, K.K., Paternoster, L., Pattie, A., Penninx, B.W.J.H., Perola, M., Peyser, P.A., Pirastu, M., Polasek, O., Power, C., Kaprio, J., Raffel, L.J., Räikkönen, K., Raitakari, O., Ridker, P.M., Ring, S.M., Roll, K., Rudan, I., Ruggiero, D., Rujescu, D., Salomaa, V., Schlessinger, D., Schmidt, H., Schmidt, R., Schupf, N., Smit, J., Sorice, R., Spector, T.D., Starr, J.M., Stöckl, D., Strauch, K., Stumvoll, M., Swertz, M.A., Thorsteinsdottir, U., Thurik, A.R., Timpson, N.J., Tung, J.Y., Uitterlinden, A.G., Vaccargiu, S., Viikari, J., Vitart, V., Völzke, H., Vollenweider, P., Vuckovic, D., Waage, J., Wagner, G.G., Wang, J.J., Wareham, N.J., Weir, D.R., Willemsen, G., Willeit, J., Wright, A.F., Zondervan, K.T., Stefansson, K., Krueger, R.F., Lee, J.J., Benjamin, D.J., Cesarini, D., Koellinger, P.D., den Hoed, M., Snieder, H. and Mills, M.C.
Abstract: The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.
BibTeX:
@article{,
  author = {Barban, Nicola and Jansen, Rick and de Vlaming, Ronald and Vaez, Ahmad and Mandemakers, Jornt J. and Tropf, Felix C. and Shen, Xia and Wilson, James F. and Chasman, Daniel I. and Nolte, Ilja M. and Tragante, Vinicius and van der Laan, Sander W. and Perry, John R B. and Kong, Augustine and , B. I. O. S Consortium and Ahluwalia, Tarunveer S. and Albrecht, Eva and Yerges-Armstrong, Laura and Atzmon, Gil and Auro, Kirsi and Ayers, Kristin and Bakshi, Andrew and Ben-Avraham, Danny and Berger, Klaus and Bergman, Aviv and Bertram, Lars and Bielak, Lawrence F. and Bjornsdottir, Gyda and Bonder, Marc Jan and Broer, Linda and Bui, Minh and Barbieri, Caterina and Cavadino, Alana and Chavarro, Jorge E. and Turman, Constance and Concas, Maria Pina and Cordell, Heather J. and Davies, Gail and Eibich, Peter and Eriksson, Nicholas and Esko, Tõnu and Eriksson, Joel and Falahi, Fahimeh and Felix, Janine F. and Fontana, Mark Alan and Franke, Lude and Gandin, Ilaria and Gaskins, Audrey J. and Gieger, Christian and Gunderson, Erica P. and Guo, Xiuqing and Hayward, Caroline and He, Chunyan and Hofer, Edith and Huang, Hongyan and Joshi, Peter K. and Kanoni, Stavroula and Karlsson, Robert and Kiechl, Stefan and Kifley, Annette and Kluttig, Alexander and Kraft, Peter and Lagou, Vasiliki and Lecoeur, Cecile and Lahti, Jari and Li-Gao, Ruifang and Lind, Penelope A. and Liu, Tian and Makalic, Enes and Mamasoula, Crysovalanto and Matteson, Lindsay and Mbarek, Hamdi and McArdle, Patrick F. and McMahon, George and Meddens, S Fleur W. and Mihailov, Evelin and Miller, Mike and Missmer, Stacey A. and Monnereau, Claire and van der Most, Peter J. and Myhre, Ronny and Nalls, Mike A. and Nutile, Teresa and Kalafati, Ioanna Panagiota and Porcu, Eleonora and Prokopenko, Inga and Rajan, Kumar B. and Rich-Edwards, Janet and Rietveld, Cornelius A. and Robino, Antonietta and Rose, Lynda M. and Rueedi, Rico and Ryan, Kathleen A. and Saba, Yasaman and Schmidt, Daniel and Smith, Jennifer A. and Stolk, Lisette and Streeten, Elizabeth and Tönjes, Anke and Thorleifsson, Gudmar and Ulivi, Sheila and Wedenoja, Juho and Wellmann, Juergen and Willeit, Peter and Yao, Jie and Yengo, Loic and Zhao, Jing Hua and Zhao, Wei and Zhernakova, Daria V. and Amin, Najaf and Andrews, Howard and Balkau, Beverley and Barzilai, Nir and Bergmann, Sven and Biino, Ginevra and Bisgaard, Hans and Bønnelykke, Klaus and Boomsma, Dorret I. and Buring, Julie E. and Campbell, Harry and Cappellani, Stefania and Ciullo, Marina and Cox, Simon R. and Cucca, Francesco and Toniolo, Daniela and Davey-Smith, George and Deary, Ian J. and Dedoussis, George and Deloukas, Panos and van Duijn, Cornelia M. and de Geus, Eco J C. and Eriksson, Johan G. and Evans, Denis A. and Faul, Jessica D. and Sala, Cinzia Felicita and Froguel, Philippe and Gasparini, Paolo and Girotto, Giorgia and Grabe, Hans-Jörgen and Greiser, Karin Halina and Groenen, Patrick J F. and de Haan, Hugoline G. and Haerting, Johannes and Harris, Tamara B. and Heath, Andrew C. and Heikkilä, Kauko and Hofman, Albert and Homuth, Georg and Holliday, Elizabeth G. and Hopper, John and Hyppönen, Elina and Jacobsson, Bo and Jaddoe, Vincent W V. and Johannesson, Magnus and Jugessur, Astanand and Kähönen, Mika and Kajantie, Eero and Kardia, Sharon L R. and Keavney, Bernard and Kolcic, Ivana and Koponen, Päivikki and Kovacs, Peter and Kronenberg, Florian and Kutalik, Zoltan and La Bianca, Martina and Lachance, Genevieve and Iacono, William G. and Lai, Sandra and Lehtimäki, Terho and Liewald, David C. and , LifeLines Cohort Study and Lindgren, Cecilia M. and Liu, Yongmei and Luben, Robert and Lucht, Michael and Luoto, Riitta and Magnus, Per and Magnusson, Patrik K E. and Martin, Nicholas G. and McGue, Matt and McQuillan, Ruth and Medland, Sarah E. and Meisinger, Christa and Mellström, Dan and Metspalu, Andres and Traglia, Michela and Milani, Lili and Mitchell, Paul and Montgomery, Grant W. and Mook-Kanamori, Dennis and de Mutsert, Renée and Nohr, Ellen A. and Ohlsson, Claes and Olsen, Jørn and Ong, Ken K. and Paternoster, Lavinia and Pattie, Alison and Penninx, Brenda W J H. and Perola, Markus and Peyser, Patricia A. and Pirastu, Mario and Polasek, Ozren and Power, Chris and Kaprio, Jaakko and Raffel, Leslie J. and Räikkönen, Katri and Raitakari, Olli and Ridker, Paul M. and Ring, Susan M. and Roll, Kathryn and Rudan, Igor and Ruggiero, Daniela and Rujescu, Dan and Salomaa, Veikko and Schlessinger, David and Schmidt, Helena and Schmidt, Reinhold and Schupf, Nicole and Smit, Johannes and Sorice, Rossella and Spector, Tim D. and Starr, John M. and Stöckl, Doris and Strauch, Konstantin and Stumvoll, Michael and Swertz, Morris A. and Thorsteinsdottir, Unnur and Thurik, A Roy and Timpson, Nicholas J. and Tung, Joyce Y. and Uitterlinden, André G. and Vaccargiu, Simona and Viikari, Jorma and Vitart, Veronique and Völzke, Henry and Vollenweider, Peter and Vuckovic, Dragana and Waage, Johannes and Wagner, Gert G. and Wang, Jie Jin and Wareham, Nicholas J. and Weir, David R. and Willemsen, Gonneke and Willeit, Johann and Wright, Alan F. and Zondervan, Krina T. and Stefansson, Kari and Krueger, Robert F. and Lee, James J. and Benjamin, Daniel J. and Cesarini, David and Koellinger, Philipp D. and den Hoed, Marcel and Snieder, Harold and Mills, Melinda C.},
  title = {Genome-wide analysis identifies 12 loci influencing human reproductive behavior.},
  journal = {Nat Genet},
  school = {Department of Sociology and Nuffield College, University of Oxford, Oxford, UK.},
  year = {2016},
  volume = {48},
  number = {12},
  pages = {1462--1472},
  url = {http://dx.doi.org/10.1038/ng.3698},
  doi = {https://doi.org/10.1038/ng.3698}
}
Wolsk, H.M. Bisgaard, H. Picornavirus-Induced Airway Mucosa Immune Profile in Asymptomatic Neonates. 2016 J Infect Dis 26655299 8,216 5
Authors: Wolsk, H.M., Følsgaard, N.V., Birch, S., Brix, S., Hansel, T.T., Johnston, S.L., Kebadze, T., Chawes, B.L., Bønnelykke, K. and Bisgaard, H.
Abstract: Bacterial airway colonization is known to alter the airway mucosa immune response in neonates whereas the impact of viruses is unknown. The objective was therefore to examine the effect of respiratory viruses on the immune signature in the airways of asymptomatic neonates.Nasal aspirates from 571 asymptomatic 1-month-old neonates from the Copenhagen Prospective Studies on Asthma in Childhood 2010 birth cohort were investigated for respiratory viruses. Simultaneously, unstimulated airway mucosal lining fluid was obtained and quantified for levels of 20 immune mediators related to type 1, type 2, type 17, and regulatory immune paths. The association between immune mediator levels and viruses was tested by conventional statistics and partial least square discriminant analysis.Picornaviruses were detected in 58 neonates (10.2 and other viruses in 10 (1.8. A general up-regulation of immune mediators was found in the neonates with picornavirus (P < .0001; partial least square discriminant analysis). The association was pronounced for type 1- and type 2-related markers and was unaffected by comprehensive confounder adjustment. Detection of picornavirus and bacteria was associated with an additive general up-regulating effect.Asymptomatic presence of picornavirus in the neonatal airway is a potent activator of the topical immune response. This is relevant to understanding the immune potentiating effect of early life exposure to viruses.
BibTeX:
@article{,
  author = {Wolsk, Helene M. and Følsgaard, Nilofar V. and Birch, Sune and Brix, Susanne and Hansel, Trevor T. and Johnston, Sebastian L. and Kebadze, Tatiana and Chawes, Bo L. and Bønnelykke, Klaus and Bisgaard, Hans},
  title = {Picornavirus-Induced Airway Mucosa Immune Profile in Asymptomatic Neonates.},
  journal = {J Infect Dis},
  school = {COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen.},
  year = {2016},
  volume = {213},
  number = {8},
  pages = {1262--1270},
  url = {http://dx.doi.org/10.1093/infdis/jiv594},
  doi = {https://doi.org/10.1093/infdis/jiv594}
}
Wolsk, H.M. Bisgaard, H. Siblings Promote a Type 1/Type 17-oriented immune response in the airways of asymptomatic neonates. 2016 Allergy 26808998 7,361 1
Authors: Wolsk, H.M., Chawes, B.L., Følsgaard, N.V., Rasmussen, M.A., Brix, S. and Bisgaard, H.
Abstract: Siblings have been shown to reduce the risk of childhood asthma and allergy, but the mechanism driving this association is unknown. The objective was to study whether siblings affect the airway immune response in healthy neonates, which could represent an underlying immune modulatory pathway.We measured 20 immune mediators related to the Type 1, Type 2, Type 17, or regulatory immune pathways in the airway mucosa of 571 one-month-old asymptomatic neonates from the Copenhagen Prospective Studies on Asthma in Childhood2010 birth cohort (COPSAC2010 ). The association between airway mediator levels and presence of siblings was investigated using conventional statistics and principle component analysis (PCA).Neonates with siblings had an upregulated level of airway immune mediators, with predominance of Type 1- and Type 17-related mediators. This was supported by the PCA showing a highly significant difference between children with vs without siblings: P < 10(-10) , which persisted after adjustment for potential confounders including pathogenic airway bacteria and viruses: P < 0.0001. The immune priming effect was inversely associated with time since last childbirth: P = 0.0015.Siblings mediate a Type 1/Type 17-related immune-stimulatory effect in the airways of asymptomatic neonates, also after adjustment for pathogenic bacteria and viruses, indicating that siblings exert a transferable early immune modulatory effect. These findings may represent an in utero immune priming effect of the fetal immune system caused by previous pregnancies as the effect was attenuated with time since last childbirth, or it could relate to the presence of unidentified microbes, but further studies are needed to confirm our findings.
BibTeX:
@article{,
  author = {Wolsk, H. M. and Chawes, B. L. and Følsgaard, N. V. and Rasmussen, M. A. and Brix, S. and Bisgaard, H.},
  title = {Siblings Promote a Type 1/Type 17-oriented immune response in the airways of asymptomatic neonates.},
  journal = {Allergy},
  school = {COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.},
  year = {2016},
  volume = {71},
  number = {6},
  pages = {820--828},
  url = {http://dx.doi.org/10.1111/all.12847},
  doi = {https://doi.org/10.1111/all.12847}
}
Stokholm, J. Bisgaard, H. Azithromycin for episodes with asthma-like symptoms in young children aged 1-3 years: a randomised, double-blind, placebo-controlled trial. 2016 Lancet Respir Med 26704020 19,287 31
Authors: Stokholm, J., Chawes, B.L., Vissing, N.H., Bjarnadóttir, E., Pedersen, T.M., Vinding, R.K., Schoos, A.-M.M., Wolsk, H.M., Thorsteinsdóttir, S., Hallas, H.W., Arianto, L., Schjørring, S., Krogfelt, K.A., Fischer, T.K., Pipper, C.B., Bønnelykke, K. and Bisgaard, H.
Abstract: Bacteria and viruses are equally associated with the risk of acute episodes of asthma-like symptoms in young children, suggesting antibiotics as a potential treatment for such episodes. We aimed to assess the effect of azithromycin on the duration of respiratory episodes in young children with recurrent asthma-like symptoms, hypothesising that it reduces the duration of the symptomatic period.In this randomised, double-blind, placebo-controlled trial, we recruited children aged 1-3 years, who were diagnosed with recurrent asthma-like symptoms from the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort; a birth cohort consisting of the general Danish population of Zealand, including Copenhagen. Exclusion criteria were macrolide allergy, heart, liver, neurological, and kidney disease, and, before each treatment, one or more clinical signs of pneumonia (respiratory frequency of ≥50 breaths per min; fever of ≥39°C; C-reactive protein concentration of ≥476·20 nmol/L [≥50 mg/L]). Each episode of asthma-like symptoms lasting at least 3 days was randomly allocated to a 3-day course of azithromycin oral solution of 10 mg/kg per day or placebo after thorough examination by a study physician at the Copenhagen Prospective Studies on Asthma research unit. Each episode was randomly allocated independently of previous treatment from a computer-generated list of random numbers in blocks of ten (generated at the Pharmacy of Glostrup). Investigators and children were masked until the youngest child turned 3 years of age and throughout the data validation and analysis phases. The primary outcome was duration of the respiratory episode after treatment, verified by prospective daily diaries and analysed with Poisson regression. Analyses were per protocol (excluding those without a primary outcome measure or who did not receive treatment). This trial is registered with ClinicalTrials.gov, number NCT01233297.Between Nov 17, 2010, and Jan 28, 2014, we randomly allocated 158 asthma-like episodes in 72 children (79 [50 to azithromycin and 79 [50 to placebo). The mean duration of the episode after treatment was 3·4 days for children receiving azithromycin compared with 7·7 days for children receiving placebo. Azithromycin caused a significant shortening of the episode of 63·3% (95% CI 56·0-69·3; p<0·0001). The effect size increased with early initiation of treatment, showing a reduction in episode duration of 83% if treatment was initiated before day 6 of the episode compared with 36% if initiated on or after day 6 (p<0·0001). We noted no differences in clinical adverse events between the azithromycin (18 [23 of 78 episodes included in final analysis) and placebo (24 [30 of 79) groups (p=0·30), but we did not investigate bacterial resistance patterns after treatment.Azithromycin reduced the duration of episodes of asthma-like symptoms in young children, suggesting that this drug could have a role in acute management of exacerbations. Further research is needed to disentangle the inflammatory versus antimicrobial aspects of this relation.Lundbeck Foundation, Danish Ministry of Health, Danish Council for Strategic Research, Capital Region Research Foundation.
BibTeX:
@article{,
  author = {Stokholm, Jakob and Chawes, Bo L. and Vissing, Nadja H. and Bjarnadóttir, El\in and Pedersen, Tine M. and Vinding, Rebecca K. and Schoos, Ann-Marie M. and Wolsk, Helene M. and Thorsteinsdóttir, Sunna and Hallas, Henrik W. and Arianto, Lambang and Schjørring, Susanne and Krogfelt, Karen A. and Fischer, Thea K. and Pipper, Christian B. and Bønnelykke, Klaus and Bisgaard, Hans},
  title = {Azithromycin for episodes with asthma-like symptoms in young children aged 1-3 years: a randomised, double-blind, placebo-controlled trial.},
  journal = {Lancet Respir Med},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. Electronic address: bisgaard@copsac.com.},
  year = {2016},
  volume = {4},
  number = {1},
  pages = {19--26},
  url = {http://dx.doi.org/10.1016/S2213-2600(15)00500-7},
  doi = {https://doi.org/10.1016/S2213-2600(15)00500-7}
}
Vissing, N.H. Bisgaard, H. Susceptibility to Lower Respiratory Infections in Childhood is Associated with Perturbation of the Cytokine Response to Pathogenic Airway Bacteria. 2016 Pediatr Infect Dis J 26910587 2,486 5
Authors: Vissing, N.H., Larsen, J.M., Rasmussen, M.A., Chawes, B.L.K., Thysen, A.H., Bønnelykke, K., Brix, S. and Bisgaard, H.
Abstract: Neonatal colonization of the airways with respiratory pathogens is associated with increased risk of lower respiratory infections (LRI) in early childhood. Therefore, we hypothesized that children developing LRI have an aberrant immune response to pathogenic bacteria in infancy. The objective was to characterize in vitro the early life systemic immune response to pathogenic bacteria and study the possible association with incidence of LRI during the first 3 years of life.The Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) is a clinical birth cohort study of 411 children born of mothers with asthma. LRI incidence was prospectively captured from 6-monthly planned visits and visits at acute respiratory episodes. The in vitro systemic immune response to Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae was characterized by the production of TNF-α, IFN-γ, IL-2, IL-5, IL-10, IL-13 and IL-17 in peripheral blood mononuclear cells isolated at age 6 months from 291 infants. Data were analyzed by Poisson regression against incidence of LRI in infancy.A multivariable model including all cytokine responses from the 3 different bacterial stimulations significantly identified children at risk of LRI (P = 0.006). The immune response pattern associated with LRI was characterized by perturbed production of several cytokines rather than production of one specific cytokine, and was independent of concurrent asthma. TNF-α and IL-5 were key drivers but did not explain the entire variation in LRI susceptibility.Children at risk of future LRI present a perturbed systemic immune response upon exposure to common airway pathogens in early life.
BibTeX:
@article{,
  author = {Vissing, Nadja Hawwa and Larsen, Jeppe Madura and Rasmussen, Morten Arendt and Chawes, Bo Lund Krogsgaard and Thysen, Anna Hammerich and Bønnelykke, Klaus and Brix, Susanne and Bisgaard, Hans},
  title = {Susceptibility to Lower Respiratory Infections in Childhood is Associated with Perturbation of the Cytokine Response to Pathogenic Airway Bacteria.},
  journal = {Pediatr Infect Dis J},
  school = { Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark; and †Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark.},
  year = {2016},
  volume = {35},
  number = {5},
  pages = {561--566},
  url = {http://dx.doi.org/10.1097/INF.0000000000001092},
  doi = {https://doi.org/10.1097/INF.0000000000001092}
}
Vinding, R.K. Bisgaard, H. Blood lipid levels associate with childhood asthma, airway obstruction, bronchial hyperresponsiveness, and aeroallergen sensitization. 2016 J Allergy Clin Immunol 26148797 13,081 7
Authors: Vinding, R.K., Stokholm, J., Chawes, B.L.K. and Bisgaard, H.
Abstract: Studies of children's blood lipid profiles in relation to asthma are few, and the results are ambiguous.We sought to examine whether the lipid profile is associated with concurrent asthma, altered lung function, and allergic sensitization in children.High-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride levels were measured at ages 5 to 7 years in the Copenhagen Prospective Studies on Asthma in Childhood2000 at-risk birth cohort. Asthma and allergic rhinitis were diagnosed based on predefined algorithms at age 7 years along with assessments of lung function, bronchial responsiveness, fraction of exhaled nitric oxide (Feno), and allergic sensitization. Associations between lipid levels and clinical outcomes were adjusted for sex, passive smoking, and body mass index.High levels of low-density lipoprotein cholesterol were associated with concurrent asthma (adjusted odds ratio [aOR], 1.93; 95% CI, 1.06-3.55; P = .03) and airway obstruction: 50% of forced expiratory flow (aβ coefficient, -0.13 L/s; 95% CI, -0.24 to -0.03 L/s; P = .01) and specific airway resistance (aβ coefficient, 0.06 kPa/s; 95% CI, 0.00-0.11 kPa/s; P = .05). High levels of high-density lipoprotein cholesterol were associated with improved specific airway resistance (aβ coefficient, -0.11 kPa/s; 95% CI, -0.21 to -0.02; P = .02), decreased bronchial responsiveness (aβ coefficient, 0.53 log-μmol; 95% CI, 0.00-1.60 log-μmol; P = .05), decreased risk of aeroallergen sensitization (aOR, 0.27; 95% CI, 0.01-0.70; P = .01), and a trend of reduced Feno levels (aβ coefficient, -0.22 log-ppb; 95% CI, -0.50 to 0.01 log-ppb; P = .06). High triglyceride levels were associated with aeroallergen sensitization (aOR, 2.01; 95% CI, 1.14-3.56; P = .02) and a trend of increased Feno levels (aβ coefficient, 0.14 log-ppb; 95% CI, -0.02 to 0.30 log-ppb; P = .08).The blood lipid profile is associated with asthma, airway obstruction, bronchial responsiveness, and aeroallergen sensitization in 7-year-old children. These findings suggest that asthma and allergy are systemic disorders with commonalities with other chronic inflammatory disorders.
BibTeX:
@article{,
  author = {Vinding, Rebecca K. and Stokholm, Jakob and Chawes, Bo L K. and Bisgaard, Hans},
  title = {Blood lipid levels associate with childhood asthma, airway obstruction, bronchial hyperresponsiveness, and aeroallergen sensitization.},
  journal = {J Allergy Clin Immunol},
  school = {COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. Electronic address: bisgaard@copsac.com.},
  year = {2016},
  volume = {137},
  number = {1},
  pages = {68--74.e4},
  url = {http://dx.doi.org/10.1016/j.jaci.2015.05.033},
  doi = {https://doi.org/10.1016/j.jaci.2015.05.033}
}
Sevelsted, A. Bisgaard, H. Risk of Asthma from Cesarean Delivery Depends on Membrane Rupture. 2016 J Pediatr 26825289 3,874 6
Authors: Sevelsted, A., Stokholm, J. and Bisgaard, H.
Abstract: To assess our prospective mother-child cohort and the national registry data to analyze the risk of asthma by delivery mode and whether cesarean delivery before or after membrane rupture affects this risk differently.The Copenhagen Prospective Studies on Asthma in Childhood2000 is a high-risk birth cohort of 411 Danish children. Asthma was diagnosed prospectively by physicians at the research site, and associations with cesarean delivery were investigated using Cox proportional hazard models. From the Danish national prospective registry we included data from 1997-2010. Childhood asthma was defined from recurrent use of inhaled corticosteroids filled at pharmacies. Cesarean delivery was classified as either before or after rupture of membranes, and the risk of asthma was compared with vaginal delivery. Results were adjusted stepwise for age and calendar year, sex, birth weight, gestational age, multiple births, parity, and maternal factors (age, smoking/antibiotics during pregnancy, employment status, and asthma).In the Copenhagen Prospective Studies on Asthma in Childhood2000 cohort, the adjusted hazard ratio for asthma was increased by cesarean delivery relative to vaginal birth 2.18 (1.27-3.73). Registry data replicated these findings. Cesarean delivery performed before rupture of membranes carried significantly higher risk of asthma, (incidence rate ratio to vaginal delivery 1.20 [1.16-1.23]) than cesarean delivery after rupture of membranes (incidence rate ratio to vaginal delivery 1.12 [1.09-1.16]).We confirmed cesarean delivery to be a risk factor for childhood asthma. This effect was more pronounced for cesarean delivery performed before rupture of membranes.
BibTeX:
@article{,
  author = {Sevelsted, Astrid and Stokholm, Jakob and Bisgaard, Hans},
  title = {Risk of Asthma from Cesarean Delivery Depends on Membrane Rupture.},
  journal = {J Pediatr},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. Electronic address: bisgaard@copsac.com.},
  year = {2016},
  volume = {171},
  pages = {38--42.e1-4},
  url = {http://dx.doi.org/10.1016/j.jpeds.2015.12.066},
  doi = {https://doi.org/10.1016/j.jpeds.2015.12.066}
}
Tyrrell, J. Freathy, R.M. Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight. 2016 JAMA 26978208 44,405 41
Authors: Tyrrell, J., Richmond, R.C., Palmer, T.M., Feenstra, B., Rangarajan, J., Metrustry, S., Cavadino, A., Paternoster, L., Armstrong, L.L., De Silva, N.M.G., Wood, A.R., Horikoshi, M., Geller, F., Myhre, R., Bradfield, J.P., Kreiner-Møller, E., Huikari, V., Painter, J.N., Hottenga, J.-J., Allard, C., Berry, D.J., Bouchard, L., Das, S., Evans, D.M., Hakonarson, H., Hayes, M.G., Heikkinen, J., Hofman, A., Knight, B., Lind, P.A., McCarthy, M.I., McMahon, G., Medland, S.E., Melbye, M., Morris, A.P., Nodzenski, M., Reichetzeder, C., Ring, S.M., Sebert, S., Sengpiel, V., Sørensen, T.I.A., Willemsen, G., de Geus, E.J.C., Martin, N.G., Spector, T.D., Power, C., Järvelin, M.-R., Bisgaard, H., Grant, S.F.A., Nohr, E.A., Jaddoe, V.W., Jacobsson, B., Murray, J.C., Hocher, B., Hattersley, A.T., Scholtens, D.M., Davey Smith, G., Hivert, M.-F., Felix, J.F., Hyppönen, E., Lowe Jr, W.L., Frayling, T.M., Lawlor, D.A., Freathy, R.M. and , E.G.G.(E.G.G.C.
Abstract: Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight.Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included.Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level.Offspring birth weight from 18 studies.Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP-raising allele (P = 1×10(-5)), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions.In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.
BibTeX:
@article{,
  author = {Tyrrell, Jessica and Richmond, Rebecca C. and Palmer, Tom M. and Feenstra, Bjarke and Rangarajan, Janani and Metrustry, Sarah and Cavadino, Alana and Paternoster, Lavinia and Armstrong, Loren L. and De Silva, N Maneka G. and Wood, Andrew R. and Horikoshi, Momoko and Geller, Frank and Myhre, Ronny and Bradfield, Jonathan P. and Kreiner-Møller, Eskil and Huikari, Ville and Painter, Jodie N. and Hottenga, Jouke-Jan and Allard, Catherine and Berry, Diane J. and Bouchard, Luigi and Das, Shikta and Evans, David M. and Hakonarson, Hakon and Hayes, M Geoffrey and Heikkinen, Jani and Hofman, Albert and Knight, Bridget and Lind, Penelope A. and McCarthy, Mark I. and McMahon, George and Medland, Sarah E. and Melbye, Mads and Morris, Andrew P. and Nodzenski, Michael and Reichetzeder, Christoph and Ring, Susan M. and Sebert, Sylvain and Sengpiel, Verena and Sørensen, Thorkild I A. and Willemsen, Gonneke and de Geus, Eco J C. and Martin, Nicholas G. and Spector, Tim D. and Power, Christine and Järvelin, Marjo-Riitta and Bisgaard, Hans and Grant, Struan F A. and Nohr, Ellen A. and Jaddoe, Vincent W. and Jacobsson, Bo and Murray, Jeffrey C. and Hocher, Berthold and Hattersley, Andrew T. and Scholtens, Denise M. and Davey Smith, George and Hivert, Marie-France and Felix, Janine F. and Hyppönen, Elina and Lowe, Jr, William L and Frayling, Timothy M. and Lawlor, Debbie A. and Freathy, Rachel M. and , Early Growth Genetics (E. G. G) Consortium},
  title = {Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight.},
  journal = {JAMA},
  school = {Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, United Kingdom5Medical Research Council Integrative Epidemiology Unit at the University of Bristol, United Kingdom.},
  year = {2016},
  volume = {315},
  number = {11},
  pages = {1129--1140}
}
Thysen, A.H. Brix, S. Season of birth shapes neonatal immune function. 2016 J Allergy Clin Immunol 26581916 13,081 6
Authors: Thysen, A.H., Rasmussen, M.A., Kreiner-Møller, E., Larsen, J.M., Følsgaard, N.V., Bønnelykke, K., Stokholm, J., Bisgaard, H. and Brix, S.
Abstract: Birth season has been reported to be a risk factor for several immune-mediated diseases. We hypothesized that this association is mediated by differential changes in neonatal immune phenotype and function with birth season.We sought to investigate the influence of season of birth on cord blood immune cell subsets and inflammatory mediators in neonatal airways.Cord blood was phenotyped for 26 different immune cell subsets, and at 1 month of age, 20 cytokines and chemokines were quantified in airway mucosal lining fluid. Multivariate partial least squares discriminant analyses were applied to determine whether certain immune profiles dominate by birth season, and correlations between individual cord blood immune cells and early airway immune mediators were defined.We found a birth season-related fluctuation in neonatal immune cell subsets and in early-life airway mucosal immune function. The seasonal airway immune pattern was associated with the number of activated and regulatory T cells in cord blood whereas it was independent of concomitant presence of pathogenic airway microbes. Specifically, summer newborns presented with the lowest levels of all cell types and mediators; fall newborns displayed high levels of activated T cells and mucosal IL-12p70, TNF-α, IL-13, IL-10, and IL-2; and winter newborns had the highest levels of innate immune cells, IL-5, type 17-related immune mediators, and activated T cells.Birth season fluctuations seem to affect neonatal immune development and result in differential potentiation of cord blood immune cells and early airway mucosal immune function.
BibTeX:
@article{,
  author = {Thysen, Anna Hammerich and Rasmussen, Morten Arendt and Kreiner-Møller, Eskil and Larsen, Jeppe Madura and Følsgaard, Nilofar Vahman and Bønnelykke, Klaus and Stokholm, Jakob and Bisgaard, Hans and Brix, Susanne},
  title = {Season of birth shapes neonatal immune function.},
  journal = {J Allergy Clin Immunol},
  school = {Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Denmark.},
  year = {2016},
  volume = {137},
  number = {4},
  pages = {1238--1246.e13},
  url = {http://dx.doi.org/10.1016/j.jaci.2015.08.041},
  doi = {https://doi.org/10.1016/j.jaci.2015.08.041}
}
Thorsteinsdottir, S. Bisgaard, H. Domestic dog exposure at birth reduces the incidence of atopic dermatitis. 2016 Allergy 27385647 7,361 4
Authors: Thorsteinsdottir, S., Thyssen, J.P., Stokholm, J., Vissing, N.H., Waage, J. and Bisgaard, H.
Abstract: While the etiopathogenesis of atopic dermatitis is complex and poorly understood, neonatal exposures are important for disease occurrence. However, the effect of dog exposure on the risk of atopic dermatitis is unresolved.We investigated whether domestic dog exposure affected the risk of atopic dermatitis in children during the first 3 years of life.Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) are ongoing prospective clinical birth cohort studies. Data from 411 children born to mothers with asthma (COPSAC2000 ) and 700 unselected children (COPSAC2010 ) were analyzed following the same protocols at the same research site. Atopic dermatitis was diagnosed prospectively according to the Hanifin-Rajka criteria. Parental history of asthma, eczema, or rhinitis was defined by self-reported physician diagnosis. In the COPSAC2000 , maternal specific serum IgE against eight inhalant allergens was sampled after the children's birth and at pregnancy week 24 in the COPSAC2010 cohort. Associations between dog exposure and atopic dermatitis were analyzed by Cox proportional hazard regression models and adjusted for lifestyle confounders.In the COPSAC2000 and COPSAC2010 cohorts, the risk of atopic dermatitis was significantly lower in children with domestic dog exposure (adjusted HR = 0.46 [0.25-0.87], P = 0.02; and adjusted HR = 0.58 [0.36-0.93], P = 0.03, respectively). The risk of atopic dermatitis decreased in a dose-dependent manner with increasing number of dogs (adjusted HR = 0.58 [0.38-0.89], P = 0.01) in the COPSAC2010 . The protective effect was restricted to children born to mothers with atopic disease in the unselected COPSAC2010 cohort (adjusted HR = 0.39 [0.19-0.82], P = 0.01), as no effect was observed in children born to mothers without atopic disease (adjusted HR = 0.92 [0.49-1.73], P = 0.79). Paternal atopic status did not affect the risk of atopic dermatitis. We found no significant interaction between the CD14 T/T genotype and domestic dog exposure in either cohort (COPSAC2000 , P = 0.36; and COPSAC2010 cohort, P = 0.42).Neonatal domestic dog exposure was associated with a strongly reduced risk of atopic dermatitis in two independent birth cohorts and in a dose-dependent manner. While the mechanisms involved are unclear, our findings raise the question of whether in utero exposures may affect the risk of atopic dermatitis and emphasize the importance of the early environment for disease trajectory.
BibTeX:
@article{,
  author = {Thorsteinsdottir, S. and Thyssen, J. P. and Stokholm, J. and Vissing, N. H. and Waage, J. and Bisgaard, H.},
  title = {Domestic dog exposure at birth reduces the incidence of atopic dermatitis.},
  journal = {Allergy},
  school = {COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.},
  year = {2016},
  volume = {71},
  number = {12},
  pages = {1736--1744},
  url = {http://dx.doi.org/10.1111/all.12980},
  doi = {https://doi.org/10.1111/all.12980}
}
Sevelsted, A. Bisgaard, H. Stable admission rate for acute asthma in Danish children since 1977. 2016 Eur J Epidemiol 26266768 7,226 3
Authors: Sevelsted, A., Pipper, C.B. and Bisgaard, H.
Abstract: Childhood asthma is consistently reported to have increased in recent decades in most westernized countries, but it is unknown if this increase is similar across severities. We aimed to study the time-trend of acute hospital admission and readmission for asthma of school-aged children in the recent 35 years in Denmark. We analyzed time-trends in the national incidence rate of hospitalization for acute severe asthma in children aged 5-15 in Denmark during the 35-year period 1977-2012 in the Danish national registry. Only in-patient admissions with a principal diagnosis of asthma (ICD-8: 493** or ICD-10: J45** or J46**) were included. Among children with asthma hospitalizations, we investigated the risk of readmission beyond 1 month of first admission. Admissions were summarized as rates per thousand person years at risk. The overall time-trend is stable with a rate of one admission per year per thousand children at risk and a per-year incidence rate ratio 0.999 [95 % CI 0.997-1.001]. The rate of any readmission decreased from approximately 20 per thousand children in the eighties to less than 10 in the early nineties before stabilizing at around 10 per thousand children from mid-nineties and onwards. During 35 years of nation-wide follow-up, we find a highly stable incidence rate of first hospital admission for acute severe asthma in children. Moreover, rates of readmission halved during the seventies and stabilized in the last twenty years. In conclusion, our data suggest that the reported increase in childhood asthma is mainly due to less severe cases.
BibTeX:
@article{,
  author = {Sevelsted, Astrid and Pipper, Christian Bressen and Bisgaard, Hans},
  title = {Stable admission rate for acute asthma in Danish children since 1977.},
  journal = {Eur J Epidemiol},
  school = {COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. bisgaard@copsac.com.},
  year = {2016},
  volume = {31},
  number = {3},
  pages = {325--329},
  url = {http://dx.doi.org/10.1007/s10654-015-0078-6},
  doi = {https://doi.org/10.1007/s10654-015-0078-6}
}
Schoos, A.-M.M. Bisgaard, H. Atopic endotype in childhood. 2016 J Allergy Clin Immunol 26597163 13,081 6
Authors: Schoos, A.-M.M., Chawes, B.L., Rasmussen, M.A., Bloch, J., Bønnelykke, K. and Bisgaard, H.
Abstract: The term atopic disorder is an early attempt to define specific endotypes of children with asthma, eczema, or both and increased IgE levels.We performed a longitudinal analysis of the relevance of the atopic endotype from birth to age 13 years.Allergic sensitization against 28 inhalant and food allergens was assessed at ½, 1½, 4, 6, and 13 years of age in 399 children from the Copenhagen Prospective Study on Asthma in Childhood2000 birth cohort by using both skin prick test responses and specific IgE levels. Asthma and eczema were diagnosed longitudinally by strictly adhering to predefined algorithms. Associations between allergic sensitization, asthma, and eczema were estimated by means of logistic regression, and a machine learning approach was used to identify temporal phenotype clusters of these traits.Allergic sensitization showed no association with asthma through early childhood (0-6 years) when analyzed as any sensitization (odds ratio [OR] range, 0.78-1.29; P ≥ .48). However, at 13 years of age, any sensitization was associated with asthma (OR range, 4.02-5.94; all P < .001). In contrast, any sensitization was associated with eczema at ½, 1½, and 6 years of age (OR range, 2.06-6.02; P ≤ .01) and borderline associated at 4 years of age (OR, 1.61 [95% CI, 0.96-2.69]; P = .07) but not at 13 years of age (OR, 1.57 [95% CI, 0.78-3.16]; P = .21). We identified 4 latent patterns of disease development that were either dominated by sensitization (37, eczema (26, asthma (14, or healthy status (24.We found very little interdependency between asthma, eczema, and allergic sensitization through childhood. The associations between those entities were strongly dependent on age, type of allergens, and method of testing for sensitization. Therefore, atopy in children is unlikely to represent a true endotype.
BibTeX:
@article{,
  author = {Schoos, Ann-Marie Malby and Chawes, Bo Lund and Rasmussen, Morten Arendt and Bloch, Joakim and Bønnelykke, Klaus and Bisgaard, Hans},
  title = {Atopic endotype in childhood.},
  journal = {J Allergy Clin Immunol},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. Electronic address: bisgaard@copsac.com.},
  year = {2016},
  volume = {137},
  number = {3},
  pages = {844--51.e4},
  url = {http://dx.doi.org/10.1016/j.jaci.2015.10.004},
  doi = {https://doi.org/10.1016/j.jaci.2015.10.004}
}
Schoos, A.-M.M. Bisgaard, H. Early indoor aeroallergen exposure is not associated with development of sensitization or allergic rhinitis in high-risk children. 2016 Allergy 26836471 7,361 4
Authors: Schoos, A.-M.M., Chawes, B.L., Jelding-Dannemand, E., Elfman, L.B. and Bisgaard, H.
Abstract: Allergen exposure is associated with the development of allergic sensitization in childhood as reflected by global variations in sensitization patterns. However, there is little evidence to support a direct association.To investigate the association between perinatal aeroallergen exposure and sensitization and rhinitis to such allergens later in childhood.Allergic sensitization to cat, dog, and house dust mites was diagnosed longitudinally using skin prick tests and specific IgE measurements at ½, 1½, 4, 6, and 13 years in 399 children from the Copenhagen Prospective Study on Asthma in Childhood2000 birth cohort. Rhinitis was diagnosed at 7 and 13 years. Allergen exposure was defined as dog or cat in the home during the 3rd trimester of pregnancy or the first year of life and as allergen levels of dog, cat, and house dust mite in bed dust samples at 1 year. Associations between exposure and outcomes were analyzed by logistic regression and stratified for eczema status and test method (skin prick test and specific IgE).We found no association between dog or cat exposure in perinatal life and sensitization or rhinitis during childhood. Similarly, there was no association between levels of allergens in bed dust samples and sensitization or rhinitis during childhood.Perinatal indoor aeroallergen exposure does not seem to affect development of allergic sensitization or rhinitis during childhood questioning the relevance of allergen avoidance as a preventive measure. Other factors such as timing of allergen exposure or other environmental adjuvants may contribute in a more complex pathway to sensitization.
BibTeX:
@article{,
  author = {Schoos, A-M M. and Chawes, B. L. and Jelding-Dannemand, E. and Elfman, L. B. and Bisgaard, H.},
  title = {Early indoor aeroallergen exposure is not associated with development of sensitization or allergic rhinitis in high-risk children.},
  journal = {Allergy},
  school = {COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.},
  year = {2016},
  volume = {71},
  number = {5},
  pages = {684--691},
  url = {http://dx.doi.org/10.1111/all.12853},
  doi = {https://doi.org/10.1111/all.12853}
}
Thorsen, J. Waage, J. Large-scale benchmarking reveals false discoveries and count transformation sensitivity in 16S rRNA gene amplicon data analysis methods used in microbiome studies. 2016 Microbiome 27884206 8,496 7
Authors: Thorsen, J., Brejnrod, A., Mortensen, M., Rasmussen, M.A., Stokholm, J., Al-Soud, W.A., Sørensen, S., Bisgaard, H. and Waage, J.
Abstract: There is an immense scientific interest in the human microbiome and its effects on human physiology, health, and disease. A common approach for examining bacterial communities is high-throughput sequencing of 16S rRNA gene hypervariable regions, aggregating sequence-similar amplicons into operational taxonomic units (OTUs). Strategies for detecting differential relative abundance of OTUs between sample conditions include classical statistical approaches as well as a plethora of newer methods, many borrowing from the related field of RNA-seq analysis. This effort is complicated by unique data characteristics, including sparsity, sequencing depth variation, and nonconformity of read counts to theoretical distributions, which is often exacerbated by exploratory and/or unbalanced study designs. Here, we assess the robustness of available methods for (1) inference in differential relative abundance analysis and (2) beta-diversity-based sample separation, using a rigorous benchmarking framework based on large clinical 16S microbiome datasets from different sources.Running more than 380,000 full differential relative abundance tests on real datasets with permuted case/control assignments and in silico-spiked OTUs, we identify large differences in method performance on a range of parameters, including false positive rates, sensitivity to sparsity and case/control balances, and spike-in retrieval rate. In large datasets, methods with the highest false positive rates also tend to have the best detection power. For beta-diversity-based sample separation, we show that library size normalization has very little effect and that the distance metric is the most important factor in terms of separation power.Our results, generalizable to datasets from different sequencing platforms, demonstrate how the choice of method considerably affects analysis outcome. Here, we give recommendations for tools that exhibit low false positive rates, have good retrieval power across effect sizes and case/control proportions, and have low sparsity bias. Result output from some commonly used methods should be interpreted with caution. We provide an easily extensible framework for benchmarking of new methods and future microbiome datasets.
BibTeX:
@article{,
  author = {Thorsen, Jonathan and Brejnrod, Asker and Mortensen, Martin and Rasmussen, Morten A. and Stokholm, Jakob and Al-Soud, Waleed Abu and Sørensen, Søren and Bisgaard, Hans and Waage, Johannes},
  title = {Large-scale benchmarking reveals false discoveries and count transformation sensitivity in 16S rRNA gene amplicon data analysis methods used in microbiome studies.},
  journal = {Microbiome},
  school = {COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. johannes.waage@dbac.dk.},
  year = {2016},
  volume = {4},
  number = {1},
  pages = {62},
  url = {http://dx.doi.org/10.1186/s40168-016-0208-8},
  doi = {https://doi.org/10.1186/s40168-016-0208-8}
}
Stokholm, J. Bisgaard, H. Cesarean section changes neonatal gut colonization. 2016 J Allergy Clin Immunol 27045582 13,081 18
Authors: Stokholm, J., Thorsen, J., Chawes, B.L., Schjørring, S., Krogfelt, K.A., Bønnelykke, K. and Bisgaard, H.
Abstract: Delivery by means of cesarean section has been associated with increased risk of childhood immune-mediated diseases, suggesting a role of early bacterial colonization patterns for immune maturation.We sought to describe the influence of delivery method on gut and airway colonization patterns in the first year of life in the Copenhagen Prospective Studies on Asthma in Childhood2010 (COPSAC2010) birth cohort.Seven hundred children from the COPSAC2010 birth cohort participated in this analysis. Fecal samples were collected at age 1 week, 1 month, and 1 year, and hypopharyngeal aspirates were collected at age 1 week, 1 month, and 3 months and cultured for bacteria. Detailed information on delivery method, intrapartum antibiotics, and lifestyle factors was obtained by personal interviews.Seventy-eight percent of the children were born by means of natural delivery, 12% by means of emergency cesarean section, and 9% by means of elective cesarean section. Birth by means of cesarean section was significantly associated with colonization of the intestinal tract by Citrobacter freundii, Clostridium species, Enterobacter cloacae, Enterococcus faecalis, Klebsiella oxytoca, Klebsiella pneumoniae, and Staphylococcus aureus at age 1 week, whereas colonization by Escherichia coli was associated with natural birth. At age 1 month, these differences were less prominent, and at age 1 year, they were not apparent, which was confirmed by means of multivariate data-driven partial least squares analyses. The initial airway microbiota was unaffected by birth method.Delivery by means of cesarean section was associated with early colonization patterns of the neonatal gut but not of the airways. The differences normalized within the first year of life. We speculate that microbial derangements, as indicated in our study, can demonstrate a possible link between delivery by means of cesarean section and immune-mediated disease.
BibTeX:
@article{,
  author = {Stokholm, Jakob and Thorsen, Jonathan and Chawes, Bo L. and Schjørring, Susanne and Krogfelt, Karen A. and Bønnelykke, Klaus and Bisgaard, Hans},
  title = {Cesarean section changes neonatal gut colonization.},
  journal = {J Allergy Clin Immunol},
  school = {COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. Electronic address: bisgaard@copsac.com.},
  year = {2016},
  volume = {138},
  number = {3},
  pages = {881--889.e2},
  url = {http://dx.doi.org/10.1016/j.jaci.2016.01.028},
  doi = {https://doi.org/10.1016/j.jaci.2016.01.028}
}
Pedersen, T.M. Stokholm, J. Incidence and Determinants of Ventilation Tubes in Denmark. 2016 PLoS One 27875554 2,806 2
Authors: Pedersen, T.M., Mora-Jensen, A.-R.C., Waage, J., Bisgaard, H. and Stokholm, J.
Abstract: Many children are treated for recurrent acute otitis media and middle ear effusion with ventilation tubes (VT). The objectives are to describe the incidence of VT in Denmark during 1997-2011 from national register data, furthermore, to analyze the determinants for VT in the Copenhagen Prospective Studies on Asthma in Childhood2010 (COPSAC2010) birth cohort.The incidence of VT in all children under 16 years from 1997-2011 were calculated in the Danish national registries. Determinants of VT were studied in the COPSAC2010 birth cohort of 700 children.Nationwide the prevalence of VT was 24% in children aged 0 to 3 three years, with a significant increase over the study period. For all children 0-15 years, the incidence of VT was 35/1,000. In the VT population, 57% was male and 43% females. In the COPSAC2010 birth cohort, the prevalence of VT during the first 3 years of life was 29%. Determinants of VT were: maternal history of middle ear disease; aHR 2.07, 95% CI [1.45-2.96] and siblings history of middle ear disease; aHR 3.02, [2.11-4.32]. Paternal history of middle ear disease, presence of older siblings in the home and diagnosis of persistent wheeze were significant in the univariate analysis but the association did not persist after adjustment.The incidence of VT is still increasing in the youngest age group in Denmark, demonstrating the highest incidence recorded in the world. Family history of middle ear disease and older siblings are the main determinants for VT.
BibTeX:
@article{,
  author = {Pedersen, Tine Marie and Mora-Jensen, Anna-Rosa Cecilie and Waage, Johannes and Bisgaard, Hans and Stokholm, Jakob},
  title = {Incidence and Determinants of Ventilation Tubes in Denmark.},
  journal = {PLoS One},
  school = {Department of Pediatrics, Naestved Hospital, Naestved; Denmark.},
  year = {2016},
  volume = {11},
  number = {11},
  pages = {e0165657},
  url = {http://dx.doi.org/10.1371/journal.pone.0165657},
  doi = {https://doi.org/10.1371/journal.pone.0165657}
}
Okbay, A. Benjamin, D.J. Genome-wide association study identifies 74 loci associated with educational attainment. 2016 Nature 27225129 40,137 111
Authors: Okbay, A., Beauchamp, J.P., Fontana, M.A., Lee, J.J., Pers, T.H., Rietveld, C.A., Turley, P., Chen, G.-B., Emilsson, V., Meddens, S.F.W., Oskarsson, S., Pickrell, J.K., Thom, K., Timshel, P., de Vlaming, R., Abdellaoui, A., Ahluwalia, T.S., Bacelis, J., Baumbach, C., Bjornsdottir, G., Brandsma, J.H., Pina Concas, M., Derringer, J., Furlotte, N.A., Galesloot, T.E., Girotto, G., Gupta, R., Hall, L.M., Harris, S.E., Hofer, E., Horikoshi, M., Huffman, J.E., Kaasik, K., Kalafati, I.P., Karlsson, R., Kong, A., Lahti, J., van der Lee, S.J., deLeeuw , C., Lind, P.A., Lindgren, K.-O., Liu, T., Mangino, M., Marten, J., Mihailov, E., Miller, M.B., van der Most, P.J., Oldmeadow, C., Payton, A., Pervjakova, N., Peyrot, W.J., Qian, Y., Raitakari, O., Rueedi, R., Salvi, E., Schmidt, B., Schraut, K.E., Shi, J., Smith, A.V., Poot, R.A., St Pourcain, B., Teumer, A., Thorleifsson, G., Verweij, N., Vuckovic, D., Wellmann, J., Westra, H.-J., Yang, J., Zhao, W., Zhu, Z., Alizadeh, B.Z., Amin, N., Bakshi, A., Baumeister, S.E., Biino, G., Bønnelykke, K., Boyle, P.A., Campbell, H., Cappuccio, F.P., Davies, G., De Neve, J.-E., Deloukas, P., Demuth, I., Ding, J., Eibich, P., Eisele, L., Eklund, N., Evans, D.M., Faul, J.D., Feitosa, M.F., Forstner, A.J., Gandin, I., Gunnarsson, B., Halldórsson, B.V., Harris, T.B., Heath, A.C., Hocking, L.J., Holliday, E.G., Homuth, G., Horan, M.A., Hottenga, J.-J., de Jager, P.L., Joshi, P.K., Jugessur, A., Kaakinen, M.A., Kähönen, M., Kanoni, S., Keltigangas-Järvinen, L., Kiemeney, L.A.L.M., Kolcic, I., Koskinen, S., Kraja, A.T., Kroh, M., Kutalik, Z., Latvala, A., Launer, L.J., Lebreton, M.P., Levinson, D.F., Lichtenstein, P., Lichtner, P., Liewald, D.C.M., , L.C.S., Loukola, A., Madden, P.A., Mägi, R., Mäki-Opas, T., Marioni, R.E., Marques-Vidal, P., Meddens, G.A., McMahon, G., Meisinger, C., Meitinger, T., Milaneschi, Y., Milani, L., Montgomery, G.W., Myhre, R., Nelson, C.P., Nyholt, D.R., Ollier, W.E.R., Palotie, A., Paternoster, L., Pedersen, N.L., Petrovic, K.E., Porteous, D.J., Räikkönen, K., Ring, S.M., Robino, A., Rostapshova, O., Rudan, I., Rustichini, A., Salomaa, V., Sanders, A.R., Sarin, A.-P., Schmidt, H., Scott, R.J., Smith, B.H., Smith, J.A., Staessen, J.A., Steinhagen-Thiessen, E., Strauch, K., Terracciano, A., Tobin, M.D., Ulivi, S., Vaccargiu, S., Quaye, L., van Rooij, F.J.A., Venturini, C., Vinkhuyzen, A.A.E., Völker, U., Völzke, H., Vonk, J.M., Vozzi, D., Waage, J., Ware, E.B., Willemsen, G., Attia, J.R., Bennett, D.A., Berger, K., Bertram, L., Bisgaard, H., Boomsma, D.I., Borecki, I.B., Bültmann, U., Chabris, C.F., Cucca, F., Cusi, D., Deary, I.J., Dedoussis, G.V., van Duijn, C.M., Eriksson, J.G., Franke, B., Franke, L., Gasparini, P., Gejman, P.V., Gieger, C., Grabe, H.-J., Gratten, J., Groenen, P.J.F., Gudnason, V., van der Harst, P., Hayward, C., Hinds, D.A., Hoffmann, W., Hyppönen, E., Iacono, W.G., Jacobsson, B., Järvelin, M.-R., Jöckel, K.-H., Kaprio, J., Kardia, S.L.R., Lehtimäki, T., Lehrer, S.F., Magnusson, P.K.E., Martin, N.G., McGue, M., Metspalu, A., Pendleton, N., Penninx, B.W.J.H., Perola, M., Pirastu, N., Pirastu, M., Polasek, O., Posthuma, D., Power, C., Province, M.A., Samani, N.J., Schlessinger, D., Schmidt, R., Sørensen, T.I.A., Spector, T.D., Stefansson, K., Thorsteinsdottir, U., Thurik, A.R., Timpson, N.J., Tiemeier, H., Tung, J.Y., Uitterlinden, A.G., Vitart, V., Vollenweider, P., Weir, D.R., Wilson, J.F., Wright, A.F., Conley, D.C., Krueger, R.F., Davey Smith, G., Hofman, A., Laibson, D.I., Medland, S.E., Meyer, M.N., Yang, J., Johannesson, M., Visscher, P.M., Esko, T., Koellinger, P.D., Cesarini, D. and Benjamin, D.J.
Abstract: Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
BibTeX:
@article{,
  author = {Okbay, Aysu and Beauchamp, Jonathan P. and Fontana, Mark Alan and Lee, James J. and Pers, Tune H. and Rietveld, Cornelius A. and Turley, Patrick and Chen, Guo-Bo and Emilsson, Valur and Meddens, S Fleur W. and Oskarsson, Sven and Pickrell, Joseph K. and Thom, Kevin and Timshel, Pascal and de Vlaming, Ronald and Abdellaoui, Abdel and Ahluwalia, Tarunveer S. and Bacelis, Jonas and Baumbach, Clemens and Bjornsdottir, Gyda and Brandsma, Johannes H. and Pina Concas, Maria and Derringer, Jaime and Furlotte, Nicholas A. and Galesloot, Tessel E. and Girotto, Giorgia and Gupta, Richa and Hall, Leanne M. and Harris, Sarah E. and Hofer, Edith and Horikoshi, Momoko and Huffman, Jennifer E. and Kaasik, Kadri and Kalafati, Ioanna P. and Karlsson, Robert and Kong, Augustine and Lahti, Jari and van der Lee, Sven J. and deLeeuw, Christiaan and Lind, Penelope A. and Lindgren, Karl-Oskar and Liu, Tian and Mangino, Massimo and Marten, Jonathan and Mihailov, Evelin and Miller, Michael B. and van der Most, Peter J. and Oldmeadow, Christopher and Payton, Antony and Pervjakova, Natalia and Peyrot, Wouter J. and Qian, Yong and Raitakari, Olli and Rueedi, Rico and Salvi, Erika and Schmidt, Börge and Schraut, Katharina E. and Shi, Jianxin and Smith, Albert V. and Poot, Raymond A. and St Pourcain, Beate and Teumer, Alexander and Thorleifsson, Gudmar and Verweij, Niek and Vuckovic, Dragana and Wellmann, Juergen and Westra, Harm-Jan and Yang, Jingyun and Zhao, Wei and Zhu, Zhihong and Alizadeh, Behrooz Z. and Amin, Najaf and Bakshi, Andrew and Baumeister, Sebastian E. and Biino, Ginevra and Bønnelykke, Klaus and Boyle, Patricia A. and Campbell, Harry and Cappuccio, Francesco P. and Davies, Gail and De Neve, Jan-Emmanuel and Deloukas, Panos and Demuth, Ilja and Ding, Jun and Eibich, Peter and Eisele, Lewin and Eklund, Niina and Evans, David M. and Faul, Jessica D. and Feitosa, Mary F. and Forstner, Andreas J. and Gandin, Ilaria and Gunnarsson, Bjarni and Halldórsson, Bjarni V. and Harris, Tamara B. and Heath, Andrew C. and Hocking, Lynne J. and Holliday, Elizabeth G. and Homuth, Georg and Horan, Michael A. and Hottenga, Jouke-Jan and de Jager, Philip L. and Joshi, Peter K. and Jugessur, Astanand and Kaakinen, Marika A. and Kähönen, Mika and Kanoni, Stavroula and Keltigangas-Järvinen, Liisa and Kiemeney, Lambertus A L M. and Kolcic, Ivana and Koskinen, Seppo and Kraja, Aldi T. and Kroh, Martin and Kutalik, Zoltan and Latvala, Antti and Launer, Lenore J. and Lebreton, Maël P. and Levinson, Douglas F. and Lichtenstein, Paul and Lichtner, Peter and Liewald, David C M. and , LifeLines Cohort Study and Loukola, Anu and Madden, Pamela A. and Mägi, Reedik and Mäki-Opas, Tomi and Marioni, Riccardo E. and Marques-Vidal, Pedro and Meddens, Gerardus A. and McMahon, George and Meisinger, Christa and Meitinger, Thomas and Milaneschi, Yusplitri and Milani, Lili and Montgomery, Grant W. and Myhre, Ronny and Nelson, Christopher P. and Nyholt, Dale R. and Ollier, William E R. and Palotie, Aarno and Paternoster, Lavinia and Pedersen, Nancy L. and Petrovic, Katja E. and Porteous, David J. and Räikkönen, Katri and Ring, Susan M. and Robino, Antonietta and Rostapshova, Olga and Rudan, Igor and Rustichini, Aldo and Salomaa, Veikko and Sanders, Alan R. and Sarin, Antti-Pekka and Schmidt, Helena and Scott, Rodney J. and Smith, Blair H. and Smith, Jennifer A. and Staessen, Jan A. and Steinhagen-Thiessen, Elisabeth and Strauch, Konstantin and Terracciano, Antonio and Tobin, Martin D. and Ulivi, Sheila and Vaccargiu, Simona and Quaye, Lydia and van Rooij, Frank J A. and Venturini, Cristina and Vinkhuyzen, Anna A E. and Völker, Uwe and Völzke, Henry and Vonk, Judith M. and Vozzi, Diego and Waage, Johannes and Ware, Erin B. and Willemsen, Gonneke and Attia, John R. and Bennett, David A. and Berger, Klaus and Bertram, Lars and Bisgaard, Hans and Boomsma, Dorret I. and Borecki, Ingrid B. and Bültmann, Ute and Chabris, Christopher F. and Cucca, Francesco and Cusi, Daniele and Deary, Ian J. and Dedoussis, George V. and van Duijn, Cornelia M. and Eriksson, Johan G. and Franke, Barbara and Franke, Lude and Gasparini, Paolo and Gejman, Pablo V. and Gieger, Christian and Grabe, Hans-Jörgen and Gratten, Jacob and Groenen, Patrick J F. and Gudnason, Vilmundur and van der Harst, Pim and Hayward, Caroline and Hinds, David A. and Hoffmann, Wolfgang and Hyppönen, Elina and Iacono, William G. and Jacobsson, Bo and Järvelin, Marjo-Riitta and Jöckel, Karl-Heinz and Kaprio, Jaakko and Kardia, Sharon L R. and Lehtimäki, Terho and Lehrer, Steven F. and Magnusson, Patrik K E. and Martin, Nicholas G. and McGue, Matt and Metspalu, Andres and Pendleton, Neil and Penninx, Brenda W J H. and Perola, Markus and Pirastu, Nicola and Pirastu, Mario and Polasek, Ozren and Posthuma, Danielle and Power, Christine and Province, Michael A. and Samani, Nilesh J. and Schlessinger, David and Schmidt, Reinhold and Sørensen, Thorkild I A. and Spector, Tim D. and Stefansson, Kari and Thorsteinsdottir, Unnur and Thurik, A Roy and Timpson, Nicholas J. and Tiemeier, Henning and Tung, Joyce Y. and Uitterlinden, André G. and Vitart, Veronique and Vollenweider, Peter and Weir, David R. and Wilson, James F. and Wright, Alan F. and Conley, Dalton C. and Krueger, Robert F. and Davey Smith, George and Hofman, Albert and Laibson, David I. and Medland, Sarah E. and Meyer, Michelle N. and Yang, Jian and Johannesson, Magnus and Visscher, Peter M. and Esko, Tõnu and Koellinger, Philipp D. and Cesarini, David and Benjamin, Daniel J.},
  title = {Genome-wide association study identifies 74 loci associated with educational attainment.},
  journal = {Nature},
  school = {Center for Economic and Social Research, University of Southern California, Los Angeles, California 90089-3332, USA.},
  year = {2016},
  volume = {533},
  number = {7604},
  pages = {539--542},
  url = {http://dx.doi.org/10.1038/nature17671},
  doi = {https://doi.org/10.1038/nature17671}
}
Mortensen, M.S. Sørensen, S.J. The developing hypopharyngeal microbiota in early life. 2016 Microbiome 28038686 8,496 2
Authors: Mortensen, M.S., Brejnrod, A.D., Roggenbuck, M., Abu Al-Soud, W., Balle, C., Krogfelt, K.A., Stokholm, J., Thorsen, J., Waage, J., Rasmussen, M.A., Bisgaard, H. and Sørensen, S.J.
Abstract: The airways of healthy humans harbor a distinct microbial community. Perturbations in the microbial community have been associated with disease, yet little is known about the formation and development of a healthy airway microbiota in early life. Our goal was to understand the establishment of the airway microbiota within the first 3 months of life. We investigated the hypopharyngeal microbiota in the unselected COPSAC2010 cohort of 700 infants, using 16S rRNA gene sequencing of hypopharyngeal aspirates from 1 week, 1 month, and 3 months of age.Our analysis shows that majority of the hypopharyngeal microbiota of healthy infants belong to each individual's core microbiota and we demonstrate five distinct community pneumotypes. Four of these pneumotypes are dominated by the genera Staphylococcus, Streptococcus, Moraxella, and Corynebacterium, respectively. Furthermore, we show temporal pneumotype changes suggesting a rapid development towards maturation of the hypopharyngeal microbiota and a significant effect from older siblings. Despite an overall common trajectory towards maturation, individual infants' microbiota are more similar to their own, than to others, over time.Our findings demonstrate a consolidation of the population of indigenous bacteria in healthy airways and indicate distinct trajectories in the early development of the hypopharyngeal microbiota.
BibTeX:
@article{,
  author = {Mortensen, Martin Steen and Brejnrod, Asker Daniel and Roggenbuck, Michael and Abu Al-Soud, Waleed and Balle, Christina and Krogfelt, Karen Angeliki and Stokholm, Jakob and Thorsen, Jonathan and Waage, Johannes and Rasmussen, Morten Arendt and Bisgaard, Hans and Sørensen, Søren Johannes},
  title = {The developing hypopharyngeal microbiota in early life.},
  journal = {Microbiome},
  school = {Department of Biology, Section of Microbiology, University of Copenhagen, Universitetsparken 15, bldg. 1, DK2100, Copenhagen, Denmark. sjs@bio.ku.dk.},
  year = {2016},
  volume = {4},
  number = {1},
  pages = {70},
  url = {http://dx.doi.org/10.1186/s40168-016-0215-9},
  doi = {https://doi.org/10.1186/s40168-016-0215-9}
}
Jepsen, A.A. Bisgaard, H. High breast milk IL-1β level is associated with reduced risk of childhood eczema. 2016 Clin Exp Allergy 27251401 5,264 3
Authors: Jepsen, A.A., Chawes, B.L., Carson, C.G., Schoos, A.-M.M., Thysen, A.H., Waage, J., Brix, S. and Bisgaard, H.
Abstract: We recently demonstrated a dual effect of breastfeeding with increased risk of eczema and decreased risk of wheezing in early childhood by increasing breastfeeding length. We hypothesize that immune mediators in breast milk could explain such association either through a direct effect or as a surrogate marker of maternal immune constitution.To investigate the possible association between cytokine and chemokine levels in breast milk and development of eczema and recurrent wheeze during early childhood.Levels of 19 pro-inflammatory and immunoregulatory cytokines and chemokines were measured in 223 breast milk samples from mothers in the Copenhagen Prospective Study on Asthma in Childhood2000 (COPSAC) high-risk birth cohort. Eczema and recurrent wheeze at the age of 0-3 years were prospectively diagnosed by COPSAC physicians adherent to predefined validated algorithms. Association analyses were performed by Cox regression adjusting for potential confounding factors and by multivariable principal component analysis.Increased IL-1β in breast milk (≥ 0.7 pg/mL) was associated with more than a halved risk of eczema before age three (aHR = 0.41; 95% CI = 0.24-0.68; P < 0.001), which remained significant after false discovery rate adjustment (P = 0.008). The principal component analysis confirmed that a mediator pattern dominated by high levels of IL-1β, IL-17A, and CCL17 and low levels of CXCL1 and TSLP in breast milk protected against eczema (aHR = 0.82; 95% CI = 0.68-0.98; P = 0.03). No associations were observed for recurrent wheeze.Elevated breast milk IL-1β level was associated with decreased risk of early childhood eczema suggesting either a direct protective effect of IL-1β or IL-1b acting as a proxy for a healthy maternal immune system protecting high-risk offspring from eczema.
BibTeX:
@article{,
  author = {Jepsen, A. A. and Chawes, B. L. and Carson, C. G. and Schoos, A-M M. and Thysen, A. H. and Waage, J. and Brix, S. and Bisgaard, H.},
  title = {High breast milk IL-1β level is associated with reduced risk of childhood eczema.},
  journal = {Clin Exp Allergy},
  school = {COPSAC, Copenhagen Prospective Study on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. bisgaard@copsac.com.},
  year = {2016},
  volume = {46},
  number = {10},
  pages = {1344--1354},
  url = {http://dx.doi.org/10.1111/cea.12770},
  doi = {https://doi.org/10.1111/cea.12770}
}
Marioni, R.E. Deary, I.J. Genetic variants linked to education predict longevity. 2016 Proc Natl Acad Sci U S A 27799538 9,661 11
Authors: Marioni, R.E., Ritchie, S.J., Joshi, P.K., Hagenaars, S.P., Okbay, A., Fischer, K., Adams, M.J., Hill, W.D., Davies, G., , S.S.G.A.C., Nagy, R., Amador, C., Läll, K., Metspalu, A., Liewald, D.C., Campbell, A., Wilson, J.F., Hayward, C., Esko, T., Bisgaard, H., Porteous, D.J., Gale, C.R. and Deary, I.J.
Abstract: Educational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = ∼17,000; UK Biobank, n = ∼115,000; and the Estonian Biobank, n = ∼6,000) to test whether education-linked genetic variants can predict lifespan length. We did so by using cohort members' polygenic profile score for education to predict their parents' longevity. Across the three cohorts, meta-analysis showed that a 1 SD higher polygenic education score was associated with ∼2.7% lower mortality risk for both mothers (total ndeaths = 79,702) and ∼2.4% lower risk for fathers (total ndeaths = 97,630). On average, the parents of offspring in the upper third of the polygenic score distribution lived 0.55 y longer compared with those of offspring in the lower third. Overall, these results indicate that the genetic contributions to educational attainment are useful in the prediction of human longevity.
BibTeX:
@article{,
  author = {Marioni, Riccardo E. and Ritchie, Stuart J. and Joshi, Peter K. and Hagenaars, Saskia P. and Okbay, Aysu and Fischer, Krista and Adams, Mark J. and Hill, W David and Davies, Gail and , Social Science Genetic Association Consortium and Nagy, Reka and Amador, Carmen and Läll, Kristi and Metspalu, Andres and Liewald, David C. and Campbell, Archie and Wilson, James F. and Hayward, Caroline and Esko, Tõnu and Porteous, David J. and Gale, Catharine R. and Deary, Ian J.},
  title = {Genetic variants linked to education predict longevity.},
  journal = {Proc Natl Acad Sci U S A},
  school = {Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom.},
  year = {2016},
  volume = {113},
  number = {47},
  pages = {13366--13371},
  url = {http://dx.doi.org/10.1073/pnas.1605334113},
  doi = {https://doi.org/10.1073/pnas.1605334113}
}
Loza, M.J. Baribaud, F. Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study. 2016 Respir Res 27978840 3,841 7
Authors: Loza, M.J., Djukanovic, R., Chung, K.F., Horowitz, D., Ma, K., Branigan, P., Barnathan, E.S., Susulic, V.S., Silkoff, P.E., Bisgaard, H., Sterk, P.J., Baribaud, F., , A.D.E.P.T.(A.D.E.f.P.T. and for the Prediction of Respiratory Disease Outcome Consortium) investigators, U.-B.I.O.P.R.E.D.(U.B.
Abstract: Asthma is a disease of varying severity and differing disease mechanisms. To date, studies aimed at stratifying asthma into clinically useful phenotypes have produced a number of phenotypes that have yet to be assessed for stability and to be validated in independent cohorts. The aim of this study was to define and validate, for the first time ever, clinically driven asthma phenotypes using two independent, severe asthma cohorts: ADEPT and U-BIOPRED.Fuzzy partition-around-medoid clustering was performed on pre-specified data from the ADEPT participants (n = 156) and independently on data from a subset of U-BIOPRED asthma participants (n = 82) for whom the same variables were available. Models for cluster classification probabilities were derived and applied to the 12-month longitudinal ADEPT data and to a larger subset of the U-BIOPRED asthma dataset (n = 397). High and low type-2 inflammation phenotypes were defined as high or low Th2 activity, indicated by endobronchial biopsies gene expression changes downstream of IL-4 or IL-13.Four phenotypes were identified in the ADEPT (training) cohort, with distinct clinical and biomarker profiles. Phenotype 1 was "mild, good lung function, early onset", with a low-inflammatory, predominantly Type-2, phenotype. Phenotype 2 had a "moderate, hyper-responsive, eosinophilic" phenotype, with moderate asthma control, mild airflow obstruction and predominant Type-2 inflammation. Phenotype 3 had a "mixed severity, predominantly fixed obstructive, non-eosinophilic and neutrophilic" phenotype, with moderate asthma control and low Type-2 inflammation. Phenotype 4 had a "severe uncontrolled, severe reversible obstruction, mixed granulocytic" phenotype, with moderate Type-2 inflammation. These phenotypes had good longitudinal stability in the ADEPT cohort. They were reproduced and demonstrated high classification probability in two subsets of the U-BIOPRED asthma cohort.Focusing on the biology of the four clinical independently-validated easy-to-assess ADEPT asthma phenotypes will help understanding the unmet need and will aid in developing tailored therapies.NCT01274507 (ADEPT), registered October 28, 2010 and NCT01982162 (U-BIOPRED), registered October 30, 2013.
BibTeX:
@article{,
  author = {Loza, Matthew J. and Djukanovic, Ratko and Chung, Kian Fan and Horowitz, Daniel and Ma, Keying and Branigan, Patrick and Barnathan, Elliot S. and Susulic, Vedrana S. and Silkoff, Philip E. and Sterk, Peter J. and Baribaud, Frédéric and , A. D. E. P. T (Airways Disease Endotyping for Personalized Therapeutics) and U-B. I. O. P. R. E. D. (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcome Consortium) investigators},
  title = {Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study.},
  journal = {Respir Res},
  school = { Development LLC, 1400 McKean Rd, Spring House, 19477, USA. fbaribau@its.jnj.com.},
  year = {2016},
  volume = {17},
  number = {1},
  pages = {165},
  url = {http://dx.doi.org/10.1186/s12931-016-0482-9},
  doi = {https://doi.org/10.1186/s12931-016-0482-9}
}
Loisel, D.A. Ober, C. Genetic associations with viral respiratory illnesses and asthma control in children. 2016 Clin Exp Allergy 26399222 5,264 5
Authors: Loisel, D.A., Du, G., Ahluwalia, T.S., Tisler, C.J., Evans, M.D., Myers, R.A., Gangnon, R.E., Kreiner-Møller, E., Bønnelykke, K., Bisgaard, H., Jackson, D.J., Lemanske Jr, R., Nicolae, D.L., Gern, J.E. and Ober, C.
Abstract: Viral respiratory infections can cause acute wheezing illnesses in children and exacerbations of asthma.We sought to identify variation in genes with known antiviral and pro-inflammatory functions to identify specific associations with more severe viral respiratory illnesses and the risk of virus-induced exacerbations during the peak fall season.The associations between genetic variation at 326 SNPs in 63 candidate genes and 10 phenotypes related to viral respiratory infection and asthma control were examined in 226 children enrolled in the RhinoGen study. Replication of asthma control phenotypes was performed in 2128 children in the Copenhagen Prospective Study on Asthma in Childhood (COPSAC). Significant associations in RhinoGen were further validated using virus-induced wheezing illness and asthma phenotypes in an independent sample of 122 children enrolled in the Childhood Origins of Asthma (COAST) birth cohort study.A significant excess of P values smaller than 0.05 was observed in the analysis of the 10 RhinoGen phenotypes. Polymorphisms in 12 genes were significantly associated with variation in the four phenotypes showing a significant enrichment of small P values. Six of those genes (STAT4, JAK2, MX1, VDR, DDX58, and EIF2AK2) also showed significant associations with asthma exacerbations in the COPSAC study or with asthma or virus-induced wheezing phenotypes in the COAST study.We identified genetic factors contributing to individual differences in childhood viral respiratory illnesses and virus-induced exacerbations of asthma. Defining mechanisms of these associations may provide insight into the pathogenesis of viral respiratory infections and virus-induced exacerbations of asthma.
BibTeX:
@article{,
  author = {Loisel, D. A. and Du, G. and Ahluwalia, T. S. and Tisler, C. J. and Evans, M. D. and Myers, R. A. and Gangnon, R. E. and Kreiner-Møller, E. and Bønnelykke, K. and Bisgaard, H. and Jackson, D. J. and Lemanske, Jr, RF and Nicolae, D. L. and Gern, J. E. and Ober, C.},
  title = {Genetic associations with viral respiratory illnesses and asthma control in children.},
  journal = {Clin Exp Allergy},
  school = {Department of Human Genetics, University of Chicago, Chicago, IL, USA.},
  year = {2016},
  volume = {46},
  number = {1},
  pages = {112--124},
  url = {http://dx.doi.org/10.1111/cea.12642},
  doi = {https://doi.org/10.1111/cea.12642}
}
Horikoshi, M. Freathy, R.M. Genome-wide associations for birth weight and correlations with adult disease. 2016 Nature 27680694 40,137 26
Authors: Horikoshi, M., Beaumont, R.N., Day, F.R., Warrington, N.M., Kooijman, M.N., Fernandez-Tajes, J., Feenstra, B., van Zuydam, N.R., Gaulton, K.J., Grarup, N., Bradfield, J.P., Strachan, D.P., Li-Gao, R., Ahluwalia, T.S., Kreiner, E., Rueedi, R., Lyytikäinen, L.-P., Cousminer, D.L., Wu, Y., Thiering, E., Wang, C.A., Have, C.T., Hottenga, J.-J., Vilor-Tejedor, N., Joshi, P.K., Boh, E.T.H., Ntalla, I., Pitkänen, N., Mahajan, A., van Leeuwen, E.M., Joro, R., Lagou, V., Nodzenski, M., Diver, L.A., Zondervan, K.T., Bustamante, M., Marques-Vidal, P., Mercader, J.M., Bennett, A.J., Rahmioglu, N., Nyholt, D.R., Ma, R.C.W., Tam, C.H.T., Tam, W.H., , C.H.A.R.G.E.C.H.W.G., Ganesh, S.K., van Rooij, F.J., Jones, S.E., Loh, P.-R., Ruth, K.S., Tuke, M.A., Tyrrell, J., Wood, A.R., Yaghootkar, H., Scholtens, D.M., Paternoster, L., Prokopenko, I., Kovacs, P., Atalay, M., Willems, S.M., Panoutsopoulou, K., Wang, X., Carstensen, L., Geller, F., Schraut, K.E., Murcia, M., van Beijsterveldt, C.E., Willemsen, G., Appel, E.V.R., Fonvig, C.E., Trier, C., Tiesler, C.M., Standl, M., Kutalik, Z., Bonas-Guarch, S., Hougaard, D.M., Sánchez, F., Torrents, D., Waage, J., Hollegaard, M.V., de Haan, H.G., Rosendaal, F.R., Medina-Gomez, C., Ring, S.M., Hemani, G., McMahon, G., Robertson, N.R., Groves, C.J., Langenberg, C., Luan, J., Scott, R.A., Zhao, J.H., Mentch, F.D., MacKenzie, S.M., Reynolds, R.M., Lowe Jr, W.L., Tönjes, A., Stumvoll, M., Lindi, V., Lakka, T.A., van Duijn, C.M., Kiess, W., Körner, A., Sørensen, T.I., Niinikoski, H., Pahkala, K., Raitakari, O.T., Zeggini, E., Dedoussis, G.V., Teo, Y.-Y., Saw, S.-M., Melbye, M., Campbell, H., Wilson, J.F., Vrijheid, M., de Geus, E.J., Boomsma, D.I., Kadarmideen, H.N., Holm, J.-C., Hansen, T., Sebert, S., Hattersley, A.T., Beilin, L.J., Newnham, J.P., Pennell, C.E., Heinrich, J., Adair, L.S., Borja, J.B., Mohlke, K.L., Eriksson, J.G., Widén, E.E., Kähönen, M., Viikari, J.S., Lehtimäki, T., Vollenweider, P., Bønnelykke, K., Bisgaard, H., Mook-Kanamori, D.O., Hofman, A., Rivadeneira, F., Uitterlinden, A.G., Pisinger, C., Pedersen, O., Power, C., Hyppönen, E., Wareham, N.J., Hakonarson, H., Davies, E., Walker, B.R., Jaddoe, V.W., Jarvelin, M.-R., Grant, S.F., Vaag, A.A., Lawlor, D.A., Frayling, T.M., Davey Smith, G., Morris, A.P., Ong, K.K., Felix, J.F., Timpson, N.J., Perry, J.R., Evans, D.M., McCarthy, M.I. and Freathy, R.M.
Abstract: Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10-8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10-13), T2D (Rg = -0.27, P = 1.1 × 10-6) and coronary artery disease (Rg = -0.30, P = 6.5 × 10-9). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.
BibTeX:
@article{,
  author = {Horikoshi, Momoko and Beaumont, Robin N. and Day, Felix R. and Warrington, Nicole M. and Kooijman, Marjolein N. and Fernandez-Tajes, Juan and Feenstra, Bjarke and van Zuydam, Natalie R. and Gaulton, Kyle J. and Grarup, Niels and Bradfield, Jonathan P. and Strachan, David P. and Li-Gao, Ruifang and Ahluwalia, Tarunveer S. and Kreiner, Eskil and Rueedi, Rico and Lyytikäinen, Leo-Pekka and Cousminer, Diana L. and Wu, Ying and Thiering, Elisabeth and Wang, Carol A. and Have, Christian T. and Hottenga, Jouke-Jan and Vilor-Tejedor, Natalia and Joshi, Peter K. and Boh, Eileen Tai Hui and Ntalla, Ioanna and Pitkänen, Niina and Mahajan, Anubha and van Leeuwen, Elisabeth M. and Joro, Raimo and Lagou, Vasiliki and Nodzenski, Michael and Diver, Louise A. and Zondervan, Krina T. and Bustamante, Mariona and Marques-Vidal, Pedro and Mercader, Josep M. and Bennett, Amanda J. and Rahmioglu, Nilufer and Nyholt, Dale R. and Ma, Ronald Ching Wan and Tam, Claudia Ha Ting and Tam, Wing Hung and , C. H. A. R. G. E Consortium Hematology Working Group and Ganesh, Santhi K. and van Rooij, Frank Ja and Jones, Samuel E. and Loh, Po-Ru and Ruth, Katherine S. and Tuke, Marcus A. and Tyrrell, Jessica and Wood, Andrew R. and Yaghootkar, Hanieh and Scholtens, Denise M. and Paternoster, Lavinia and Prokopenko, Inga and Kovacs, Peter and Atalay, Mustafa and Willems, Sara M. and Panoutsopoulou, Kalliope and Wang, Xu and Carstensen, Lisbeth and Geller, Frank and Schraut, Katharina E. and Murcia, Mario and van Beijsterveldt, Catharina Em and Willemsen, Gonneke and Appel, Emil V R. and Fonvig, Cilius E. and Trier, Caecilie and Tiesler, Carla Mt and Standl, Marie and Kutalik, Zoltán and Bonas-Guarch, S\ilvia and Hougaard, David M. and Sánchez, Friman and Torrents, David and Waage, Johannes and Hollegaard, Mads V. and de Haan, Hugoline G. and Rosendaal, Frits R. and Medina-Gomez, Carolina and Ring, Susan M. and Hemani, Gibran and McMahon, George and Robertson, Neil R. and Groves, Christopher J. and Langenberg, Claudia and Luan, Jian'an and Scott, Robert A. and Zhao, Jing Hua and Mentch, Frank D. and MacKenzie, Scott M. and Reynolds, Rebecca M. and Lowe, Jr, William L and Tönjes, Anke and Stumvoll, Michael and Lindi, Virpi and Lakka, Timo A. and van Duijn, Cornelia M. and Kiess, Wieland and Körner, Antje and Sørensen, Thorkild Ia and Niinikoski, Harri and Pahkala, Katja and Raitakari, Olli T. and Zeggini, Eleftheria and Dedoussis, George V. and Teo, Yik-Ying and Saw, Seang-Mei and Melbye, Mads and Campbell, Harry and Wilson, James F. and Vrijheid, Martine and de Geus, Eco Jcn and Boomsma, Dorret I. and Kadarmideen, Haja N. and Holm, Jens-Christian and Hansen, Torben and Sebert, Sylvain and Hattersley, Andrew T. and Beilin, Lawrence J. and Newnham, John P. and Pennell, Craig E. and Heinrich, Joachim and Adair, Linda S. and Borja, Judith B. and Mohlke, Karen L. and Eriksson, Johan G. and Widén, Elisabeth E. and Kähönen, Mika and Viikari, Jorma S. and Lehtimäki, Terho and Vollenweider, Peter and Bønnelykke, Klaus and Bisgaard, Hans and Mook-Kanamori, Dennis O. and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, André G. and Pisinger, Charlotta and Pedersen, Oluf and Power, Christine and Hyppönen, Elina and Wareham, Nicholas J. and Hakonarson, Hakon and Davies, Eleanor and Walker, Brian R. and Jaddoe, Vincent Wv and Jarvelin, Marjo-Riitta and Grant, Struan Fa and Vaag, Allan A. and Lawlor, Debbie A. and Frayling, Timothy M. and Davey Smith, George and Morris, Andrew P. and Ong, Ken K. and Felix, Janine F. and Timpson, Nicholas J. and Perry, John Rb and Evans, David M. and McCarthy, Mark I. and Freathy, Rachel M.},
  title = {Genome-wide associations for birth weight and correlations with adult disease.},
  journal = {Nature},
  school = {Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.},
  year = {2016},
  volume = {538},
  number = {7624},
  pages = {248--252},
  url = {http://dx.doi.org/10.1038/nature19806},
  doi = {https://doi.org/10.1038/nature19806}
}
Grønbæk, J. Bisgaard, H. New time-saving predictor algorithm for multiple breath washout in adolescents. 2016 Pediatr Res 27002983 2,882 3
Authors: Grønbæk, J., Hallas, H.W., Arianto, L., Pedersen, K., Thomsen, A., Chawes, B.L. and Bisgaard, H.
Abstract: Multiple breath washout (MBW) is an informative but time-consuming test. This study evaluates the uncertainty of a time-saving predictor algorithm in adolescents.Adolescents were recruited from the Copenhagen Prospective Study on Asthma in Childhood (COPSAC2000) birth cohort. MBW trials were performed at 13 y of age with Innocor model Inn00400 using sulfur hexafluoride (SF6) as tracer gas. Measurements were analyzed using a mixed model focusing on two prediction points doubling (t5 and quadrupling (t10 the standard end point (t2.5.One hundred and seventy-two MBW trials conducted in 78 adolescents with and without asthma from COPSAC2000 were included. At t10 the washout time (WoT) was reduced by 41 and an uncertainty of 0.159 lung clearance index (LCI) units was introduced (±2 SD), ±1.27). At t5 the WoT was reduced by 25 with an uncertainty of 0.083 LCI units (±0.558). The optimal prediction point, which led to most saved time and least uncertainty was t5%.The predictor algorithm is capable of shortening the MBW test time but introduces an increasing uncertainty with earlier prediction points. This first-of-a-kind prediction algorithm holds promise in shortening the MBW test in children but should be used with caution in subjects with normal LCI values.
BibTeX:
@article{,
  author = {Grønbæk, Jonathan and Hallas, Henrik Wegener and Arianto, Lambang and Pedersen, Knud and Thomsen, Arne and Chawes, Bo Lund and Bisgaard, Hans},
  title = {New time-saving predictor algorithm for multiple breath washout in adolescents.},
  journal = {Pediatr Res},
  school = {COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.},
  year = {2016},
  volume = {80},
  number = {1},
  pages = {49--53},
  url = {http://dx.doi.org/10.1038/pr.2016.57},
  doi = {https://doi.org/10.1038/pr.2016.57}
}
Garn, H. Renz, H. Current concepts in chronic inflammatory diseases: Interactions between microbes, cellular metabolism, and inflammation. 2016 J Allergy Clin Immunol 27373325 13,081 2
Authors: Garn, H., Bahn, S., Baune, B.T., Binder, E.B., Bisgaard, H., Chatila, T.A., Chavakis, T., Culmsee, C., Dannlowski, U., Gay, S., Gern, J., Haahtela, T., Kircher, T., Müller-Ladner, U., Neurath, M.F., Preissner, K.T., Reinhardt, C., Rook, G., Russell, S., Schmeck, B., Stappenbeck, T., Steinhoff, U., van Os, J., Weiss, S., Zemlin, M. and Renz, H.
Abstract: Recent research indicates that chronic inflammatory diseases, including allergies and autoimmune and neuropsychiatric diseases, share common pathways of cellular and molecular dysregulation. It was the aim of the International von-Behring-Röntgen Symposium (October 16-18, 2014, in Marburg, Germany) to discuss recent developments in this field. These include a concept of biodiversity; the contribution of urbanization, lifestyle factors, and nutrition (eg, vitamin D); and new mechanisms of metabolic and immune dysregulation, such as extracellular and intracellular RNAs and cellular and mitochondrial stress. Epigenetic mechanisms contribute further to altered gene expression and therefore to the development of chronic inflammation. These novel findings provide the foundation for further development of preventive and therapeutic strategies.
BibTeX:
@article{,
  author = {Garn, Holger and Bahn, Sabine and Baune, Bernhard T. and Binder, Elisabeth B. and Bisgaard, Hans and Chatila, Talal A. and Chavakis, Triantafyllos and Culmsee, Carsten and Dannlowski, Udo and Gay, Steffen and Gern, James and Haahtela, Tari and Kircher, Tilo and Müller-Ladner, Ulf and Neurath, Markus F. and Preissner, Klaus T. and Reinhardt, Christoph and Rook, Graham and Russell, Shannon and Schmeck, Bernd and Stappenbeck, Thaddeus and Steinhoff, Ulrich and van Os, Jim and Weiss, Scott and Zemlin, Michael and Renz, Harald},
  title = {Current concepts in chronic inflammatory diseases: Interactions between microbes, cellular metabolism, and inflammation.},
  journal = {J Allergy Clin Immunol},
  school = {Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, University of Marburg, Marburg, Germany. Electronic address: harald.renz@uk-gm.de.},
  year = {2016},
  volume = {138},
  number = {1},
  pages = {47--56},
  url = {http://dx.doi.org/10.1016/j.jaci.2016.02.046},
  doi = {https://doi.org/10.1016/j.jaci.2016.02.046}
}
Kragh, M.Brix, S. Brix, S. Divergent response profile in activated cord blood T cells from first-born child implies birth-order-associated in utero immune programming. 2016 Allergy 26505887 7,361 3
Authors: Kragh, M., Larsen, J.M., Thysen, A.H., Rasmussen, M.A., Wolsk, H.M., Bisgaard, H. and Brix, S.
Abstract: First-born children are at higher risk of developing a range of immune-mediated diseases. The underlying mechanism of 'birth-order effects' on disease risk is largely unknown, but in utero programming of the child's immune system may play a role.We studied the association between birth order and the functional response of stimulated cord blood T cells.Purified cord blood T cells were polyclonally activated with anti-CD3-/anti-CD28-coated beads in a subgroup of 28 children enrolled in the COPSAC2010 birth cohort. Expression levels of seven activation markers on helper and cytotoxic T cells as well as the percentage of CD4(+) CD25(+) T cells were assessed by flow cytometry. Production of IFN-γ, TNF-α, IL-17, IL-4, IL-5, IL-13, and IL-10 was measured in the supernatants.IL-10 secretion (P = 0.007) and CD25 expression on CD4(+) helper T cells (P = 0.0003) in the activated cord blood T cells were selectively reduced in first-born children, while the percentage of circulating CD4(+) CD25(+) cord blood T cells was independent of birth order.First-born infants display a reduced anti-inflammatory profile in T cells at birth. This possible in utero 'birth-order' T-cell programming may contribute to later development of immune-mediated diseases by increasing overall immune reactivity in first-born children as compared to younger siblings.
BibTeX:
@article{,
  author = {Kragh, M. and Larsen, J. M. and Thysen, A. H. and Rasmussen, M. A. and Wolsk, H. M. and Bisgaard, H. and Brix, S.},
  title = {Divergent response profile in activated cord blood T cells from first-born child implies birth-order-associated in utero immune programming.},
  journal = {Allergy},
  school = {Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.},
  year = {2016},
  volume = {71},
  number = {3},
  pages = {323--332},
  url = {http://dx.doi.org/10.1111/all.12799},
  doi = {https://doi.org/10.1111/all.12799}
}
Felix, J.F. Jaddoe, V.W.V. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index. 2016 Hum Mol Genet 26604143 5,340 37
Authors: Felix, J.F., Bradfield, J.P., Monnereau, C., van der Valk, R.J.P., Stergiakouli, E., Chesi, A., Gaillard, R., Feenstra, B., Thiering, E., Kreiner-Møller, E., Mahajan, A., Pitkänen, N., Joro, R., Cavadino, A., Huikari, V., Franks, S., Groen-Blokhuis, M.M., Cousminer, D.L., Marsh, J.A., Lehtimäki, T., Curtin, J.A., Vioque, J., Ahluwalia, T.S., Myhre, R., Price, T.S., Vilor-Tejedor, N., Yengo, L., Grarup, N., Ntalla, I., Ang, W., Atalay, M., Bisgaard, H., Blakemore, A.I., Bonnefond, A., Carstensen, L., , B.M.D.i.C.S.(B.M.D.C.S., , E.G., consortium , L.E.(E., Eriksson, J., Flexeder, C., Franke, L., Geller, F., Geserick, M., Hartikainen, A.-L., Haworth, C.M.A., Hirschhorn, J.N., Hofman, A., Holm, J.-C., Horikoshi, M., Hottenga, J.J., Huang, J., Kadarmideen, H.N., Kähönen, M., Kiess, W., Lakka, H.-M., Lakka, T.A., Lewin, A.M., Liang, L., Lyytikäinen, L.-P., Ma, B., Magnus, P., McCormack, S.E., McMahon, G., Mentch, F.D., Middeldorp, C.M., Murray, C.S., Pahkala, K., Pers, T.H., Pfäffle, R., Postma, D.S., Power, C., Simpson, A., Sengpiel, V., Tiesler, C.M.T., Torrent, M., Uitterlinden, A.G., van Meurs, J.B., Vinding, R., Waage, J., Wardle, J., Zeggini, E., Zemel, B.S., Dedoussis, G.V., Pedersen, O., Froguel, P., Sunyer, J., Plomin, R., Jacobsson, B., Hansen, T., Gonzalez, J.R., Custovic, A., Raitakari, O.T., Pennell, C.E., Widén, E., Boomsma, D.I., Koppelman, G.H., Sebert, S., Järvelin, M.-R., Hyppönen, E., McCarthy, M.I., Lindi, V., Harri, N., Körner, A., Bønnelykke, K., Heinrich, J., Melbye, M., Rivadeneira, F., Hakonarson, H., Ring, S.M., Smith, G.D., Sørensen, T.I.A., Timpson, N.J., Grant, S.F.A., Jaddoe, V.W.V., , E.G.G.(E.G.G.C. and , B.M.D.i.C.S.B.M.D.C.S.
Abstract: A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.
BibTeX:
@article{,
  author = {Felix, Janine F. and Bradfield, Jonathan P. and Monnereau, Claire and van der Valk, Ralf J P. and Stergiakouli, Evie and Chesi, Alessandra and Gaillard, Romy and Feenstra, Bjarke and Thiering, Elisabeth and Kreiner-Møller, Eskil and Mahajan, Anubha and Pitkänen, Niina and Joro, Raimo and Cavadino, Alana and Huikari, Ville and Franks, Steve and Groen-Blokhuis, Maria M. and Cousminer, Diana L. and Marsh, Julie A. and Lehtimäki, Terho and Curtin, John A. and Vioque, Jesus and Ahluwalia, Tarunveer S. and Myhre, Ronny and Price, Thomas S. and Vilor-Tejedor, Natalia and Yengo, Lo\ic and Grarup, Niels and Ntalla, Ioanna and Ang, Wei and Atalay, Mustafa and Bisgaard, Hans and Blakemore, Alexandra I. and Bonnefond, Amelie and Carstensen, Lisbeth and , Bone Mineral Density in Childhood Study (B. M. D. C. S) and , Early Genetics and Lifecourse Epidemiology (EAGLE) consortium and Eriksson, Johan and Flexeder, Claudia and Franke, Lude and Geller, Frank and Geserick, Mandy and Hartikainen, Anna-Liisa and Haworth, Claire M A. and Hirschhorn, Joel N. and Hofman, Albert and Holm, Jens-Christian and Horikoshi, Momoko and Hottenga, Jouke Jan and Huang, Jinyan and Kadarmideen, Haja N. and Kähönen, Mika and Kiess, Wieland and Lakka, Hanna-Maaria and Lakka, Timo A. and Lewin, Alexandra M. and Liang, Liming and Lyytikäinen, Leo-Pekka and Ma, Baoshan and Magnus, Per and McCormack, Shana E. and McMahon, George and Mentch, Frank D. and Middeldorp, Christel M. and Murray, Clare S. and Pahkala, Katja and Pers, Tune H. and Pfäffle, Roland and Postma, Dirkje S. and Power, Christine and Simpson, Angela and Sengpiel, Verena and Tiesler, Carla M T. and Torrent, Maties and Uitterlinden, André G. and van Meurs, Joyce B. and Vinding, Rebecca and Waage, Johannes and Wardle, Jane and Zeggini, Eleftheria and Zemel, Babette S. and Dedoussis, George V. and Pedersen, Oluf and Froguel, Philippe and Sunyer, Jordi and Plomin, Robert and Jacobsson, Bo and Hansen, Torben and Gonzalez, Juan R. and Custovic, Adnan and Raitakari, Olli T. and Pennell, Craig E. and Widén, Elisabeth and Boomsma, Dorret I. and Koppelman, Gerard H. and Sebert, Sylvain and Järvelin, Marjo-Riitta and Hyppönen, Elina and McCarthy, Mark I. and Lindi, Virpi and Harri, Niinikoski and Körner, Antje and Bønnelykke, Klaus and Heinrich, Joachim and Melbye, Mads and Rivadeneira, Fernando and Hakonarson, Hakon and Ring, Susan M. and Smith, George Davey and Sørensen, Thorkild I A. and Timpson, Nicholas J. and Grant, Struan F A. and Jaddoe, Vincent W V. and , Early Growth Genetics (E. G. G) Consortium and , Bone Mineral Density in Childhood Study B. M. D. C. S.},
  title = {Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index.},
  journal = {Hum Mol Genet},
  school = {The Generation R Study Group, Department of Pediatrics, Department of Epidemiology.},
  year = {2016},
  volume = {25},
  number = {2},
  pages = {389--403},
  url = {http://dx.doi.org/10.1093/hmg/ddv472},
  doi = {https://doi.org/10.1093/hmg/ddv472}
}
den Dekker, H.T. Duijts, L. Early growth characteristics and the risk of reduced lung function and asthma: A meta-analysis of 25,000 children. 2016 J Allergy Clin Immunol 26548843 13,081 24
Authors: den Dekker, H.T., Sonnenschein-van der Voort, A.M.M., de Jongste, J.C., Anessi-Maesano, I., Arshad, S.H., Barros, H., Beardsmore, C.S., Bisgaard, H., Phar, S.C., Craig, L., Devereux, G., van der Ent, C.K., Esplugues, A., Fantini, M.P., Flexeder, C., Frey, U., Forastiere, F., Gehring, U., Gori, D., van der Gugten, A.C., Henderson, A.J., Heude, B., Ibarluzea, J., Inskip, H.M., Keil, T., Kogevinas, M., Kreiner-Møller, E., Kuehni, C.E., Lau, S., Mélen, E., Mommers, M., Morales, E., Penders, J., Pike, K.C., Porta, D., Reiss, I.K., Roberts, G., Schmidt, A., Schultz, E.S., Schulz, H., Sunyer, J., Torrent, M., Vassilaki, M., Wijga, A.H., Zabaleta, C., Jaddoe, V.W.V. and Duijts, L.
Abstract: Children born preterm or with a small size for gestational age are at increased risk for childhood asthma.We sought to assess the hypothesis that these associations are explained by reduced airway patency.We used individual participant data of 24,938 children from 24 birth cohorts to examine and meta-analyze the associations of gestational age, size for gestational age, and infant weight gain with childhood lung function and asthma (age range, 3.9-19.1 years). Second, we explored whether these lung function outcomes mediated the associations of early growth characteristics with childhood asthma.Children born with a younger gestational age had a lower FEV1, FEV1/forced vital capacity (FVC) ratio, and forced expiratory volume after exhaling 75% of vital capacity (FEF75), whereas those born with a smaller size for gestational age at birth had a lower FEV1 but higher FEV1/FVC ratio (P < .05). Greater infant weight gain was associated with higher FEV1 but lower FEV1/FVC ratio and FEF75 in childhood (P < .05). All associations were present across the full range and independent of other early-life growth characteristics. Preterm birth, low birth weight, and greater infant weight gain were associated with an increased risk of childhood asthma (pooled odds ratio, 1.34 [95% CI, 1.15-1.57], 1.32 [95% CI, 1.07-1.62], and 1.27 [95% CI, 1.21-1.34], respectively). Mediation analyses suggested that FEV1, FEV1/FVC ratio, and FEF75 might explain 7% (95% CI, 2% to 10 to 45% (95% CI, 15% to 81 of the associations between early growth characteristics and asthma.Younger gestational age, smaller size for gestational age, and greater infant weight gain were across the full ranges associated with childhood lung function. These associations explain the risk of childhood asthma to a substantial extent.
BibTeX:
@article{,
  author = {den Dekker, Herman T. and Sonnenschein-van der Voort, Agnes M M. and de Jongste, Johan C. and Anessi-Maesano, Isabella and Arshad, S Hasan and Barros, Henrique and Beardsmore, Caroline S. and Bisgaard, Hans and Phar, Sofia Correia and Craig, Leone and Devereux, Graham and van der Ent, C Kors and Esplugues, Ana and Fantini, Maria P. and Flexeder, Claudia and Frey, Urs and Forastiere, Francesco and Gehring, Ulrike and Gori, Davide and van der Gugten, Anne C. and Henderson, A John and Heude, Barbara and Ibarluzea, Jesús and Inskip, Hazel M. and Keil, Thomas and Kogevinas, Manolis and Kreiner-Møller, Eskil and Kuehni, Claudia E. and Lau, Susanne and Mélen, Erik and Mommers, Monique and Morales, Eva and Penders, John and Pike, Katy C. and Porta, Daniela and Reiss, Irwin K. and Roberts, Graham and Schmidt, Anne and Schultz, Erica S. and Schulz, Holger and Sunyer, Jordi and Torrent, Matias and Vassilaki, Maria and Wijga, Alet H. and Zabaleta, Carlos and Jaddoe, Vincent W V. and Duijts, Liesbeth},
  title = {Early growth characteristics and the risk of reduced lung function and asthma: A meta-analysis of 25,000 children.},
  journal = {J Allergy Clin Immunol},
  school = {Department of Pediatrics, Division of Respiratory Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Pediatrics, Division of Neonatology, Erasmus University Medical Center, Rotterdam, The Netherlands. Electronic address: l.duijts@erasmusmc.nl.},
  year = {2016},
  volume = {137},
  number = {4},
  pages = {1026--1035},
  url = {http://dx.doi.org/10.1016/j.jaci.2015.08.050},
  doi = {https://doi.org/10.1016/j.jaci.2015.08.050}
}
Chawes, B.L. Bisgaard, H. Effect of Vitamin D3 Supplementation During Pregnancy on Risk of Persistent Wheeze in the Offspring: A Randomized Clinical Trial. 2016 JAMA 26813208 44,405 54
Authors: Chawes, B.L., Bønnelykke, K., Stokholm, J., Vissing, N.H., Bjarnadóttir, E., Schoos, A.-M.M., Wolsk, H.M., Pedersen, T.M., Vinding, R.K., Thorsteinsdóttir, S., Arianto, L., Hallas, H.W., Heickendorff, L., Brix, S., Rasmussen, M.A. and Bisgaard, H.
Abstract: Observational studies have suggested that increased dietary vitamin D intake during pregnancy may protect against wheezing in the offspring, but the preventive effect of vitamin D supplementation to pregnant women is unknown.To determine whether supplementation of vitamin D3 during the third trimester of pregnancy reduces the risk of persistent wheeze in the offspring.A double-blind, single-center, randomized clinical trial conducted within the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort. Enrollment began March 2009 with a goal of 708 participants, but due to delayed ethical approval, only 623 women were recruited at 24 weeks of pregnancy. Follow-up of the children (N = 581) was completed when the youngest child reached age 3 years in March 2014.Vitamin D3 (2400 IU/d; n = 315) or matching placebo tablets (n = 308) from pregnancy week 24 to 1 week postpartum. All women received 400 IU/d of vitamin D3 as part of usual pregnancy care.Age at onset of persistent wheeze in the first 3 years of life. Secondary outcomes included number of episodes of troublesome lung symptoms, asthma, respiratory tract infections, and neonatal airway immunology. Adverse events were assessed.Of the 581 children, persistent wheeze was diagnosed during the first 3 years of life in 47 children (16 in the vitamin D3 group and 57 children (20 in the control group. Vitamin D3 supplementation was not associated with the risk of persistent wheeze, but the number of episodes of troublesome lung symptoms was reduced, and the airway immune profile was up-regulated (principal component analysis, P = .04). There was no effect on additional end points. Intrauterine death was observed in 1 fetus (<1 in the vitamin D3 group vs 3 fetuses (1 in the control group and congenital malformations in 17 neonates (5 in the vitamin D3 group vs 23 neonates (8 in the control group. [table: see text].The use of 2800 IU/d of vitamin D3 during the third trimester of pregnancy compared with 400 IU/d did not result in a statistically significant reduced risk of persistent wheeze in the offspring through age 3 years. However, interpretation of the study is limited by a wide CI that includes a clinically important protective effect.clinicaltrials.gov Identifier: NCT00856947.
BibTeX:
@article{,
  author = {Chawes, Bo L. and Bønnelykke, Klaus and Stokholm, Jakob and Vissing, Nadja H. and Bjarnadóttir, El\in and Schoos, Ann-Marie M. and Wolsk, Helene M. and Pedersen, Tine Marie and Vinding, Rebecca K. and Thorsteinsdóttir, Sunna and Arianto, Lambang and Hallas, Henrik W. and Heickendorff, Lene and Brix, Susanne and Rasmussen, Morten A. and Bisgaard, Hans},
  title = {Effect of Vitamin D3 Supplementation During Pregnancy on Risk of Persistent Wheeze in the Offspring: A Randomized Clinical Trial.},
  journal = {JAMA},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.},
  year = {2016},
  volume = {315},
  number = {4},
  pages = {353--361},
  url = {http://dx.doi.org/10.1001/jama.2015.18318},
  doi = {https://doi.org/10.1001/jama.2015.18318}
}
Bustamante, M. Sunyer, J. A genome-wide association meta-analysis of diarrhoeal disease in young children identifies FUT2 locus and provides plausible biological pathways. 2016 Hum Mol Genet 27559109 5,340 2
Authors: Bustamante, M., Standl, M., Bassat, Q., Vilor-Tejedor, N., Medina-Gomez, C., Bonilla, C., Ahluwalia, T.S., Bacelis, J., Bradfield, J.P., Tiesler, C.M.T., Rivadeneira, F., Ring, S., Vissing, N.H., Fink, N.R., Jugessur, A., Mentch, F.D., Ballester, F., Kriebel, J., Kiefte-de Jong, J.C., Wolsk, H.M., Llop, S., Thiering, E., Beth, S.A., Timpson, N.J., Andersen, J., Schulz, H., Jaddoe, V.W.V., Evans, D.M., Waage, J., Hakonarson, H., Grant, S.F.A., Jacobsson, B., Bønnelykke, K., Bisgaard, H., Davey Smith, G., Moll, H.A., Heinrich, J., Estivill, X. and Sunyer, J.
Abstract: More than a million childhood diarrhoeal episodes occur worldwide each year, and in developed countries a considerable part of them are caused by viral infections. In this study, we aimed to search for genetic variants associated with diarrhoeal disease in young children by meta-analyzing genome-wide association studies, and to elucidate plausible biological mechanisms. The study was conducted in the context of the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Data about diarrhoeal disease in two time windows (around 1 year of age and around 2 years of age) was obtained via parental questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data. The meta-analysis (N = 5758) followed by replication (N = 3784) identified a genome-wide significant association between rs8111874 and diarrhoea at age 1 year. Conditional analysis suggested that the causal variant could be rs601338 (W154X) in the FUT2 gene. Children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhoea. FUT2 participates in the production of histo-blood group antigens and has previously been implicated in the susceptibility to infections, including Rotavirus and Norovirus Gene-set enrichment analysis suggested pathways related to the histo-blood group antigen production, and the regulation of ion transport and blood pressure. Among others, the gastrointestinal tract, and the immune and neuro-secretory systems were detected as relevant organs. In summary, this genome-wide association meta-analysis suggests the implication of the FUT2 gene in diarrhoeal disease in young children from the general population.
BibTeX:
@article{,
  author = {Bustamante, Mariona and Standl, Marie and Bassat, Quique and Vilor-Tejedor, Natalia and Medina-Gomez, Carolina and Bonilla, Carolina and Ahluwalia, Tarunveer S. and Bacelis, Jonas and Bradfield, Jonathan P. and Tiesler, Carla M T. and Rivadeneira, Fernando and Ring, Susan and Vissing, Nadja H. and Fink, Nadia R. and Jugessur, Astanand and Mentch, Frank D. and Ballester, Ferran and Kriebel, Jennifer and Kiefte-de Jong, Jessica C. and Wolsk, Helene M. and Llop, Sabrina and Thiering, Elisabeth and Beth, Systke A. and Timpson, Nicholas J. and Andersen, Josefine and Schulz, Holger and Jaddoe, Vincent W V. and Evans, David M. and Waage, Johannes and Hakonarson, Hakon and Grant, Struan F A. and Jacobsson, Bo and Bønnelykke, Klaus and Bisgaard, Hans and Davey Smith, George and Moll, Henriette A. and Heinrich, Joachim and Estivill, Xavier and Sunyer, Jordi},
  title = {A genome-wide association meta-analysis of diarrhoeal disease in young children identifies FUT2 locus and provides plausible biological pathways.},
  journal = {Hum Mol Genet},
  school = {IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.},
  year = {2016},
  volume = {25},
  number = {18},
  pages = {4127--4142},
  url = {http://dx.doi.org/10.1093/hmg/ddw264},
  doi = {https://doi.org/10.1093/hmg/ddw264}
}
Bisgaard, H. Bønnelykke, K. Fish Oil-Derived Fatty Acids in Pregnancy and Wheeze and Asthma in Offspring. 2016 N Engl J Med 28029926 72,406 31
Authors: Bisgaard, H., Stokholm, J., Chawes, B.L., Vissing, N.H., Bjarnadóttir, E., Schoos, A.-M.M., Wolsk, H.M., Pedersen, T.M., Vinding, R.K., Thorsteinsdóttir, S., Følsgaard, N.V., Fink, N.R., Thorsen, J., Pedersen, A.G., Waage, J., Rasmussen, M.A., Stark, K.D., Olsen, S.F. and Bønnelykke, K.
Abstract: Reduced intake of n-3 long-chain polyunsaturated fatty acids (LCPUFAs) may be a contributing factor to the increasing prevalence of wheezing disorders. We assessed the effect of supplementation with n-3 LCPUFAs in pregnant women on the risk of persistent wheeze and asthma in their offspring.We randomly assigned 736 pregnant women at 24 weeks of gestation to receive 2.4 g of n-3 LCPUFA (fish oil) or placebo (olive oil) per day. Their children formed the Copenhagen Prospective Studies on Asthma in Childhood2010 (COPSAC2010) cohort and were followed prospectively with extensive clinical phenotyping. Neither the investigators nor the participants were aware of group assignments during follow-up for the first 3 years of the children's lives, after which there was a 2-year follow-up period during which only the investigators were unaware of group assignments. The primary end point was persistent wheeze or asthma, and the secondary end points included lower respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization.A total of 695 children were included in the trial, and 95.5% completed the 3-year, double-blind follow-up period. The risk of persistent wheeze or asthma in the treatment group was 16.9 versus 23.7% in the control group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.97; P=0.035), corresponding to a relative reduction of 30.7%. Prespecified subgroup analyses suggested that the effect was strongest in the children of women whose blood levels of eicosapentaenoic acid and docosahexaenoic acid were in the lowest third of the trial population at randomization: 17.5% versus 34.1% (hazard ratio, 0.46; 95% CI, 0.25 to 0.83; P=0.011). Analyses of secondary end points showed that supplementation with n-3 LCPUFA was associated with a reduced risk of infections of the lower respiratory tract (31.7% vs. 39.1 hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.033), but there was no statistically significant association between supplementation and asthma exacerbations, eczema, or allergic sensitization.Supplementation with n-3 LCPUFA in the third trimester of pregnancy reduced the absolute risk of persistent wheeze or asthma and infections of the lower respiratory tract in offspring by approximately 7 percentage points, or one third. (Funded by the Lundbeck Foundation and others; ClinicalTrials.gov number, NCT00798226 .).
BibTeX:
@article{,
  author = {Bisgaard, Hans and Stokholm, Jakob and Chawes, Bo L. and Vissing, Nadja H. and Bjarnadóttir, Elin and Schoos, Ann-Marie M. and Wolsk, Helene M. and Pedersen, Tine M. and Vinding, Rebecca K. and Thorsteinsdóttir, Sunna and Følsgaard, Nilofar V. and Fink, Nadia R. and Thorsen, Jonathan and Pedersen, Anders G. and Waage, Johannes and Rasmussen, Morten A. and Stark, Ken D. and Olsen, Sjurdur F. and Bønnelykke, Klaus},
  title = {Fish Oil-Derived Fatty Acids in Pregnancy and Wheeze and Asthma in Offspring.},
  journal = {N Engl J Med},
  school = {From COPSAC (Copenhagen Prospective Studies on Asthma in Childhood), Herlev and Gentofte Hospital, University of Copenhagen (H.B., J.S., B.L.C., N.H.V., E.B., A.-M.M.S., H.M.W., T.M.P., R.K.V., S.T., N.V.F., N.R.F., J.T., J.W., M.A.R., K.B.), and the Center for Fetal Programming, Statens Serum Institut (S.F.O.), Copenhagen, the Department of Pediatrics, Naestved Hospital, Naestved (J.S., E.B., T.M.P., R.K.V.), DTU Bioinformatics, Technical University of Denmark, Kongens Lyngby (A.G.P.), and Faculty of Science, Chemometrics and Analytical Technology, University of Copenhagen (M.A.R.) - all in Denmark; the Department of Kinesiology, University of Waterloo, Waterloo, ON, Canada (K.D.S.); and the Department of Nutrition, Harvard School of Public Health, Boston (S.F.O.).},
  year = {2016},
  volume = {375},
  number = {26},
  pages = {2530--2539},
  url = {http://dx.doi.org/10.1056/NEJMoa1503734},
  doi = {https://doi.org/10.1056/NEJMoa1503734}
}
Bischoff, A.L. Bisgaard, H. Airway mucosal immune-suppression in neonates of mothers receiving A(H1N1)pnd09 vaccination during pregnancy. 2015 Pediatr Infect Dis J 25229268 2,486 2
Authors: Bischoff, A.L., Følsgaard, N.V., Vissing, N.H., Birch, S., Brix, S. and Bisgaard, H.
BibTeX:
@article{,
  author = {Bischoff, Anne L. and Følsgaard, Nilofar V. and Vissing, Nadja H. and Birch, Sune and Brix, Susanne and Bisgaard, Hans},
  title = {Airway mucosal immune-suppression in neonates of mothers receiving A(H1N1)pnd09 vaccination during pregnancy.},
  journal = {Pediatr Infect Dis J},
  school = {*From the Copenhagen Prospective Studies on Asthma in Childhood: COPSAC, Health Sciences, University of Copenhagen, Copenhagen University Hospital, Copenhagen; and †Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.},
  year = {2015},
  volume = {34},
  number = {1},
  pages = {84--90},
  url = {http://dx.doi.org/10.1097/INF.0000000000000529},
  doi = {https://doi.org/10.1097/INF.0000000000000529}
}
Bønnelykke, K. Bisgaard, H. Association between respiratory infections in early life and later asthma is independent of virus type. 2015 J Allergy Clin Immunol 25910716 13,081 44
Authors: Bønnelykke, K., Vissing, N.H., Sevelsted, A., Johnston, S.L. and Bisgaard, H.
Abstract: Lower respiratory tract infections in the first years of life are associated with later asthma, and this observation has led to a focus on the potential causal role of specific respiratory viruses, such as rhinoviruses and respiratory syncytial virus, in asthma development. However, many respiratory viruses and bacteria trigger similar respiratory symptoms and it is possible that the important risk factors for asthma are the underlying susceptibility to infection and the exaggerated reaction to such triggers rather than the particular triggering agent.We sought to study the association between specific infections in early life and development of asthma later in childhood.Three hundred thirteen children were followed prospectively in the Copenhagen Prospective Studies of Asthma in Childhood2000 high-risk birth cohort. Nine respiratory virus types (respiratory syncytial virus, rhinoviruses, other picornaviruses, coronaviruses 229E and OC43, parainfluenza viruses 1-3, influenza viruses AH1, AH3, and B, human metapneumovirus, adenoviruses, and bocavirus) and 3 pathogenic airway bacteria (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) were identified in airway secretions sampled during episodes of troublesome lung symptoms in the first 3 years of life. Asthma was determined by age 7 years.In unadjusted analyses, all viruses and pathogenic bacteria identified during episodes of troublesome lung symptoms were associated with increased risk of asthma by age 7 years with similar odds ratios for all viruses and pathogenic bacteria. After adjustment for the frequency of respiratory episodes, the particular triggers were no longer associated with asthma.The number of respiratory episodes in the first years of life, but not the particular viral trigger, was associated with later asthma development. This suggests that future research should focus on the susceptibility and exaggerated response to lower respiratory tract infections in general rather than on the specific triggering agent.
BibTeX:
@article{,
  author = {Bønnelykke, Klaus and Vissing, Nadja Hawwa and Sevelsted, Astrid and Johnston, Sebastian L. and Bisgaard, Hans},
  title = {Association between respiratory infections in early life and later asthma is independent of virus type.},
  journal = {J Allergy Clin Immunol},
  school = { Danish Pediatric Asthma Center, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. Electronic address: bisgaard@copsac.com.},
  year = {2015},
  volume = {136},
  number = {1},
  pages = {81--86.e4},
  url = {http://dx.doi.org/10.1016/j.jaci.2015.02.024},
  doi = {https://doi.org/10.1016/j.jaci.2015.02.024}
}
Bønnelykke, K. Andersen, Z.J. Postmenopausal hormone therapy and asthma-related hospital admission. 2015 J Allergy Clin Immunol 25579482 13,081 3
Authors: Bønnelykke, K., Raaschou-Nielsen, O., Tjønneland, A., Ulrik, C.S., Bisgaard, H. and Andersen, Z.J.
BibTeX:
@article{,
  author = {Bønnelykke, Klaus and Raaschou-Nielsen, Ole and Tjønneland, Anne and Ulrik, Charlotte Suppli and Bisgaard, Hans and Andersen, Zorana Jovanovic},
  title = {Postmenopausal hormone therapy and asthma-related hospital admission.},
  journal = {J Allergy Clin Immunol},
  school = {Department of Public Health, Center for Epidemiology and Screening, University of Copenhagen, Copenhagen, Denmark.},
  year = {2015},
  volume = {135},
  number = {3},
  pages = {813--6.e5},
  url = {http://dx.doi.org/10.1016/j.jaci.2014.11.019},
  doi = {https://doi.org/10.1016/j.jaci.2014.11.019}
}
West, C.E. Prescott, S.L. The gut microbiota and inflammatory noncommunicable diseases: associations and potentials for gut microbiota therapies. 2015 J Allergy Clin Immunol 25567038 13,081 79
Authors: West, C.E., Renz, H., Jenmalm, M.C., Bisgaard, H., Kozyrskyj, A.L., Allen, K.J., Vuillermin, P., Prescott, S.L. and , i.-F.L.A.M.E.M.I.G.
Abstract: Rapid environmental transition and modern lifestyles are likely driving changes in the biodiversity of the human gut microbiota. With clear effects on physiologic, immunologic, and metabolic processes in human health, aberrations in the gut microbiome and intestinal homeostasis have the capacity for multisystem effects. Changes in microbial composition are implicated in the increasing propensity for a broad range of inflammatory diseases, such as allergic disease, asthma, inflammatory bowel disease (IBD), obesity, and associated noncommunicable diseases (NCDs). There are also suggestive implications for neurodevelopment and mental health. These diverse multisystem influences have sparked interest in strategies that might favorably modulate the gut microbiota to reduce the risk of many NCDs. For example, specific prebiotics promote favorable intestinal colonization, and their fermented products have anti-inflammatory properties. Specific probiotics also have immunomodulatory and metabolic effects. However, when evaluated in clinical trials, the effects are variable, preliminary, or limited in magnitude. Fecal microbiota transplantation is another emerging therapy that regulates inflammation in experimental models. In human subjects it has been successfully used in cases of Clostridium difficile infection and IBD, although controlled trials are lacking for IBD. Here we discuss relationships between gut colonization and inflammatory NCDs and gut microbiota modulation strategies for their treatment and prevention.
BibTeX:
@article{,
  author = {West, Christina E. and Renz, Harald and Jenmalm, Maria C. and Kozyrskyj, Anita L. and Allen, Katrina J. and Vuillermin, Peter and Prescott, Susan L. and , in-F. L. A. M. E Microbiome Interest Group},
  title = {The gut microbiota and inflammatory noncommunicable diseases: associations and potentials for gut microbiota therapies.},
  journal = {J Allergy Clin Immunol},
  school = {International Inflammation (in-FLAME) Network of the World Universities Network; Tolerance Immunitaire, Université de Nice Sophia-Antipolis, Nice, France.},
  year = {2015},
  volume = {135},
  number = {1},
  pages = {3--13; quiz 14},
  url = {http://dx.doi.org/10.1016/j.jaci.2014.11.012},
  doi = {https://doi.org/10.1016/j.jaci.2014.11.012}
}
Shaw, D.E. Chung, K.F. Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort. 2015 Eur Respir J 26357963 10,569 69
Authors: Shaw, D.E., Sousa, A.R., Fowler, S.J., Fleming, L.J., Roberts, G., Corfield, J., Pandis, I., Bansal, A.T., Bel, E.H., Auffray, C., Compton, C.H., Bisgaard, H., Bucchioni, E., Caruso, M., Chanez, P., Dahlén, B., Dahlen, S.-E., Dyson, K., Frey, U., Geiser, T., Gerhardsson de Verdier, M., Gibeon, D., Guo, Y.-K., Hashimoto, S., Hedlin, G., Jeyasingham, E., Hekking, P.-P.W., Higenbottam, T., Horváth, I., Knox, A.J., Krug, N., Erpenbeck, V.J., Larsson, L.X., Lazarinis, N., Matthews, J.G., Middelveld, R., Montuschi, P., Musial, J., Myles, D., Pahus, L., Sandström, T., Seibold, W., Singer, F., Strandberg, K., Vestbo, J., Vissing, N., von Garnier, C., Adcock, I.M., Wagers, S., Rowe, A., Howarth, P., Wagener, A.H., Djukanovic, R., Sterk, P.J., Chung, K.F. and , U.-B.I.O.P.R.E.D.S.G.
Abstract: U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach.This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements.Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05 p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids.Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of "omic" datasets that are at the core of this systems medicine approach.
BibTeX:
@article{,
  author = {Shaw, Dominick E. and Sousa, Ana R. and Fowler, Stephen J. and Fleming, Louise J. and Roberts, Graham and Corfield, Julie and Pandis, Ioannis and Bansal, Aruna T. and Bel, Elisabeth H. and Auffray, Charles and Compton, Chris H. and Bisgaard, Hans and Bucchioni, Enrica and Caruso, Massimo and Chanez, Pascal and Dahlén, Barbro and Dahlen, Sven-Erik and Dyson, Kerry and Frey, Urs and Geiser, Thomas and Gerhardsson de Verdier, Maria and Gibeon, David and Guo, Yi-Ke and Hashimoto, Simone and Hedlin, Gunilla and Jeyasingham, Elizabeth and Hekking, Pieter-Paul W. and Higenbottam, Tim and Horváth, Ildikó and Knox, Alan J. and Krug, Norbert and Erpenbeck, Veit J. and Larsson, Lars X. and Lazarinis, Nikos and Matthews, John G. and Middelveld, Roelinde and Montuschi, Paolo and Musial, Jacek and Myles, David and Pahus, Laurie and Sandström, Thomas and Seibold, Wolfgang and Singer, Florian and Strandberg, Karin and Vestbo, Jorgen and Vissing, Nadja and von Garnier, Christophe and Adcock, Ian M. and Wagers, Scott and Rowe, Anthony and Howarth, Peter and Wagener, Ariane H. and Djukanovic, Ratko and Sterk, Peter J. and Chung, Kian Fan and , U-B. I. O. P. R. E. D Study Group},
  title = {Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort.},
  journal = {Eur Respir J},
  school = { Harefield NHS Trust, London, UK Joint last authors.},
  year = {2015},
  volume = {46},
  number = {5},
  pages = {1308--1321},
  url = {http://dx.doi.org/10.1183/13993003.00779-2015},
  doi = {https://doi.org/10.1183/13993003.00779-2015}
}
van der Valk, R.J.P. Jaddoe, V.W.V. A novel common variant in DCST2 is associated with length in early life and height in adulthood. 2015 Hum Mol Genet 25281659 5,340 17
Authors: van der Valk, R.J.P., Kreiner-Møller, E., Kooijman, M.N., Guxens, M., Stergiakouli, E., Sääf, A., Bradfield, J.P., Geller, F., Hayes, M.G., Cousminer, D.L., Körner, A., Thiering, E., Curtin, J.A., Myhre, R., Huikari, V., Joro, R., Kerkhof, M., Warrington, N.M., Pitkänen, N., Ntalla, I., Horikoshi, M., Veijola, R., Freathy, R.M., Teo, Y.-Y., Barton, S.J., Evans, D.M., Kemp, J.P., St Pourcain, B., Ring, S.M., Davey Smith, G., Bergström, A., Kull, I., Hakonarson, H., Mentch, F.D., Bisgaard, H., Chawes, B., Stokholm, J., Waage, J., Eriksen, P., Sevelsted, A., Melbye, M., , E.G., Consortium, L.E.(E., van Duijn, C.M., Medina-Gomez, C., Hofman, A., de Jongste, J.C., Taal, H.R., Uitterlinden, A.G., , G.I.o.A.N.T.(G.I.A.N.T.C., Armstrong, L.L., Eriksson, J., Palotie, A., Bustamante, M., Estivill, X., Gonzalez, J.R., Llop, S., Kiess, W., Mahajan, A., Flexeder, C., Tiesler, C.M.T., Murray, C.S., Simpson, A., Magnus, P., Sengpiel, V., Hartikainen, A.-L., Keinanen-Kiukaanniemi, S., Lewin, A., Da Silva Couto Alves, A., Blakemore, A.I., Buxton, J.L., Kaakinen, M., Rodriguez, A., Sebert, S., Vaarasmaki, M., Lakka, T., Lindi, V., Gehring, U., Postma, D.S., Ang, W., Newnham, J.P., Lyytikäinen, L.-P., Pahkala, K., Raitakari, O.T., Panoutsopoulou, K., Zeggini, E., Boomsma, D.I., Groen-Blokhuis, M., Ilonen, J., Franke, L., Hirschhorn, J.N., Pers, T.H., Liang, L., Huang, J., Hocher, B., Knip, M., Saw, S.-M., Holloway, J.W., Melén, E., Grant, S.F.A., Feenstra, B., Lowe, W.L., Widén, E., Sergeyev, E., Grallert, H., Custovic, A., Jacobsson, B., Jarvelin, M.-R., Atalay, M., Koppelman, G.H., Pennell, C.E., Niinikoski, H., Dedoussis, G.V., Mccarthy, M.I., Frayling, T.M., Sunyer, J., Timpson, N.J., Rivadeneira, F., Bønnelykke, K., Jaddoe, V.W.V. and , E.G.G.(E.G.G.C.
Abstract: Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05. Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.
BibTeX:
@article{,
  author = {van der Valk, Ralf J P. and Kreiner-Møller, Eskil and Kooijman, Marjolein N. and Guxens, Mònica and Stergiakouli, Evangelia and Sääf, Annika and Bradfield, Jonathan P. and Geller, Frank and Hayes, M Geoffrey and Cousminer, Diana L. and Körner, Antje and Thiering, Elisabeth and Curtin, John A. and Myhre, Ronny and Huikari, Ville and Joro, Raimo and Kerkhof, Marjan and Warrington, Nicole M. and Pitkänen, Niina and Ntalla, Ioanna and Horikoshi, Momoko and Veijola, Riitta and Freathy, Rachel M. and Teo, Yik-Ying and Barton, Sheila J. and Evans, David M. and Kemp, John P. and St Pourcain, Beate and Ring, Susan M. and Davey Smith, George and Bergström, Anna and Kull, Inger and Hakonarson, Hakon and Mentch, Frank D. and Bisgaard, Hans and Chawes, Bo and Stokholm, Jakob and Waage, Johannes and Eriksen, Patrick and Sevelsted, Astrid and Melbye, Mads and , Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium and van Duijn, Cornelia M. and Medina-Gomez, Carolina and Hofman, Albert and de Jongste, Johan C. and Taal, H Rob and Uitterlinden, André G. and , Genetic Investigation of A. Nthropometric Traits (G. I. A. N. T) Consortium and Armstrong, Loren L. and Eriksson, Johan and Palotie, Aarno and Bustamante, Mariona and Estivill, Xavier and Gonzalez, Juan R. and Llop, Sabrina and Kiess, Wieland and Mahajan, Anubha and Flexeder, Claudia and Tiesler, Carla M T. and Murray, Clare S. and Simpson, Angela and Magnus, Per and Sengpiel, Verena and Hartikainen, Anna-Liisa and Keinanen-Kiukaanniemi, Sirkka and Lewin, Alexandra and Da Silva Couto Alves, Alexessander and Blakemore, Alexandra I. and Buxton, Jessica L. and Kaakinen, Marika and Rodriguez, Alina and Sebert, Sylvain and Vaarasmaki, Marja and Lakka, Timo and Lindi, Virpi and Gehring, Ulrike and Postma, Dirkje S. and Ang, Wei and Newnham, John P. and Lyytikäinen, Leo-Pekka and Pahkala, Katja and Raitakari, Olli T. and Panoutsopoulou, Kalliope and Zeggini, Eleftheria and Boomsma, Dorret I. and Groen-Blokhuis, Maria and Ilonen, Jorma and Franke, Lude and Hirschhorn, Joel N. and Pers, Tune H. and Liang, Liming and Huang, Jinyan and Hocher, Berthold and Knip, Mikael and Saw, Seang-Mei and Holloway, John W. and Melén, Erik and Grant, Struan F A. and Feenstra, Bjarke and Lowe, William L. and Widén, Elisabeth and Sergeyev, Elena and Grallert, Harald and Custovic, Adnan and Jacobsson, Bo and Jarvelin, Marjo-Riitta and Atalay, Mustafa and Koppelman, Gerard H. and Pennell, Craig E. and Niinikoski, Harri and Dedoussis, George V. and Mccarthy, Mark I. and Frayling, Timothy M. and Sunyer, Jordi and Timpson, Nicholas J. and Rivadeneira, Fernando and Bønnelykke, Klaus and Jaddoe, Vincent W V. and , Early Growth Genetics (E. G. G) Consortium},
  title = {A novel common variant in DCST2 is associated with length in early life and height in adulthood.},
  journal = {Hum Mol Genet},
  school = {Department of Epidemiology, Department of Paediatrics, The Generation R Study Group, v.jaddoe@erasmusmc.nl.},
  year = {2015},
  volume = {24},
  number = {4},
  pages = {1155--1168}
}
Thysen, A.H. Brix, S. Prelabor cesarean section bypasses natural immune cell maturation. 2015 J Allergy Clin Immunol 26094084 13,081 4
Authors: Thysen, A.H., Larsen, J.M., Rasmussen, M.A., Stokholm, J., Bønnelykke, K., Bisgaard, H. and Brix, S.
BibTeX:
@article{,
  author = {Thysen, Anna Hammerich and Larsen, Jeppe Madura and Rasmussen, Morten Arendt and Stokholm, Jakob and Bønnelykke, Klaus and Bisgaard, Hans and Brix, Susanne},
  title = {Prelabor cesarean section bypasses natural immune cell maturation.},
  journal = {J Allergy Clin Immunol},
  school = {Department of Systems Biology, Center for Biological Sequence Analysis, Technical University of Denmark, Kgs. Lyngby, Denmark.},
  year = {2015},
  volume = {136},
  number = {4},
  pages = {1123--5.e6},
  url = {http://dx.doi.org/10.1016/j.jaci.2015.04.044},
  doi = {https://doi.org/10.1016/j.jaci.2015.04.044}
}
Sevelsted, A. Bisgaard, H. Cesarean section and chronic immune disorders. 2015 Pediatrics 25452656 5,705 85
Authors: Sevelsted, A., Stokholm, J., Bønnelykke, K. and Bisgaard, H.
Abstract: Immune diseases such as asthma, allergy, inflammatory bowel disease, and type 1 diabetes have shown a parallel increase in prevalence during recent decades in westernized countries. The rate of cesarean delivery has also increased in this period and has been associated with the development of some of these diseases.Mature children born by cesarean delivery were analyzed for risk of hospital contact for chronic immune diseases recorded in the Danish national registries in the 35-year period 1977-2012. Two million term children participated in the primary analysis. We studied childhood diseases with a suspected relation to a deviant immune-maturation and a debut at young age. The effect of cesarean delivery on childhood disease incidences were estimated by means of confounder-adjusted incidence rate ratios with 95% confidence intervals obtained in Poisson regression analyses.Children delivered by cesarean delivery had significantly increased risk of asthma, systemic connective tissue disorders, juvenile arthritis, inflammatory bowel disease, immune deficiencies, and leukemia. No associations were found between cesarean delivery and type 1 diabetes, psoriasis, or celiac disease.Cesarean delivery exemplifies a shared environmental risk factor in early life associating with several chronic immune diseases. Understanding commonalities in the underlying mechanisms behind chronic diseases may give novel insight into their origin and allow prevention.
BibTeX:
@article{,
  author = {Sevelsted, Astrid and Stokholm, Jakob and Bønnelykke, Klaus and Bisgaard, Hans},
  title = {Cesarean section and chronic immune disorders.},
  journal = {Pediatrics},
  school = { Danish Pediatric Asthma Center, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; and.},
  year = {2015},
  volume = {135},
  number = {1},
  pages = {e92--e98},
  url = {http://dx.doi.org/10.1542/peds.2014-0596},
  doi = {https://doi.org/10.1542/peds.2014-0596}
}
Schoos, A.-M.M. Bisgaard, H. Disagreement between skin prick test and specific IgE in young children. 2015 Allergy 25224528 7,361 25
Authors: Schoos, A.-M.M., Chawes, B.L.K., Følsgaard, N.V., Samandari, N., Bønnelykke, K. and Bisgaard, H.
Abstract: Skin prick test (SPT) and measurement of serum-specific IgE (sIgE) level are important tools for the clinician to diagnose allergic sensitization. However, little is known about the agreement between the two methods in young children.SPT and sIgE levels were assessed simultaneously for 16 common inhalant and food allergens at age ½, 1½, 4, and 6 years in 389 children from the Copenhagen Prospective Study on Asthma in Childhood2000 (COPSAC2000 ) at-risk birth cohort. Agreement between the two methods for diagnosing inhalant and food allergic sensitization at the four age points was analyzed using kappa statistics.The prevalence of inhalant allergen sensitization increased during childhood diagnosed by both sIgE levels (0.6% to 4.2% to 18.1% to 24.8 P < 0.0001) and SPT results (1.5% to 3.8% to 8.4% to 15.4 P < 0.0001). In contrast, the prevalence of food sensitization increased during childhood when diagnosed from sIgE (7.8% to 12.1% to 15.0% to 18.9 P < 0.0001), but decreased when diagnosed from SPT (5.3% to 5.1% to 3.7% to 3.0 P = 0.05). Overall, the agreement between SPT and sIgE levels was poor to moderate (all κ-coefficients ≤ 0.60) and decreased from moderate to slight for food allergens by increasing age (κ-coefficients: 0.46 to 0.31 to 0.16 to 0.14).There is a substantial disagreement between SPT and sIgE for diagnosing allergic sensitization in young children, which increases with age for food sensitization. Choice of assessment method therefore has major impact on results with wide implications for both clinical practice and research.
BibTeX:
@article{,
  author = {Schoos, A-M M. and Chawes, B L K. and Følsgaard, N. V. and Samandari, N. and Bønnelykke, K. and Bisgaard, H.},
  title = {Disagreement between skin prick test and specific IgE in young children.},
  journal = {Allergy},
  school = { Danish Pediatric Asthma Center, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.},
  year = {2015},
  volume = {70},
  number = {1},
  pages = {41--48},
  url = {http://dx.doi.org/10.1111/all.12523},
  doi = {https://doi.org/10.1111/all.12523}
}
Paternoster, L. Weidinger, S. Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis. 2015 Nat Genet 26482879 27,959 57
Authors: Paternoster, L., Standl, M., Waage, J., Baurecht, H., Hotze, M., Strachan, D.P., Curtin, J.A., Bønnelykke, K., Tian, C., Takahashi, A., Esparza-Gordillo, J., Alves, A.C., Thyssen, J.P., den Dekker, H.T., Ferreira, M.A., Altmaier, E., Sleiman, P.M., Xiao, F.L., Gonzalez, J.R., Marenholz, I., Kalb, B., Yanes, M.P., Xu, C.-J., Carstensen, L., Groen-Blokhuis, M.M., Venturini, C., Pennell, C.E., Barton, S.J., Levin, A.M., Curjuric, I., Bustamante, M., Kreiner-Møller, E., Lockett, G.A., Bacelis, J., Bunyavanich, S., Myers, R.A., Matanovic, A., Kumar, A., Tung, J.Y., Hirota, T., Kubo, M., McArdle, W.L., Henderson, A.J., Kemp, J.P., Zheng, J., Smith, G.D., Rüschendorf, F., Bauerfeind, A., Lee-Kirsch, M.A., Arnold, A., Homuth, G., Schmidt, C.O., Mangold, E., Cichon, S., Keil, T., Rodr\iguez, E., Peters, A., Franke, A., Lieb, W., Novak, N., Fölster-Holst, R., Horikoshi, M., Pekkanen, J., Sebert, S., Husemoen, L.L., Grarup, N., de Jongste, J.C., Rivadeneira, F., Hofman, A., Jaddoe, V.W., Pasmans, S.G., Elbert, N.J., Uitterlinden, A.G., Marks, G.B., Thompson, P.J., Matheson, M.C., Robertson, C.F., , A.A.G.C.(A.A.G.C., Ried, J.S., Li, J., Zuo, X.B., Zheng, X.D., Yin, X.Y., Sun, L.D., McAleer, M.A., O'Regan, G.M., Fahy, C.M., Campbell, L.E., Macek, M., Kurek, M., Hu, D., Eng, C., Postma, D.S., Feenstra, B., Geller, F., Hottenga, J.J., Middeldorp, C.M., Hysi, P., Bataille, V., Spector, T., Tiesler, C.M., Thiering, E., Pahukasahasram, B., Yang, J.J., Imboden, M., Huntsman, S., Vilor-Tejedor, N., Relton, C.L., Myhre, R., Nystad, W., Custovic, A., Weiss, S.T., Meyers, D.A., Söderhäll, C., Melén, E., Ober, C., Raby, B.A., Simpson, A., Jacobsson, B., Holloway, J.W., Bisgaard, H., Sunyer, J., Hensch, N.M.P., Williams, L.K., Godfrey, K.M., Wang, C.A., Boomsma, D.I., Melbye, M., Koppelman, G.H., Jarvis, D., McLean, W.I., Irvine, A.D., Zhang, X.J., Hakonarson, H., Gieger, C., Burchard, E.G., Martin, N.G., Duijts, L., Linneberg, A., Jarvelin, M.-R., Noethen, M.M., Lau, S., Hübner, N., Lee, Y.-A., Tamari, M., Hinds, D.A., Glass, D., Brown, S.J., Heinrich, J., Evans, D.M. and Weidinger, S.
Abstract: Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.
BibTeX:
@article{,
  author = {Paternoster, Lavinia and Standl, Marie and Waage, Johannes and Baurecht, Hansjörg and Hotze, Melanie and Strachan, David P. and Curtin, John A. and Bønnelykke, Klaus and Tian, Chao and Takahashi, Atsushi and Esparza-Gordillo, Jorge and Alves, Alexessander Couto and Thyssen, Jacob P. and den Dekker, Herman T. and Ferreira, Manuel A. and Altmaier, Elisabeth and Sleiman, Patrick Ma and Xiao, Feng Li and Gonzalez, Juan R. and Marenholz, Ingo and Kalb, Birgit and Yanes, Maria Pino and Xu, Cheng-Jian and Carstensen, Lisbeth and Groen-Blokhuis, Maria M. and Venturini, Cristina and Pennell, Craig E. and Barton, Sheila J. and Levin, Albert M. and Curjuric, Ivan and Bustamante, Mariona and Kreiner-Møller, Eskil and Lockett, Gabrielle A. and Bacelis, Jonas and Bunyavanich, Supinda and Myers, Rachel A. and Matanovic, Anja and Kumar, Ashish and Tung, Joyce Y. and Hirota, Tomomitsu and Kubo, Michiaki and McArdle, Wendy L. and Henderson, A. J. and Kemp, John P. and Zheng, Jie and Smith, George Davey and Rüschendorf, Franz and Bauerfeind, Anja and Lee-Kirsch, Min Ae and Arnold, Andreas and Homuth, Georg and Schmidt, Carsten O. and Mangold, Elisabeth and Cichon, Sven and Keil, Thomas and Rodr\iguez, Elke and Peters, Annette and Franke, Andre and Lieb, Wolfgang and Novak, Natalija and Fölster-Holst, Regina and Horikoshi, Momoko and Pekkanen, Juha and Sebert, Sylvain and Husemoen, Lise L. and Grarup, Niels and de Jongste, Johan C. and Rivadeneira, Fernando and Hofman, Albert and Jaddoe, Vincent Wv and Pasmans, Suzanne Gma and Elbert, Niels J. and Uitterlinden, André G. and Marks, Guy B. and Thompson, Philip J. and Matheson, Melanie C. and Robertson, Colin F. and , Australian Asthma Genetics Consortium (A. A. G. C) and Ried, Janina S. and Li, Jin and Zuo, Xian Bo and Zheng, Xiao Dong and Yin, Xian Yong and Sun, Liang Dan and McAleer, Maeve A. and O'Regan, Grainne M. and Fahy, Caoimhe Mr and Campbell, Linda E. and Macek, Milan and Kurek, Michael and Hu, Donglei and Eng, Celeste and Postma, Dirkje S. and Feenstra, Bjarke and Geller, Frank and Hottenga, Jouke Jan and Middeldorp, Christel M. and Hysi, Pirro and Bataille, Veronique and Spector, Tim and Tiesler, Carla Mt and Thiering, Elisabeth and Pahukasahasram, Badri and Yang, James J. and Imboden, Medea and Huntsman, Scott and Vilor-Tejedor, Natàlia and Relton, Caroline L. and Myhre, Ronny and Nystad, Wenche and Custovic, Adnan and Weiss, Scott T. and Meyers, Deborah A. and Söderhäll, Cilla and Melén, Erik and Ober, Carole and Raby, Benjamin A. and Simpson, Angela and Jacobsson, Bo and Holloway, John W. and Bisgaard, Hans and Sunyer, Jordi and Hensch, Nicole M Probst and Williams, L Keoki and Godfrey, Keith M. and Wang, Carol A. and Boomsma, Dorret I. and Melbye, Mads and Koppelman, Gerard H. and Jarvis, Deborah and McLean, Wh Irwin and Irvine, Alan D. and Zhang, Xue Jun and Hakonarson, Hakon and Gieger, Christian and Burchard, Esteban G. and Martin, Nicholas G. and Duijts, Liesbeth and Linneberg, Allan and Jarvelin, Marjo-Riitta and Noethen, Markus M. and Lau, Susanne and Hübner, Norbert and Lee, Young-Ae and Tamari, Mayumi and Hinds, David A. and Glass, Daniel and Brown, Sara J. and Heinrich, Joachim and Evans, David M. and Weidinger, Stephan},
  title = {Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis.},
  journal = {Nat Genet},
  school = {These authors jointly directed this work.},
  year = {2015},
  volume = {47},
  number = {12},
  pages = {1449--1456},
  url = {http://dx.doi.org/10.1038/ng.3424},
  doi = {https://doi.org/10.1038/ng.3424}
}
Muc, M. Lauritzen, L. Maternal fatty acid desaturase genotype correlates with infant immune responses at 6 months. 2015 Br J Nutr 26283408 3,706 3
Authors: Muc, M., Kreiner-Møller, E., Larsen, J.M., Birch, S., Brix, S., Bisgaard, H. and Lauritzen, L.
Abstract: Breast milk long-chain PUFA (LCPUFA) have been associated with changes in early life immune responses and may modulate T-cell function in infancy. We studied the effect of maternal fatty acid desaturase (FADS) genotype and breast milk LCPUFA levels on infants' blood T-cell profiles and ex vivo-produced cytokines after anti-CD3/CD28 stimulation of peripheral blood mononuclear cells in 6-month-old infants from the Copenhagen Prospective Study of Asthma in Childhood birth cohort. LCPUFA concentrations of breast milk were assessed at 4 weeks of age, and FADS SNP were determined in both mothers and infants (n 109). In general, breast milk arachidonic acid (AA) levels were inversely correlated with the production of IL-10 (r -0.25; P=0.004), IL-17 (r -0.24; P=0.005), IL-5 (r -0.21; P=0.014) and IL-13 (r -0.17; P=0.047), whereas EPA was positively correlated with the counts of blood regulatory T-cells and cytotoxic T-cells and decreased T-helper cell counts. The minor FADS alleles were associated with lower breast milk AA and EPA, and infants of mothers carrying the minor allele of FADS SNP rs174556 had higher production of IL-10 (r -0.23; P=0.018), IL-17 (r -0.25; P=0.009) and IL-5 (r -0.21; P=0.038) from ex vivo-activated immune cells. We observed no association between T-cell distribution and maternal or infant FADS gene variants. We conclude that increased maternal LCPUFA synthesis and breast milk AA are associated with decreased levels of IL-5, IL-13 (type-2 related), IL-17 (type-17 related) and IL-10 (regulatory immune responses), but not with interferon-γ and TNF-α, which could be due to an effect of the maternal FADS variants on the offspring immune response transferred via breast milk LCPUFA.
BibTeX:
@article{,
  author = {Muc, Magdalena and Kreiner-Møller, Eskil and Larsen, Jeppe M. and Birch, Sune and Brix, Susanne and Bisgaard, Hans and Lauritzen, Lotte},
  title = {Maternal fatty acid desaturase genotype correlates with infant immune responses at 6 months.},
  journal = {Br J Nutr},
  school = {4Department of Nutrition,Exercise and Sports,University of Copenhagen,1958 Frederiksberg,Denmark.},
  year = {2015},
  volume = {114},
  number = {6},
  pages = {891--898},
  url = {http://dx.doi.org/10.1017/S0007114515002561},
  doi = {https://doi.org/10.1017/S0007114515002561}
}
Joshi, P.K. Wilson, J.F. Directional dominance on stature and cognition in diverse human populations. 2015 Nature 26131930 40,137 40
Authors: Joshi, P.K., Esko, T., Mattsson, H., Eklund, N., Gandin, I., Nutile, T., Jackson, A.U., Schurmann, C., Smith, A.V., Zhang, W., Okada, Y., Stančáková, A., Faul, J.D., Zhao, W., Bartz, T.M., Concas, M.P., Franceschini, N., Enroth, S., Vitart, V., Trompet, S., Guo, X., Chasman, D.I., O'Connel, J.R., Corre, T., Nongmaithem, S.S., Chen, Y., Mangino, M., Ruggiero, D., Traglia, M., Farmaki, A.-E., Kacprowski, T., Bjonnes, A., van der Spek, A., Wu, Y., Giri, A.K., Yanek, L.R., Wang, L., Hofer, E., Rietveld, C.A., McLeod, O., Cornelis, M.C., Pattaro, C., Verweij, N., Baumbach, C., Abdellaoui, A., Warren, H.R., Vuckovic, D., Mei, H., Bouchard, C., Perry, J.R.B., Cappellani, S., Mirza, S.S., Benton, M.C., Broeckel, U., Medland, S.E., Lind, P.A., Malerba, G., Drong, A., Yengo, L., Bielak, L.F., Zhi, D., van der Most, P.J., Shriner, D., Mägi, R., Hemani, G., Karaderi, T., Wang, Z., Liu, T., Demuth, I., Zhao, J.H., Meng, W., Lataniotis, L., van der Laan, S.W., Bradfield, J.P., Wood, A.R., Bonnefond, A., Ahluwalia, T.S., Hall, L.M., Salvi, E., Yazar, S., Carstensen, L., de Haan, H.G., Abney, M., Afzal, U., Allison, M.A., Amin, N., Asselbergs, F.W., Bakker, S.J.L., Barr, R.G., Baumeister, S.E., Benjamin, D.J., Bergmann, S., Boerwinkle, E., Bottinger, E.P., Campbell, A., Chakravarti, A., Chan, Y., Chanock, S.J., Chen, C., Chen, Y.-D.I., Collins, F.S., Connell, J., Correa, A., Cupples, L.A., Smith, G.D., Davies, G., Dörr, M., Ehret, G., Ellis, S.B., Feenstra, B., Feitosa, M.F., Ford, I., Fox, C.S., Frayling, T.M., Friedrich, N., Geller, F., Scotland, G., Gillham-Nasenya, I., Gottesman, O., Graff, M., Grodstein, F., Gu, C., Haley, C., Hammond, C.J., Harris, S.E., Harris, T.B., Hastie, N.D., Heard-Costa, N.L., Heikkilä, K., Hocking, L.J., Homuth, G., Hottenga, J.-J., Huang, J., Huffman, J.E., Hysi, P.G., Ikram, M.A., Ingelsson, E., Joensuu, A., Johansson, Å., Jousilahti, P., Jukema, J.W., Kähönen, M., Kamatani, Y., Kanoni, S., Kerr, S.M., Khan, N.M., Koellinger, P., Koistinen, H.A., Kooner, M.K., Kubo, M., Kuusisto, J., Lahti, J., Launer, L.J., Lea, R.A., Lehne, B., Lehtimäki, T., Liewald, D.C.M., Lind, L., Loh, M., Lokki, M.-L., London, S.J., Loomis, S.J., Loukola, A., Lu, Y., Lumley, T., Lundqvist, A., Männistö, S., Marques-Vidal, P., Masciullo, C., Matchan, A., Mathias, R.A., Matsuda, K., Meigs, J.B., Meisinger, C., Meitinger, T., Menni, C., Mentch, F.D., Mihailov, E., Milani, L., Montasser, M.E., Montgomery, G.W., Morrison, A., Myers, R.H., Nadukuru, R., Navarro, P., Nelis, M., Nieminen, M.S., Nolte, I.M., O'Connor, G.T., Ogunniyi, A., Padmanabhan, S., Palmas, W.R., Pankow, J.S., Patarcic, I., Pavani, F., Peyser, P.A., Pietilainen, K., Poulter, N., Prokopenko, I., Ralhan, S., Redmond, P., Rich, S.S., Rissanen, H., Robino, A., Rose, L.M., Rose, R., Sala, C., Salako, B., Salomaa, V., Sarin, A.-P., Saxena, R., Schmidt, H., Scott, L.J., Scott, W.R., Sennblad, B., Seshadri, S., Sever, P., Shrestha, S., Smith, B.H., Smith, J.A., Soranzo, N., Sotoodehnia, N., Southam, L., Stanton, A.V., Stathopoulou, M.G., Strauch, K., Strawbridge, R.J., Suderman, M.J., Tandon, N., Tang, S.-T., Taylor, K.D., Tayo, B.O., Töglhofer, A.M., Tomaszewski, M., Tšernikova, N., Tuomilehto, J., Uitterlinden, A.G., Vaidya, D., van Hylckama Vlieg, A., van Setten, J., Vasankari, T., Vedantam, S., Vlachopoulou, E., Vozzi, D., Vuoksimaa, E., Waldenberger, M., Ware, E.B., Wentworth-Shields, W., Whitfield, J.B., Wild, S., Willemsen, G., Yajnik, C.S., Yao, J., Zaza, G., Zhu, X., Project, T.B.J., Salem, R.M., Melbye, M., Bisgaard, H., Samani, N.J., Cusi, D., Mackey, D.A., Cooper, R.S., Froguel, P., Pasterkamp, G., Grant, S.F.A., Hakonarson, H., Ferrucci, L., Scott, R.A., Morris, A.D., Palmer, C.N.A., Dedoussis, G., Deloukas, P., Bertram, L., Lindenberger, U., Berndt, S.I., Lindgren, C.M., Timpson, N.J., Tönjes, A., Munroe, P.B., Sørensen, T.I.A., Rotimi, C.N., Arnett, D.K., Oldehinkel, A.J., Kardia, S.L.R., Balkau, B., Gambaro, G., Morris, A.P., Eriksson, J.G., Wright, M.J., Martin, N.G., Hunt, S.C., Starr, J.M., Deary, I.J., Griffiths, L.R., Tiemeier, H., Pirastu, N., Kaprio, J., Wareham, N.J., Pérusse, L., Wilson, J.G., Girotto, G., Caulfield, M.J., Raitakari, O., Boomsma, D.I., Gieger, C., van der Harst, P., Hicks, A.A., Kraft, P., Sinisalo, J., Knekt, P., Johannesson, M., Magnusson, P.K.E., Hamsten, A., Schmidt, R., Borecki, I.B., Vartiainen, E., Becker, D.M., Bharadwaj, D., Mohlke, K.L., Boehnke, M., van Duijn, C.M., Sanghera, D.K., Teumer, A., Zeggini, E., Metspalu, A., Gasparini, P., Ulivi, S., Ober, C., Toniolo, D., Rudan, I., Porteous, D.J., Ciullo, M., Spector, T.D., Hayward, C., Dupuis, J., Loos, R.J.F., Wright, A.F., Chandak, G.R., Vollenweider, P., Shuldiner, A., Ridker, P.M., Rotter, J.I., Sattar, N., Gyllensten, U., North, K.E., Pirastu, M., Psaty, B.M., Weir, D.R., Laakso, M., Gudnason, V., Takahashi, A., Chambers, J.C., Kooner, J.S., Strachan, D.P., Campbell, H., Hirschhorn, J.N., Perola, M., Polašek, O. and Wilson, J.F.
Abstract: Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
BibTeX:
@article{,
  author = {Joshi, Peter K. and Esko, Tonu and Mattsson, Hannele and Eklund, Niina and Gandin, Ilaria and Nutile, Teresa and Jackson, Anne U. and Schurmann, Claudia and Smith, Albert V. and Zhang, Weihua and Okada, Yukinori and Stančáková, Alena and Faul, Jessica D. and Zhao, Wei and Bartz, Traci M. and Concas, Maria Pina and Franceschini, Nora and Enroth, Stefan and Vitart, Veronique and Trompet, Stella and Guo, Xiuqing and Chasman, Daniel I. and O'Connel, Jeffery R. and Corre, Tanguy and Nongmaithem, Suraj S. and Chen, Yuning and Mangino, Massimo and Ruggiero, Daniela and Traglia, Michela and Farmaki, Aliki-Eleni and Kacprowski, Tim and Bjonnes, Andrew and van der Spek, Ashley and Wu, Ying and Giri, Anil K. and Yanek, Lisa R. and Wang, Lihua and Hofer, Edith and Rietveld, Cornelius A. and McLeod, Olga and Cornelis, Marilyn C. and Pattaro, Cristian and Verweij, Niek and Baumbach, Clemens and Abdellaoui, Abdel and Warren, Helen R. and Vuckovic, Dragana and Mei, Hao and Bouchard, Claude and Perry, John R B. and Cappellani, Stefania and Mirza, Saira S. and Benton, Miles C. and Broeckel, Ulrich and Medland, Sarah E. and Lind, Penelope A. and Malerba, Giovanni and Drong, Alexander and Yengo, Loic and Bielak, Lawrence F. and Zhi, Degui and van der Most, Peter J. and Shriner, Daniel and Mägi, Reedik and Hemani, Gibran and Karaderi, Tugce and Wang, Zhaoming and Liu, Tian and Demuth, Ilja and Zhao, Jing Hua and Meng, Weihua and Lataniotis, Lazaros and van der Laan, Sander W. and Bradfield, Jonathan P. and Wood, Andrew R. and Bonnefond, Amelie and Ahluwalia, Tarunveer S. and Hall, Leanne M. and Salvi, Erika and Yazar, Seyhan and Carstensen, Lisbeth and de Haan, Hugoline G. and Abney, Mark and Afzal, Uzma and Allison, Matthew A. and Amin, Najaf and Asselbergs, Folkert W. and Bakker, Stephan J L. and Barr, R Graham and Baumeister, Sebastian E. and Benjamin, Daniel J. and Bergmann, Sven and Boerwinkle, Eric and Bottinger, Erwin P. and Campbell, Archie and Chakravarti, Aravinda and Chan, Yingleong and Chanock, Stephen J. and Chen, Constance and Chen, Y-D Ida and Collins, Francis S. and Connell, John and Correa, Adolfo and Cupples, L Adrienne and Smith, George Davey and Davies, Gail and Dörr, Marcus and Ehret, Georg and Ellis, Stephen B. and Feenstra, Bjarke and Feitosa, Mary F. and Ford, Ian and Fox, Caroline S. and Frayling, Timothy M. and Friedrich, Nele and Geller, Frank and Scotland, Generation and Gillham-Nasenya, Irina and Gottesman, Omri and Graff, Misa and Grodstein, Francine and Gu, Charles and Haley, Chris and Hammond, Christopher J. and Harris, Sarah E. and Harris, Tamara B. and Hastie, Nicholas D. and Heard-Costa, Nancy L. and Heikkilä, Kauko and Hocking, Lynne J. and Homuth, Georg and Hottenga, Jouke-Jan and Huang, Jinyan and Huffman, Jennifer E. and Hysi, Pirro G. and Ikram, M Arfan and Ingelsson, Erik and Joensuu, Anni and Johansson, Åsa and Jousilahti, Pekka and Jukema, J Wouter and Kähönen, Mika and Kamatani, Yoichiro and Kanoni, Stavroula and Kerr, Shona M. and Khan, Nazir M. and Koellinger, Philipp and Koistinen, Heikki A. and Kooner, Manraj K. and Kubo, Michiaki and Kuusisto, Johanna and Lahti, Jari and Launer, Lenore J. and Lea, Rodney A. and Lehne, Benjamin and Lehtimäki, Terho and Liewald, David C M. and Lind, Lars and Loh, Marie and Lokki, Marja-Liisa and London, Stephanie J. and Loomis, Stephanie J. and Loukola, Anu and Lu, Yingchang and Lumley, Thomas and Lundqvist, Annamari and Männistö, Satu and Marques-Vidal, Pedro and Masciullo, Corrado and Matchan, Angela and Mathias, Rasika A. and Matsuda, Koichi and Meigs, James B. and Meisinger, Christa and Meitinger, Thomas and Menni, Cristina and Mentch, Frank D. and Mihailov, Evelin and Milani, Lili and Montasser, May E. and Montgomery, Grant W. and Morrison, Alanna and Myers, Richard H. and Nadukuru, Rajiv and Navarro, Pau and Nelis, Mari and Nieminen, Markku S. and Nolte, Ilja M. and O'Connor, George T. and Ogunniyi, Adesola and Padmanabhan, Sandosh and Palmas, Walter R. and Pankow, James S. and Patarcic, Inga and Pavani, Francesca and Peyser, Patricia A. and Pietilainen, Kirsi and Poulter, Neil and Prokopenko, Inga and Ralhan, Sarju and Redmond, Paul and Rich, Stephen S. and Rissanen, Harri and Robino, Antonietta and Rose, Lynda M. and Rose, Richard and Sala, Cinzia and Salako, Babatunde and Salomaa, Veikko and Sarin, Antti-Pekka and Saxena, Richa and Schmidt, Helena and Scott, Laura J. and Scott, William R. and Sennblad, Bengt and Seshadri, Sudha and Sever, Peter and Shrestha, Smeeta and Smith, Blair H. and Smith, Jennifer A. and Soranzo, Nicole and Sotoodehnia, Nona and Southam, Lorraine and Stanton, Alice V. and Stathopoulou, Maria G. and Strauch, Konstantin and Strawbridge, Rona J. and Suderman, Matthew J. and Tandon, Nikhil and Tang, Sian-Tsun and Taylor, Kent D. and Tayo, Bamidele O. and Töglhofer, Anna Maria and Tomaszewski, Maciej and Tšernikova, Natalia and Tuomilehto, Jaakko and Uitterlinden, Andre G. and Vaidya, Dhananjay and van Hylckama Vlieg, Astrid and van Setten, Jessica and Vasankari, Tuula and Vedantam, Sailaja and Vlachopoulou, Efthymia and Vozzi, Diego and Vuoksimaa, Eero and Waldenberger, Melanie and Ware, Erin B. and Wentworth-Shields, William and Whitfield, John B. and Wild, Sarah and Willemsen, Gonneke and Yajnik, Chittaranjan S. and Yao, Jie and Zaza, Gianluigi and Zhu, Xiaofeng and Project, The BioBank Japan and Salem, Rany M. and Melbye, Mads and Bisgaard, Hans and Samani, Nilesh J. and Cusi, Daniele and Mackey, David A. and Cooper, Richard S. and Froguel, Philippe and Pasterkamp, Gerard and Grant, Struan F A. and Hakonarson, Hakon and Ferrucci, Luigi and Scott, Robert A. and Morris, Andrew D. and Palmer, Colin N A. and Dedoussis, George and Deloukas, Panos and Bertram, Lars and Lindenberger, Ulman and Berndt, Sonja I. and Lindgren, Cecilia M. and Timpson, Nicholas J. and Tönjes, Anke and Munroe, Patricia B. and Sørensen, Thorkild I A. and Rotimi, Charles N. and Arnett, Donna K. and Oldehinkel, Albertine J. and Kardia, Sharon L R. and Balkau, Beverley and Gambaro, Giovanni and Morris, Andrew P. and Eriksson, Johan G. and Wright, Margie J. and Martin, Nicholas G. and Hunt, Steven C. and Starr, John M. and Deary, Ian J. and Griffiths, Lyn R. and Tiemeier, Henning and Pirastu, Nicola and Kaprio, Jaakko and Wareham, Nicholas J. and Pérusse, Louis and Wilson, James G. and Girotto, Giorgia and Caulfield, Mark J. and Raitakari, Olli and Boomsma, Dorret I. and Gieger, Christian and van der Harst, Pim and Hicks, Andrew A. and Kraft, Peter and Sinisalo, Juha and Knekt, Paul and Johannesson, Magnus and Magnusson, Patrik K E. and Hamsten, Anders and Schmidt, Reinhold and Borecki, Ingrid B. and Vartiainen, Erkki and Becker, Diane M. and Bharadwaj, Dwaipayan and Mohlke, Karen L. and Boehnke, Michael and van Duijn, Cornelia M. and Sanghera, Dharambir K. and Teumer, Alexander and Zeggini, Eleftheria and Metspalu, Andres and Gasparini, Paolo and Ulivi, Sheila and Ober, Carole and Toniolo, Daniela and Rudan, Igor and Porteous, David J. and Ciullo, Marina and Spector, Tim D. and Hayward, Caroline and Dupuis, Josée and Loos, Ruth J F. and Wright, Alan F. and Chandak, Giriraj R. and Vollenweider, Peter and Shuldiner, Alan and Ridker, Paul M. and Rotter, Jerome I. and Sattar, Naveed and Gyllensten, Ulf and North, Kari E. and Pirastu, Mario and Psaty, Bruce M. and Weir, David R. and Laakso, Markku and Gudnason, Vilmundur and Takahashi, Atsushi and Chambers, John C. and Kooner, Jaspal S. and Strachan, David P. and Campbell, Harry and Hirschhorn, Joel N. and Perola, Markus and Polašek, Ozren and Wilson, James F.},
  title = {Directional dominance on stature and cognition in diverse human populations.},
  journal = {Nature},
  school = {MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, EH4 2XU, Edinburgh, UK.},
  year = {2015},
  volume = {523},
  number = {7561},
  pages = {459--462},
  url = {http://dx.doi.org/10.1038/nature14618},
  doi = {https://doi.org/10.1038/nature14618}
}
Jelding-Dannemand, E. Bisgaard, H. Breast-feeding does not protect against allergic sensitization in early childhood and allergy-associated disease at age 7 years. 2015 J Allergy Clin Immunol 25843315 13,081 16
Authors:Jelding-Dannemand, E., Malby Schoos, A.-M. and Bisgaard, H.
Abstract: Extended breast-feeding is recommended for newborn children at risk of allergy-associated diseases, but the evidence of a protective effect on sensitization and these diseases remains elusive.The aim of this study was to investigate the effects of the duration of exclusive breast-feeding on the development of sensitization in preschool children.Information on breast-feeding was gathered by interviews involving 335 children aged 1, 6, and 12 months from the Copenhagen Prospective Study on Asthma in Childhood2000 birth cohort born to mothers with a history of asthma. Skin prick test responses and specific IgE levels against 12 common inhalant and 10 food allergens were assessed longitudinally at ages ½ year, 1½ years, 4 years, and 6 years. Eczema, wheeze/asthma, and allergic rhinitis were diagnosed at the Copenhagen Prospective Studies on Asthma in Childhood clinic at 7 years of age, strictly adhering to predefined algorithms. Associations between duration of exclusive breast-feeding and outcomes were analyzed by logistic regression.We found no significant association between duration of exclusive breast-feeding and development of sensitization in the first 6 years of life (odds ratio [OR]: ½ year, 1.10 [95% CI, 0.90-1.36]; 1½ years, 1.15 [95% CI, 0.97-1.36]; 4 years, 1.08 [95% CI, 0.93-1.25]; and 6 years, 0.96 [95% CI, 0.84-1.10]) or with current eczema, wheeze/asthma, and allergic rhinitis at age 7 years (OR, 1.07 [95% CI, 0.92-1.24]; OR, 0.97 [95% CI, 0.82-1.14]; and OR, 1.02 [95% CI, 0.84-1.23], respectively). Adjusting for reverse causation by excluding children with eczema, wheeze, or a positive skin prick test response before ending exclusive breast-feeding did not alter the results.Exclusive breast-feeding does not affect sensitization in early childhood or associated diseases at 7 years of age in at-risk children.
BibTeX:
@article{,
  author = {Jelding-Dannemand, Ea and Malby Schoos, Ann-Marie and Bisgaard, Hans},
  title = {Breast-feeding does not protect against allergic sensitization in early childhood and allergy-associated disease at age 7 years.},
  journal = {J Allergy Clin Immunol},
  school = { Danish Pediatric Asthma Center, Gentofte Hospital, University of Copenhagen, Gentofte, Denmark. Electronic address: bisgaard@copsac.com.},
  year = {2015},
  volume = {136},
  number = {5},
  pages = {1302--8.e1-13},
  url = {http://dx.doi.org/10.1016/j.jaci.2015.02.023},
  doi = {https://doi.org/10.1016/j.jaci.2015.02.023}
}
Kreiner-Møller, E. Bønnelykke, K. 17q21 gene variation is not associated with asthma in adulthood. 2015 Allergy 25331618 7,361 4
Authors: Kreiner-Møller, E., Strachan, D.P., Linneberg, A., Husemoen, L.L.N., Bisgaard, H. and Bønnelykke, K.
Abstract: 17q21 gene variants are the strongest known genetic determinants for childhood asthma and have been reported to interact with environmental tobacco smoke exposure in childhood. It remains unclear whether individuals with 17q21 risk variants have increased risk of asthma or reduced lung function in adulthood. The aim was to examine the association between the 17q21 region and current adult asthma and lung function, and interaction with active smoking.We investigated the single nucleotide polymorphism rs7216389 at the 17q21 locus in 3471 adults from the Health2006 cross-sectional study and in 7008 adults from The British 1958 Birth Cohort and examined the association with current asthma, spirometry measures, and related atopic traits. Analyses were performed for interaction with active smoking.We found no association between rs7216389[T] and asthma when meta-analyzed (OR = 1.02 [0.92-1.13], P = 0.81). The risk variant was associated with reduced FEV1 as compared to normal FEV1 (OR = 1.10 [1.01-1.12], P = 0.033) and with allergic sensitization (OR = 1.10 [1.03-1.17], P = 0.003). Individuals with rs7216389 risk variants smoked as frequently as individuals without risk variants, and there was no evidence that smoking modified the association between rs7216389 and asthma.Our study suggests that the 17q21 rs7216389 locus variant does not substantially influence asthma risk in adulthood or susceptibility to detrimental effects of active smoking. This contrasts the findings in children and suggests that this locus is associated with a childhood-specific asthma endotype.
BibTeX:
@article{,
  author = {Kreiner-Møller, E. and Strachan, D. P. and Linneberg, A. and Husemoen, L L N. and Bisgaard, H. and Bønnelykke, K.},
  title = {17q21 gene variation is not associated with asthma in adulthood.},
  journal = {Allergy},
  school = {COPSAC, The Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; The Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark.},
  year = {2015},
  volume = {70},
  number = {1},
  pages = {107--114},
  url = {http://dx.doi.org/10.1111/all.12537},
  doi = {https://doi.org/10.1111/all.12537}
}
Govoni, M. Bisgaard, H. The systemic exposure to inhaled beclometasone/formoterol pMDI with valved holding chamber is independent of age and body size. 2015 Pulm Pharmacol Ther 24746942 2,525 4
Authors: Govoni, M., Piccinno, A., Lucci, G., Poli, G., Acerbi, D., Baronio, R., Singh, D., Kuna, P., Chawes, B.L.K. and Bisgaard, H.
Abstract: Asthma guidelines recommend prescription of inhaled corticosteroids at a reduced dosage in children compared to older patients in order to minimize the systemic exposure and risk of unwanted side effects. In children, pressurized metered dose inhalers (pMDI) are recommended in combination with a valved holding chamber (VHC) to overcome the problem of coordinating inhalation with actuation. However, the influence of age and body size on the systemic exposure of drugs to be administered via a pMDI with VHC is still not fully elucidated. Therefore, we aimed to compare the systemic exposure to the active ingredients of a fixed combination of beclometasone-dipropionate/formoterol-fumarate administered via pMDI with VHC in children, adolescents and adults.The pharmacokinetics of formoterol and beclometasone-17-monopropionate (active metabolite of beclometasone-dipropionate) was evaluated over 8 h from three studies, each performed in a different age and body size group. Children (7-11 years, n = 20), adolescents (12-17 years, n = 29) and adults (≥18 years, n = 24) received a single dose of beclometasone/formoterol (children: 200 μg/24 μg, adolescents and adults: 400 μg/24 μg) via pMDI with AeroChamber Plus™.The systemic exposure in children in comparison to adolescents was equivalent for formoterol while it was halved for beclometasone-17-monopropionate in accordance with the halved dose of beclometasone administered in children (90% CIs within 0.8-1.25 for formoterol and 0.4-0.625 for beclometasone-17-monopropionate). The systemic exposure to beclometasone-17-monopropionate and formoterol was equivalent between adolescents and adults.The systemic exposure to the active ingredients of a fixed dose combination of beclometasone/formoterol administered via pMDI with AeroChamber Plus™ correlates with the nominal dose independently of patient age and body size. Thus, dose reduction in relation to age when using a pMDI with VHC may be unnecessary for reducing the systemic exposure in children.
BibTeX:
@article{,
  author = {Govoni, Mirco and Piccinno, Annalisa and Lucci, Germano and Poli, Gianluigi and Acerbi, Daniela and Baronio, Roberta and Singh, Dave and Kuna, Piotr and Chawes, Bo L K. and Bisgaard, Hans},
  title = {The systemic exposure to inhaled beclometasone/formoterol pMDI with valved holding chamber is independent of age and body size.},
  journal = {Pulm Pharmacol Ther},
  school = { Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark.},
  year = {2015},
  volume = {30},
  pages = {102--109},
  url = {http://dx.doi.org/10.1016/j.pupt.2014.04.003},
  doi = {https://doi.org/10.1016/j.pupt.2014.04.003}
}
Fleming, L. Roberts, G. The burden of severe asthma in childhood and adolescence: results from the paediatric U-BIOPRED cohorts. 2015 Eur Respir J 26405287 10,569 33
Authors: Fleming, L., Murray, C., Bansal, A.T., Hashimoto, S., Bisgaard, H., Bush, A., Frey, U., Hedlin, G., Singer, F., van Aalderen, W.M., Vissing, N.H., Zolkipli, Z., Selby, A., Fowler, S., Shaw, D., Chung, K.F., Sousa, A.R., Wagers, S., Corfield, J., Pandis, I., Rowe, A., Formaggio, E., Sterk, P.J., Roberts, G. and , U.-B.I.O.P.R.E.D.S.G.
Abstract: U-BIOPRED aims to characterise paediatric and adult severe asthma using conventional and innovative systems biology approaches. A total of 99 school-age children with severe asthma and 81 preschoolers with severe wheeze were compared with 49 school-age children with mild/moderate asthma and 53 preschoolers with mild/moderate wheeze in a cross-sectional study. Despite high-dose treatment, the severe cohorts had more severe exacerbations compared with the mild/moderate ones (annual medians: school-aged 3.0 versus 1.1, preschool 3.9 versus 1.8; p<0.001). Exhaled tobacco exposure was common in the severe wheeze cohort. Almost all participants in each cohort were atopic and had a normal body mass index. Asthma-related quality of life, as assessed by the Paediatric Asthma Quality of Life Questionnaire (PAQLQ) and the Paediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ), was worse in the severe cohorts (mean±se school-age PAQLQ: 4.77±0.15 versus 5.80±0.19; preschool PACQLQ: 4.27±0.18 versus 6.04±0.18; both p≤0.001); however, mild/moderate cohorts also had significant morbidity. Impaired quality of life was associated with poor control and airway obstruction. Otherwise, the severe and mild/moderate cohorts were clinically very similar. Children with severe preschool wheeze or severe asthma are usually atopic and have impaired quality of life that is associated with poor control and airflow limitation: a very different phenotype from adult severe asthma. In-depth phenotyping of these children, integrating clinical data with high-dimensional biomarkers, may help to improve and tailor their clinical management.
BibTeX:
@article{,
  author = {Fleming, Louise and Murray, Clare and Bansal, Aruna T. and Hashimoto, Simone and Bisgaard, Hans and Bush, Andrew and Frey, Urs and Hedlin, Gunilla and Singer, Florian and van Aalderen, Wim M. and Vissing, Nadja H. and Zolkipli, Zaraquiza and Selby, Anna and Fowler, Stephen and Shaw, Dominick and Chung, Kian Fan and Sousa, Ana R. and Wagers, Scott and Corfield, Julie and Pandis, Ioannis and Rowe, Anthony and Formaggio, Elena and Sterk, Peter J. and Roberts, Graham and , U-B. I. O. P. R. E. D Study Group},
  title = {The burden of severe asthma in childhood and adolescence: results from the paediatric U-BIOPRED cohorts.},
  journal = {Eur Respir J},
  school = {NIHR Southampton Respiratory Biomedical Research Unit, Clinical and Experimental Sciences and Human Development and Health, Southampton, UK Faculty of Medicine, University of Southampton, Southampton, UK The David Hide Asthma and Allergy Research Centre, St Mary's Hospital, Isle of Wight, UK g.c.roberts@soton.ac.uk.},
  year = {2015},
  volume = {46},
  number = {5},
  pages = {1322--1333},
  url = {http://dx.doi.org/10.1183/13993003.00780-2015},
  doi = {https://doi.org/10.1183/13993003.00780-2015}
}
Chawes, B.L.K. Bisgaard, H. Neonates with reduced neonatal lung function have systemic low-grade inflammation. 2015 J Allergy Clin Immunol 25579483 13,081 10
Authors: Chawes, B.L.K., Stokholm, J., Bønnelykke, K., Brix, S. and Bisgaard, H.
Abstract: Children and adults with asthma and impaired lung function have been reported to have low-grade systemic inflammation, but it is unknown whether this inflammation starts before symptoms and in particular whether low-grade inflammation is present in asymptomatic neonates with reduced lung function.We sought to investigate the possible association between neonatal lung function and biomarkers of systemic inflammation.Plasma levels of high-sensitivity C-reactive protein (hs-CRP), IL-1β, IL-6, TNF-α, and CXCL8 (IL-8) were measured at age 6 months in 300 children of the Copenhagen Prospective Study on Asthma in Childhood2000 birth cohort who had completed neonatal lung function testing at age 4 weeks. Associations between neonatal lung function indices and inflammatory biomarkers were investigated by conventional statistics and unsupervised principal component analysis.The neonatal forced expiratory volume at 0.5 seconds was inversely associated with hs-CRP (β-coefficient, -0.12; 95% CI, -0.21 to -0.04; P < .01) and IL-6 (β-coefficient, -0.10; 95% CI, -0.18 to -0.01; P = .03) levels. The multivariate principal component analysis approach, including hs-CRP, IL-6, TNF-α, and CXCL8, confirmed a uniform upregulated inflammatory profile in children with reduced forced expiratory volume at 0.5 seconds (P = .02). Adjusting for body mass index at birth, maternal smoking, older children in the home, neonatal bacterial airway colonization, infections 14 days before, and asthmatic symptoms, as well as virus-induced wheezing, at any time before biomarker assessment at age 6 months did not affect the associations.Diminished neonatal lung function is associated with upregulated systemic inflammatory markers, such as hs-CRP.
BibTeX:
@article{,
  author = {Chawes, Bo L K. and Stokholm, Jakob and Bønnelykke, Klaus and Brix, Susanne and Bisgaard, Hans},
  title = {Neonates with reduced neonatal lung function have systemic low-grade inflammation.},
  journal = {J Allergy Clin Immunol},
  school = { Danish Pediatric Asthma Center, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. Electronic address: bisgaard@copsac.com.},
  year = {2015},
  volume = {135},
  number = {6},
  pages = {1450--6.e1},
  url = {http://dx.doi.org/10.1016/j.jaci.2014.11.020},
  doi = {https://doi.org/10.1016/j.jaci.2014.11.020}
}
Chawes, B.L.K. Bisgaard, H. DENND1B gene variants associate with elevated exhaled nitric oxide in healthy high-risk neonates. 2015 Pediatr Pulmonol 24347560 2,758 5
Authors: Chawes, B.L.K., Bischoff, A.L., Kreiner-Møller, E., Buchvald, F., Hakonarson, H. and Bisgaard, H.
Abstract: Increased neonatal fraction of exhaled nitric oxide (FeNO) is associated with lung symptoms early in life, while predictors of neonatal FeNO levels are unknown. The objective of this study was to investigate perinatal and genetic predictors of FeNO in healthy at-risk neonates.FeNO was measured during sedation by single-breath and tidal-breathing techniques in 253 one-month-old neonates from the Copenhagen Prospective Study on Asthma in Childhood (COPSAC2000 ) birth cohort. The risk factor analyses included genetic variants in DENND1B, Filaggrin, and ORMDL3; anthropometrics; demographics; socioeconomics; paternal atopy; maternal smoking, and mother's consumption of paracetamol and antibiotics during 3rd trimester; and neonatal bacterial airway colonization.FeNO values measured by the single-breath versus tidal-breathing technique yielded slightly higher values (median, 21.0 ppb; range, 2.0-74.0 ppb vs. 16.0 ppb; 1.0-67.0 ppb; P<0.0001) with increasing differences conditional on increasing FeNO values (P<0.0001). The multivariable analysis including all risk factors showed that the DENND1B rs2786098 C allele was associated with increasing levels of FeNO (additive model; +2.30 ppb per C allele; 95% CI, 0.10-5.00 ppb; P=0.04) and that children of atopic fathers had elevated FeNO (+2.90 ppb; 95% CI, 0.38-5.43 ppb; P=0.02). We did not detect association between the remaining risk factors and neonatal FeNO levels.Increased FeNO in healthy newborns seems strongly influenced by genetics including father's atopy and child's variants in the DENND1B locus at chromosome 1q31.3.
BibTeX:
@article{,
  author = {Chawes, Bo L K. and Bischoff, Anne Louise and Kreiner-Møller, Eskil and Buchvald, Frederik and Hakonarson, Hakon and Bisgaard, Hans},
  title = {DENND1B gene variants associate with elevated exhaled nitric oxide in healthy high-risk neonates.},
  journal = {Pediatr Pulmonol},
  school = {Copenhagen Prospective Studies on Asthma in Childhood; COPSAC, Health Sciences, University of Copenhagen, Copenhagen University Hospital, Gentofte, Ledreborg Allé 34, Gentofte, 2820, Copenhagen, Denmark.},
  year = {2015},
  volume = {50},
  number = {2},
  pages = {109--117},
  url = {http://dx.doi.org/10.1002/ppul.22958},
  doi = {https://doi.org/10.1002/ppul.22958}
}
Carlsson, C.J. Bisgaard, H. Duration of wheezy episodes in early childhood is independent of the microbial trigger. 2015 J Allergy Clin Immunol 26100088 13,081 10
Authors: Carlsson, C.J., Vissing, N.H., Sevelsted, A., Johnston, S.L., Bønnelykke, K. and Bisgaard, H.
Abstract: Wheezy episodes in young children are often triggered by viral and bacterial respiratory tract infections, but there is little evidence supporting the hypothesis that symptom duration depends on the specific microbial trigger.We sought to investigate whether the duration of wheezy episodes in young children depends on the microbial trigger.Two hundred eighty-three children from the Copenhagen Prospective Study on Asthma in Childhood2000 at-risk birth cohort were prospectively examined for common airway pathogenic bacteria and viruses during acute wheezy episodes in the first 3 years of life. Findings were related to symptomatic duration of episodes, as monitored in daily diary cards from birth.Eight hundred thirty-seven samples were investigated for viruses, bacteria, or both. Both viruses and bacteria were identified in 55% of episodes, bacteria were identified exclusively in 31% of episodes, and viruses were identified exclusively in 10% of episodes. The median duration of acute symptoms was 9 days (interquartile range, 5-16 days), and duration was independent of bacterial or viral species.The duration of wheezy episodes was independent of pathogenic airway bacterial or viral species. This suggests that symptom burden from infections is dependent on other factors, such as environmental exposures or host factors. The common term viral wheeze seems inappropriate in view of the finding of pathogenic bacteria in 86% of wheezy episodes.
BibTeX:
@article{,
  author = {Carlsson, Christian J. and Vissing, Nadja H. and Sevelsted, Astrid and Johnston, Sebastian L. and Bønnelykke, Klaus and Bisgaard, Hans},
  title = {Duration of wheezy episodes in early childhood is independent of the microbial trigger.},
  journal = {J Allergy Clin Immunol},
  school = {COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. Electronic address: bisgaard@copsac.com.},
  year = {2015},
  volume = {136},
  number = {5},
  pages = {1208--14.e1-5},
  url = {http://dx.doi.org/10.1016/j.jaci.2015.05.003},
  doi = {https://doi.org/10.1016/j.jaci.2015.05.003}
}
Brix, S. Bisgaard, H. Metagenomic heterogeneity explains dual immune effects of endotoxins. 2015 J Allergy Clin Immunol 25445821 13,081 11
Authors: Brix, S., Eriksen, C., Larsen, J.M. and Bisgaard, H.
BibTeX:
@article{,
  author = {Brix, Susanne and Eriksen, Carsten and Larsen, Jeppe Madura and Bisgaard, Hans},
  title = {Metagenomic heterogeneity explains dual immune effects of endotoxins.},
  journal = {J Allergy Clin Immunol},
  school = {Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Copenhagen University, and the Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark.},
  year = {2015},
  volume = {135},
  number = {1},
  pages = {277--280},
  url = {http://dx.doi.org/10.1016/j.jaci.2014.09.036},
  doi = {https://doi.org/10.1016/j.jaci.2014.09.036}
}
Bønnelykke, K. Bisgaard, H. A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations. 2014 Nat Genet 24241537 27,959 144
Authors: Bønnelykke, K., Sleiman, P., Nielsen, K., Kreiner-Møller, E., Mercader, J.M., Belgrave, D., den Dekker, H.T., Husby, A., Sevelsted, A., Faura-Tellez, G., Mortensen, L.J., Paternoster, L., Flaaten, R., Mølgaard, A., Smart, D.E., Thomsen, P.F., Rasmussen, M.A., Bonàs-Guarch, S., Holst, C., Nohr, E.A., Yadav, R., March, M.E., Blicher, T., Lackie, P.M., Jaddoe, V.W.V., Simpson, A., Holloway, J.W., Duijts, L., Custovic, A., Davies, D.E., Torrents, D., Gupta, R., Hollegaard, M.V., Hougaard, D.M., Hakonarson, H. and Bisgaard, H.
BibTeX:
@article{,
  author = {Bønnelykke, Klaus and Sleiman, Patrick and Nielsen, Kasper and Kreiner-Møller, Eskil and Mercader, Josep M. and Belgrave, Danielle and den Dekker, Herman T. and Husby, Anders and Sevelsted, Astrid and Faura-Tellez, Grissel and Mortensen, Li Juel and Paternoster, Lavinia and Flaaten, Richard and Mølgaard, Anne and Smart, David E. and Thomsen, Philip F. and Rasmussen, Morten A. and Bonàs-Guarch, Silvia and Holst, Claus and Nohr, Ellen A. and Yadav, Rachita and March, Michael E. and Blicher, Thomas and Lackie, Peter M. and Jaddoe, Vincent W V. and Simpson, Angela and Holloway, John W. and Duijts, Liesbeth and Custovic, Adnan and Davies, Donna E. and Torrents, David and Gupta, Ramneek and Hollegaard, Mads V. and Hougaard, David M. and Hakonarson, Hakon and Bisgaard, Hans},
  title = {A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations.},
  journal = {Nat Genet},
  school = { Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark. [2].},
  year = {2014},
  volume = {46},
  number = {1},
  pages = {51--55},
  url = {http://dx.doi.org/10.1038/ng.2830},
  doi = {https://doi.org/10.1038/ng.2830}
}
Stokholm, J. Bisgaard, H. Antibiotic use during pregnancy alters the commensal vaginal microbiota. 2014 Clin Microbiol Infect 24118384 5,292 33
Authors: Stokholm, J., Schjørring, S., Eskildsen, C.E., Pedersen, L., Bischoff, A.L., Følsgaard, N., Carson, C.G., Chawes, B.L.K., Bønnelykke, K., Mølgaard, A., Jacobsson, B., Krogfelt, K.A. and Bisgaard, H.
Abstract: Antibiotics may induce alterations in the commensal microbiota of the birth canal in pregnant women. Therefore, we studied the effect of antibiotic administration during pregnancy on commensal vaginal bacterial colonization at gestational week 36. Six hundred and sixty-eight pregnant women from the novel unselected Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010 ) pregnancy cohort participated in this analysis. Detailed information on oral antibiotic prescriptions during pregnancy filled at the pharmacy was obtained and verified prospectively. Vaginal samples were obtained at pregnancy week 36 and cultured for bacteria. Women who received oral antibiotics during any pregnancy trimester had an increased rate of colonization by Staphylococcus species in the vaginal samples as compared with samples obtained from women without any antibiotic treatment during pregnancy (adjusted OR 1.63, 95% CI 1.06-2.52, p 0.028). Oral antibiotic administration in the third trimester were also associated with increased colonization by Staphylococcus species (adjusted OR 1.98, 95% CI 1.04-3.76, p 0.037). These bacteriological changes were associated with urinary tract infection antibiotics. Women treated in the third trimester of pregnancy were more often colonized by Escherichia coli than women without antibiotic treatment in the third trimester (adjusted OR 1.91, 95% CI 1.04-3.52, p 0.038). This change was associated with respiratory tract infection (RTI) antibiotics. We did not observe any significant changes in vaginal Streptococcus agalactiae (group B streptoccocus) or Staphylococcus aureus colonization following antibiotic treatment in pregnancy. Antibiotic administration during pregnancy leads to alterations in the vaginal microbiological ecology prior to birth, with potential morbidity, and long-term effects on the early microbial colonization of the neonate.
BibTeX:
@article{,
  author = {Stokholm, J. and Schjørring, S. and Eskildsen, C. E. and Pedersen, L. and Bischoff, A. L. and Følsgaard, N. and Carson, C. G. and Chawes, B L K. and Bønnelykke, K. and Mølgaard, A. and Jacobsson, B. and Krogfelt, K. A. and Bisgaard, H.},
  title = {Antibiotic use during pregnancy alters the commensal vaginal microbiota.},
  journal = {Clin Microbiol Infect},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen, Naestved Hospital, Naestved, Denmark; Department of Food Science, Faculty of Life Sciences, University of Copenhagen, Copenhagen, Denmark.},
  year = {2014},
  volume = {20},
  number = {7},
  pages = {629--635},
  url = {http://dx.doi.org/10.1111/1469-0691.12411},
  doi = {https://doi.org/10.1111/1469-0691.12411}
}
Sonnenschein-van der Voort, A.M.M. Duijts, L. Preterm birth, infant weight gain, and childhood asthma risk: a meta-analysis of 147,000 European children. 2014 J Allergy Clin Immunol 24529685 13,081 26
Authors: Sonnenschein-van der Voort, A.M.M., Arends, L.R., de Jongste, J.C., Annesi-Maesano, I., Arshad, S.H., Barros, H., Basterrechea, M., Bisgaard, H., Chatzi, L., Corpeleijn, E., Correia, S., Craig, L.C., Devereux, G., Dogaru, C., Dostal, M., Duchen, K., Eggesbø, M., van der Ent, C.K., Fantini, M.P., Forastiere, F., Frey, U., Gehring, U., Gori, D., van der Gugten, A.C., Hanke, W., Henderson, A.J., Heude, B., Iñiguez, C., Inskip, H.M., Keil, T., Kelleher, C.C., Kogevinas, M., Kreiner-Møller, E., Kuehni, C.E., Küpers, L.K., Lancz, K., Larsen, P.S., Lau, S., Ludvigsson, J., Mommers, M., Nybo Andersen, A.-M., Palkovicova, L., Pike, K.C., Pizzi, C., Polanska, K., Porta, D., Richiardi, L., Roberts, G., Schmidt, A., Sram, R.J., Sunyer, J., Thijs, C., Torrent, M., Viljoen, K., Wijga, A.H., Vrijheid, M., Jaddoe, V.W.V. and Duijts, L.
Abstract: Preterm birth, low birth weight, and infant catch-up growth seem associated with an increased risk of respiratory diseases in later life, but individual studies showed conflicting results.We performed an individual participant data meta-analysis for 147,252 children of 31 birth cohort studies to determine the associations of birth and infant growth characteristics with the risks of preschool wheezing (1-4 years) and school-age asthma (5-10 years).First, we performed an adjusted 1-stage random-effect meta-analysis to assess the combined associations of gestational age, birth weight, and infant weight gain with childhood asthma. Second, we performed an adjusted 2-stage random-effect meta-analysis to assess the associations of preterm birth (gestational age <37 weeks) and low birth weight (<2500 g) with childhood asthma outcomes.Younger gestational age at birth and higher infant weight gain were independently associated with higher risks of preschool wheezing and school-age asthma (P < .05). The inverse associations of birth weight with childhood asthma were explained by gestational age at birth. Compared with term-born children with normal infant weight gain, we observed the highest risks of school-age asthma in children born preterm with high infant weight gain (odds ratio [OR], 4.47; 95% CI, 2.58-7.76). Preterm birth was positively associated with an increased risk of preschool wheezing (pooled odds ratio [pOR], 1.34; 95% CI, 1.25-1.43) and school-age asthma (pOR, 1.40; 95% CI, 1.18-1.67) independent of birth weight. Weaker effect estimates were observed for the associations of low birth weight adjusted for gestational age at birth with preschool wheezing (pOR, 1.10; 95% CI, 1.00-1.21) and school-age asthma (pOR, 1.13; 95% CI, 1.01-1.27).Younger gestational age at birth and higher infant weight gain were associated with childhood asthma outcomes. The associations of lower birth weight with childhood asthma were largely explained by gestational age at birth.
BibTeX:
@article{,
  author = {Sonnenschein-van der Voort, Agnes M M. and Arends, Lidia R. and de Jongste, Johan C. and Annesi-Maesano, Isabella and Arshad, S Hasan and Barros, Henrique and Basterrechea, Mikel and Bisgaard, Hans and Chatzi, Leda and Corpeleijn, Eva and Correia, Sofia and Craig, Leone C. and Devereux, Graham and Dogaru, Cristian and Dostal, Miroslav and Duchen, Karel and Eggesbø, Merete and van der Ent, C Kors and Fantini, Maria P. and Forastiere, Francesco and Frey, Urs and Gehring, Ulrike and Gori, Davide and van der Gugten, Anne C. and Hanke, Wojciech and Henderson, A John and Heude, Barbara and Iñiguez, Carmen and Inskip, Hazel M. and Keil, Thomas and Kelleher, Cecily C. and Kogevinas, Manolis and Kreiner-Møller, Eskil and Kuehni, Claudia E. and Küpers, Leanne K. and Lancz, Kinga and Larsen, Pernille S. and Lau, Susanne and Ludvigsson, Johnny and Mommers, Monique and Nybo Andersen, Anne-Marie and Palkovicova, Lubica and Pike, Katharine C. and Pizzi, Costanza and Polanska, Kinga and Porta, Daniela and Richiardi, Lorenzo and Roberts, Graham and Schmidt, Anne and Sram, Radim J. and Sunyer, Jordi and Thijs, Carel and Torrent, Maties and Viljoen, Karien and Wijga, Alet H. and Vrijheid, Martine and Jaddoe, Vincent W V. and Duijts, Liesbeth},
  title = {Preterm birth, infant weight gain, and childhood asthma risk: a meta-analysis of 147,000 European children.},
  journal = {J Allergy Clin Immunol},
  school = {Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Paediatrics, Division of Respiratory Medicine, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Paediatrics, Division of Neonatology, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address: l.duijts@erasmusmc.nl.},
  year = {2014},
  volume = {133},
  number = {5},
  pages = {1317--1329},
  url = {http://dx.doi.org/10.1016/j.jaci.2013.12.1082},
  doi = {https://doi.org/10.1016/j.jaci.2013.12.1082}
}
van der Valk, R.J. de Jongste, J.C. Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants. 2014 J Allergy Clin Immunol 24315451 13,081 18
Authors: van der Valk, R.J., Duijts, L., Timpson, N.J., Salam, M.T., Standl, M., Curtin, J.A., Genuneit, J., Kerhof, M., Kreiner-Møller, E., Cáceres, A., Gref, A., Liang, L.L., Taal, H.R., Bouzigon, E., Demenais, F., Nadif, R., Ober, C., Thompson, E.E., Estrada, K., Hofman, A., Uitterlinden, A.G., van Duijn, C., Rivadeneira, F., Li, X., Eckel, S.P., Berhane, K., Gauderman, W.J., Granell, R., Evans, D.M., St Pourcain, B., McArdle, W., Kemp, J.P., Smith, G.D., Tiesler, C.M., Flexeder, C., Simpson, A., Murray, C.S., Fuchs, O., Postma, D.S., Bønnelykke, K., Torrent, M., Andersson, M., Sleiman, P., Hakonarson, H., Cookson, W.O., Moffatt, M.F., Paternoster, L., Melén, E., Sunyer, J., Bisgaard, H., Koppelman, G.H., Ege, M., Custovic, A., Heinrich, J., Gilliland, F.D., Henderson, A.J., Jaddoe, V.W., de Jongste, J.C. and , E.A.G.&.L.E.(E.A.G.L.E.C.
Abstract: The fraction of exhaled nitric oxide (Feno) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants associated with childhood Feno values might help to define biological mechanisms related to specific asthma phenotypes.We sought to identify the genetic variants associated with childhood Feno values and their relation with asthma.Feno values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with Feno values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110).We identified 3 SNPs associated with Feno values: rs3751972 in LYR motif containing 9 (LYRM9; P = 1.97 × 10(-10)) and rs944722 in inducible nitric oxide synthase 2 (NOS2; P = 1.28 × 10(-9)), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB; P = 1.88 × 10(-8)) at 17q12-q21. We found a cis expression quantitative trait locus for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. rs8069176 at 17q12-q21, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma.This study identified 3 variants associated with Feno values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of Feno values. This study highlights that both shared and distinct genetic factors affect Feno values and childhood asthma.
BibTeX:
@article{,
  author = {van der Valk, Ralf Jp and Duijts, Liesbeth and Timpson, Nicolas J. and Salam, Muhammad T. and Standl, Marie and Curtin, John A. and Genuneit, Jon and Kerhof, Marjan and Kreiner-Møller, Eskil and Cáceres, Alejandro and Gref, Anna and Liang, Liming L. and Taal, H Rob and Bouzigon, Emmanuelle and Demenais, Florence and Nadif, Rachel and Ober, Carole and Thompson, Emma E. and Estrada, Karol and Hofman, Albert and Uitterlinden, André G. and van Duijn, Cornélia and Rivadeneira, Fernando and Li, Xia and Eckel, Sandrah P. and Berhane, Kiros and Gauderman, W James and Granell, Raquel and Evans, David M. and St Pourcain, Beate and McArdle, Wendy and Kemp, John P. and Smith, George Davey and Tiesler, Carla Mt and Flexeder, Claudia and Simpson, Angela and Murray, Clare S. and Fuchs, Oliver and Postma, Dirkje S. and Bønnelykke, Klaus and Torrent, Maties and Andersson, Martin and Sleiman, Patrick and Hakonarson, Hakon and Cookson, William O. and Moffatt, Miriam F. and Paternoster, Lavinia and Melén, Erik and Sunyer, Jordi and Bisgaard, Hans and Koppelman, Gerard H. and Ege, Markus and Custovic, Adnan and Heinrich, Joachim and Gilliland, Frank D. and Henderson, Alexander J. and Jaddoe, Vincent Wv and de Jongste, Johan C. and , E. Arly Genetics & Lifecourse Epidemiology (E. A. G. L. E) Consortium},
  title = {Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants.},
  journal = {J Allergy Clin Immunol},
  school = {Department of Pediatrics, Erasmus Medical Center, Rotterdam, The Netherlands.},
  year = {2014},
  volume = {134},
  number = {1},
  pages = {46--55}
}
Stokholm, J. Bisgaard, H. Maternal propensity for infections and risk of childhood asthma: a registry-based cohort study. 2014 Lancet Respir Med 25066330 19,287 24
Authors: Stokholm, J., Sevelsted, A., Bønnelykke, K. and Bisgaard, H.
Abstract: Maternal use of antibiotics during pregnancy has been associated with the development of asthmatic disorders in the offspring. The human microbiome has been suggested to act as an intermediary in this process. To provide clarification on this theory, we studied the temporal relation between maternal use of antibiotics and the risk of childhood asthma.According to national registries, during the observation period (1997-2010), 910,301 children were born in Denmark and were included in the analysis. From these registries, data for cases of childhood asthma were obtained based on hospital admissions, outpatient attendance at a hospital, or use of inhaled corticosteroids. The effect of timing of maternal antibiotic use on the risk of asthma in the offspring was studied by analysis of maternal antibiotic use in the 80 weeks before pregnancy, during pregnancy, and the 80 weeks after pregnancy. Results were adjusted for age and calendar year, birthweight, gestational age, sex, mode of delivery, parity, multiple births, season of birth, and several maternal factors (age, smoking during pregnancy, employment status, and asthma).In this study, we replicated our previous finding that maternal use of antibiotics in pregnancy was associated with an increased risk of childhood asthma: the adjusted incidence rate ratio (aIRR) was 1·24 (95% CI 1·18-1·30) for inpatient admission, 1·22 (1·18-1·26) for outpatient attendance, and 1·18 (1·15-1·20) for inhaled corticosteroid use. A similar and independent association was also recorded for maternal antibiotic use in the 80 weeks before and after the pregnancy. A dose-related association occurred between the risk of childhood asthma and the number of maternal antibiotic treatments and was recorded separately for antibiotic treatment for respiratory tract infections and for other types of infections.Maternal use of antibiotics has a dose-related association with the risk of asthma in the offspring, but this association is independent of the temporal relationship with the pregnancy period. This finding suggests that maternal antibiotic use is a surrogate marker of a mother's general propensity for infections as the underlying link between a mother's use of antibiotics and risk of asthma in the offspring.The Danish Council for Strategic Research, The Lundbeck Foundation, The Pharmacy Foundation of 1991, the Danish Medical Research Council, and National Finance Act.
BibTeX:
@article{,
  author = {Stokholm, Jakob and Sevelsted, Astrid and Bønnelykke, Klaus and Bisgaard, Hans},
  title = {Maternal propensity for infections and risk of childhood asthma: a registry-based cohort study.},
  journal = {Lancet Respir Med},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen, Gentofte, Denmark; The Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark. Electronic address: bisgaard@copsac.com.},
  year = {2014},
  volume = {2},
  number = {8},
  pages = {631--637},
  url = {http://dx.doi.org/10.1016/S2213-2600(14)70152-3},
  doi = {https://doi.org/10.1016/S2213-2600(14)70152-3}
}
Nilsson, E. Bisgaard, H. Effect of delivery device on systemic exposure to inhaled fluticasone propionate in children with asthma. 2014 Br J Clin Pharmacol 24527946 3,493 1
Authors: Nilsson, E., Chawes, B.L.K., Bønnelykke, K., Vindfeld, S., Moore, A.C. and Bisgaard, H.
BibTeX:
@article{,
  author = {Nilsson, Erik and Chawes, Bo L K. and Bønnelykke, Klaus and Vindfeld, Signe and Moore, Alison C. and Bisgaard, Hans},
  title = {Effect of delivery device on systemic exposure to inhaled fluticasone propionate in children with asthma.},
  journal = {Br J Clin Pharmacol},
  school = { Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark.},
  year = {2014},
  volume = {78},
  number = {2},
  pages = {435--437},
  url = {http://dx.doi.org/10.1111/bcp.12340},
  doi = {https://doi.org/10.1111/bcp.12340}
}
Mortensen, L.J. Bisgaard, H. The PCDH1 gene and asthma in early childhood. 2014 Eur Respir J 23988763 10,569 8
Authors: Mortensen, L.J., Kreiner-Møller, E., Hakonarson, H., Bønnelykke, K. and Bisgaard, H.
Abstract: Previous studies have suggested that variants in the protocadherin-1 (PCDH1) gene, which is important for cell-cell adhesion, are associated with asthma, bronchial, hyperresponsiveness and atopic dermatitis in school children. Our aim was to associate common variants of the PCDH1 gene with longitudinally assessed asthma phenotypes and atopic dermatitis in early childhood. We analysed eight single-nucleotide polymorphisms in PCDH1 from 411 children born to asthmatic mothers from the Copenhagen Prospective Studies on Asthma in Childhood birth cohort. Asthma and atopic dermatitis were diagnosed prospectively to the age of 7 years and asthma was categorised by temporal pattern: transient early respiratory symptoms, persistent symptoms and late-onset symptoms. Bronchial responsiveness was measured at age 6 years. We used additive genetic models. Kaplan-Meier plots revealed early onset in hetero- and homozygotes for the rs10063472-T allele. Significant association was observed between the transient early phenotype and rs10063472-T (transient early versus all: OR 1.91, 95% CI 1.21-3.01, p=0.0058; transient early versus asymptomatic: OR 2.00, 95% CI 1.23-3.25, p=0.0053). No association was observed for other symptom patterns or bronchial responsiveness. Significant association was observed for atopic dermatitis and rs11167761-A (OR 1.85, 95% CI 1.24-2.75, p=0.0026). Common variations in PCDH1 increase the risk of developing both transient early asthma and atopic dermatitis in early childhood.
BibTeX:
@article{,
  author = {Mortensen, Li J. and Kreiner-Møller, Eskil and Hakonarson, Hakon and Bønnelykke, Klaus and Bisgaard, Hans},
  title = {The PCDH1 gene and asthma in early childhood.},
  journal = {Eur Respir J},
  school = {Danish Pediatric Asthma Center, Health Sciences, University of Copenhagen, Copenhagen University Hospital, Gentofte, Denmark.},
  year = {2014},
  volume = {43},
  number = {3},
  pages = {792--800},
  url = {http://dx.doi.org/10.1183/09031936.00021613},
  doi = {https://doi.org/10.1183/09031936.00021613}
}
Larsen, J.M. Bisgaard, H. Children with asthma by school age display aberrant immune responses to pathogenic airway bacteria as infants. 2014 J Allergy Clin Immunol 24612682 13,081 21
Authors: Larsen, J.M., Brix, S., Thysen, A.H., Birch, S., Rasmussen, M.A. and Bisgaard, H.
Abstract: Asthma is a highly prevalent chronic lung disease that commonly originates in early childhood. Colonization of neonatal airways with the pathogenic bacterial strains Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae is associated with increased risk of later childhood asthma. We hypothesized that children with asthma have an abnormal immune response to pathogenic bacteria in infancy.We aimed to assess the bacterial immune response in asymptomatic infants and the association with later development of asthma by age 7 years.The Copenhagen Prospective Studies on Asthma in Childhood birth cohort was followed prospectively, and asthma was diagnosed at age 7 years. The immune response to H influenzae, M catarrhalis, and S pneumoniae was analyzed in 292 infants using PBMCs isolated and stored since the age of 6 months. The immune response was assessed based on the pattern of cytokines produced and T-cell activation.The immune response to pathogenic bacteria was different in infants with asthma by 7 years of age (P = .0007). In particular, prospective asthmatic subjects had aberrant production of IL-5 (P = .008), IL-13 (P = .057), IL-17 (P = .001), and IL-10 (P = .028), whereas there were no differences in T-cell activation or peripheral T-cell composition.Children with asthma by school age exhibited an aberrant immune response to pathogenic bacteria in infancy. We propose that an abnormal immune response to pathogenic bacteria colonizing the airways in early life might lead to chronic airway inflammation and childhood asthma.
BibTeX:
@article{,
  author = {Larsen, Jeppe Madura and Brix, Susanne and Thysen, Anna Hammerich and Birch, Sune and Rasmussen, Morten Arendt and Bisgaard, Hans},
  title = {Children with asthma by school age display aberrant immune responses to pathogenic airway bacteria as infants.},
  journal = {J Allergy Clin Immunol},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen, Copenhagen University Hospital, Gentofte, Denmark. Electronic address: bisgaard@copsac.com.},
  year = {2014},
  volume = {133},
  number = {4},
  pages = {1008--1013},
  url = {http://dx.doi.org/10.1016/j.jaci.2014.01.010},
  doi = {https://doi.org/10.1016/j.jaci.2014.01.010}
}
Kreiner-Møller, E. Bønnelykke, K. Prenatal and postnatal genetic influence on lung function development. 2014 J Allergy Clin Immunol 24857373 13,081 7
Authors: Kreiner-Møller, E., Bisgaard, H. and Bønnelykke, K.
Abstract: It is unknown to what extent adult lung function genes affect lung function development from birth to childhood.Our aim was to study the association of candidate genetic variants with neonatal lung function and lung function development until age 7 years.Lung function measurement by means of spirometry with the raised-volume thoracoabdominal compression technique and bronchial responsiveness to methacholine challenge were assessed in 411 high-risk newborns from the Copenhagen Prospective Study on Asthma in Childhood 2000 (COPSAC2000) cohort. Measures were repeated at age 7 years. Genetic risk scores were calculated based on reported single nucleotide polymorphisms for adult lung function (FEV1/forced expiratory vital capacity [FVC] ratio and FEV1) as the number of risk alleles weighted on known effect size. These genetic risk scores were analyzed against lung function measures as z scores at birth (forced expiratory volume in 0.5 seconds [FEV0.5], forced expiratory flow at 50% of functional vital capacity [FEF50], and provocative dose of methacholine causing a 15% decrease in lung function [PD15]) and at age 7 years (FEV1, FEF50, and provocative dose of methacholine causing a 20% decrease in lung function [PD20]) and with development from birth to age 7 years (FEV0.5/1, FEF50, and PD15/20).The genetic risk scores were not associated with lung function measures at age 1 month, but the FEV1/FVC genetic risk score was associated with reduced FEF50 values at age 7 years (P = .01) and similarly with reduced growth in FEF50 from birth to age 7 years (P = .02). This score was also associated with increased bronchial responsiveness (reduced PD20) at age 7 years (P = .02) and change in responsiveness from birth to age 7 years (P = .05).Lung function genetic variants identified in adults were not associated with neonatal lung function or bronchial responsiveness but with the development of these lung function measures during early childhood, suggesting a window of opportunity for interventions targeting these genetic mechanisms.
BibTeX:
@article{,
  author = {Kreiner-Møller, Eskil and Bisgaard, Hans and Bønnelykke, Klaus},
  title = {Prenatal and postnatal genetic influence on lung function development.},
  journal = {J Allergy Clin Immunol},
  school = {COPSAC, the Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health Sciences, University of Copenhagen, and the Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark.},
  year = {2014},
  volume = {134},
  number = {5},
  pages = {1036--42.e15},
  url = {http://dx.doi.org/10.1016/j.jaci.2014.04.003},
  doi = {https://doi.org/10.1016/j.jaci.2014.04.003}
}
Chawes, B.L. Bisgaard, H. A clinical pharmacology study of fixed vs. free combination of inhaled beclometasone dipropionate and formoterol fumarate dry powder inhalers in asthmatic adolescents. 2014 Br J Clin Pharmacol 24830339 3,493 2
Authors: Chawes, B.L., Govoni, M., Piccinno, A., Kreiner-Møller, E., Vissing, N.H., Mortensen, L., Nilsson, E., Bisgaard, A., Deleuran, M., Skytt, N., Samandari, N., Acerbi, D. and Bisgaard, H.
BibTeX:
@article{,
  author = {Chawes, Bo L. and Govoni, Mirco and Piccinno, Annalisa and Kreiner-Møller, Eskil and Vissing, Nadja H. and Mortensen, Li and Nilsson, Erik and Bisgaard, Amalie and Deleuran, Maja and Skytt, Nanna and Samandari, Nasim and Acerbi, Daniela and Bisgaard, Hans},
  title = {A clinical pharmacology study of fixed vs. free combination of inhaled beclometasone dipropionate and formoterol fumarate dry powder inhalers in asthmatic adolescents.},
  journal = {Br J Clin Pharmacol},
  school = { Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark.},
  year = {2014},
  volume = {78},
  number = {5},
  pages = {1169--1171},
  url = {http://dx.doi.org/10.1111/bcp.12424},
  doi = {https://doi.org/10.1111/bcp.12424}
}
Chawes, B.L.Bisgaard, H. Bisgaard, H. Systemic exposure to inhaled beclometasone/formoterol DPI is age and body size dependent. 2014 Respir Med 24993817 3,217 0
Authors: Chawes, B.L., Govoni, M., Kreiner-Møller, E., Vissing, N.H., Poorisrisak, P., Mortensen, L., Nilsson, E., Bisgaard, A., Dossing, A., Deleuran, M., Skytt, N.L., Samandari, N., Piccinno, A., Sergio, F., Ciurlia, G., Poli, G., Acerbi, D., Singh, D. and Bisgaard, H.
Abstract: Prescription of inhaled corticosteroids to children with asthma is recommended at half the nominal dose of adults in order to reduce the risk of systemic side effects. However, there is a lack of pharmacokinetic trials supporting such dose reduction regimens. Therefore, we aimed to compare the systemic exposure to the active ingredients of a fixed dose combination of beclometasone-dipropionate (BDP) and formoterol after dry powder inhaler (DPI) administration in children, adolescents and adults.The pharmacokinetic profiles of formoterol and beclometasone-17-monopropionate (B17MP; active metabolite of BDP) were evaluated over 8 h from two independent studies comprising children (6-11yrs, n = 27), adolescents (12-17 yrs, n = 28) and adults (≥18 yrs, n = 30) receiving a single, fixed dose of BDP/formoterol (children: 200 μg/24 μg, adolescents and adults: 400 μg/24 μg) via DPI.The systemic exposure (AUC) for children versus adults was almost doubled for formoterol and similar for B17MP despite the halved BDP dose administered in children. In adolescents the AUC for formoterol and B17MP were approximately one third higher than in adults for both compounds. Upon normalization for the BDP/formoterol dose in the three populations the AUC and peak concentration (C(max)) correlated inversely with age and body surface area of the patients (r ≤ -0.53; p < 0.0001).The systemic exposure to the active ingredients of BDP/formoterol administered as DPI correlates inversely with age and body size suggesting that dry powder dosage regimens should be adjusted for age and body size to avoid high systemic drug levels in children.
BibTeX:
@article{,
  author = {Chawes, B. L. and Govoni, M. and Kreiner-Møller, E. and Vissing, N. H. and Poorisrisak, P. and Mortensen, L. and Nilsson, E. and Bisgaard, A. and Dossing, A. and Deleuran, M. and Skytt, N. L. and Samandari, N. and Piccinno, A. and Sergio, F. and Ciurlia, G. and Poli, G. and Acerbi, D. and Singh, D. and Bisgaard, H.},
  title = {Systemic exposure to inhaled beclometasone/formoterol DPI is age and body size dependent.},
  journal = {Respir Med},
  school = { Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark. Electronic address: bisgaard@copsac.com.},
  year = {2014},
  volume = {108},
  number = {8},
  pages = {1108--1116},
  url = {http://dx.doi.org/10.1016/j.rmed.2014.05.007},
  doi = {https://doi.org/10.1016/j.rmed.2014.05.007}
}
Chawes, B.L. Bisgaard, H. Cord blood 25(OH)-vitamin D deficiency and childhood asthma, allergy and eczema: the COPSAC2000 birth cohort study. 2014 PLoS One 24925304 2,806 41
Authors: Chawes, B.L., Bønnelykke, K., Jensen, P.F., Schoos, A.-M.M., Heickendorff, L. and Bisgaard, H.
Abstract: Epidemiological studies have suggested an association between maternal vitamin D dietary intake during pregnancy and risk of asthma and allergy in the offspring. However, prospective clinical studies on vitamin D measured in cord blood and development of clinical end-points are sparse.To investigate the interdependence of cord blood 25-hydroxyvitamin D (25(OH)-Vitamin D) level and investigator-diagnosed asthma- and allergy-related conditions during preschool-age.Cord blood 25(OH)-Vitamin D level was measured in 257 children from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2000) at-risk mother-child cohort. Troublesome lung symptoms (TROLS), asthma, respiratory infections, allergic rhinitis, and eczema, at age 0-7 yrs were diagnosed exclusively by the COPSAC pediatricians strictly adhering to predefined algorithms. Objective assessments of lung function and sensitization were performed repeatedly from birth.After adjusting for season of birth, deficient cord blood 25(OH)-Vitamin D level (<50 nmol/L) was associated with a 2.7-fold increased risk of recurrent TROLS (HR = 2.65; 95% CI = 1.02-6.86), but showed no association with respiratory infections or asthma. We saw no association between cord blood 25(OH)-Vitamin D level and lung function, sensitization, rhinitis or eczema. The effects were unaffected from adjusting for multiple lifestyle factors.Cord blood 25(OH)-Vitamin D deficiency associated with increased risk of recurrent TROLS till age 7 years. Randomized controlled trials of vitamin D supplementation during pregnancy are needed to prove causality.
BibTeX:
@article{,
  author = {Chawes, Bo L. and Bønnelykke, Klaus and Jensen, Pia F. and Schoos, Ann-Marie M. and Heickendorff, Lene and Bisgaard, Hans},
  title = {Cord blood 25(OH)-vitamin D deficiency and childhood asthma, allergy and eczema: the COPSAC2000 birth cohort study.},
  journal = {PLoS One},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen, Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark.},
  year = {2014},
  volume = {9},
  number = {6},
  pages = {e99856},
  url = {http://dx.doi.org/10.1371/journal.pone.0099856},
  doi = {https://doi.org/10.1371/journal.pone.0099856}
}
Bisgaard, H. Stokholm, J. Immune-mediated diseases and microbial exposure in early life. 2014 Clin Exp Allergy 24533884 5,264 16
Authors: Bisgaard, H., Bønnelykke, K. and Stokholm, J.
Abstract: The non-communicable disease pandemic includes immune-mediated diseases such as asthma and allergy, which are likely originating in early life where the immature immune system is prone to alterations caused by the exposome. The timing of exposure seems critical for the developing immune system, and certain exposures may have detrimental effects in the earliest life, but no or even beneficial effects later. The human microbiome and infections are candidates as intermediary in the interaction between the host and the environment. The evidence seems inconsistent as infections as well as particular colonization patterns in neonates drive both short-term and long-term asthma symptoms, while, on the other hand, the composition of the microbiome in early life may protect against asthma and allergy in later life. This apparent contradiction may be explained by a deeper disease heterogeneity than we are currently able to discriminate, and in particular, the indiscriminate lumping together of different diseases into one atopic disease category. Also, the microbiome needs a differentiated understanding, considering balance between microbial groups, diversity and microbial genetic capability. Furthermore, the effects of the microbial exposure may only affect individuals with certain susceptibility genes. Few of the observations have been replicated, and publication bias is likely. Therefore, we are still far from understanding, or having proved, causal effects of the human microbiome. Still, the microbiome-gene interaction is a fascinating paradigm that fosters exiting research and promises a breakthrough in the understanding of the mechanisms driving asthma, allergy and eczema, and potentially also other immune-mediated non-communicable diseases.
BibTeX:
@article{,
  author = {Bisgaard, H. and Bønnelykke, K. and Stokholm, J.},
  title = {Immune-mediated diseases and microbial exposure in early life.},
  journal = {Clin Exp Allergy},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen, Gentofte, Copenhagen, Denmark; The Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark.},
  year = {2014},
  volume = {44},
  number = {4},
  pages = {475--481},
  url = {http://dx.doi.org/10.1111/cea.12291},
  doi = {https://doi.org/10.1111/cea.12291}
}
Bischoff, A.L. Bisgaard, H. Altered response to A(H1N1)pnd09 vaccination in pregnant women: a single blinded randomized controlled trial. 2013 PLoS One 23637733 2,806 23
Authors: Bischoff, A.L., Følsgaard, N.V., Carson, C.G., Stokholm, J., Pedersen, L., Holmberg, M., Bisgaard, A., Birch, S., Tsai, T.F. and Bisgaard, H.
Abstract: Pregnant women were suspected to be at particular risk when H1N1pnd09 influenza became pandemic in 2009. Our primary objective was to compare the immune responses conferred by MF59®-adjuvanted vaccine (Focetria®) in H1N1pnd09-naïve pregnant and non-pregnant women. The secondary aims were to compare influences of dose and adjuvant on the immune response.The study was nested in the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010) pregnancy cohort in 2009-2010 and conducted as a single-blinded block-randomised [1∶1∶1] controlled clinical trial in pregnant women after gestational week 20: (1) 7.5 µg H1N1pnd09 antigen with MF59-adjuvant (Pa7.5 µg); (2) 3.75 µg antigen half MF59-adjuvanted (Pa3.75 µg); (3) 15 µg antigen unadjuvanted (P15 µg); and in non-pregnant women receiving (4) 7.5 µg antigen full adjuvanted (NPa7.5 µg). Blood samples were collected at baseline, 3 weeks, 3 and 10 months after vaccination, adverse events were recorded prospectively.58 pregnant women were allocated to Pa7.5 µg and 149 non-pregnant women were recruited to NPa7.5 µg. The sero-conversion rate was significantly increased in non-pregnant (NPa7.5 µg) compared with pregnant (Pa7.5 µg) women (OR = 2.48 [1.03-5.95], p = 0.04) and geometric mean titers trended towards being higher, but this difference was not statistically significant (ratio 1.27 [0.85-1.93], p = 0.23). The significant titer increase rate showed no difference between pregnant (Pa7.5 µg) and non-pregnant (NPa7.5 µg) groups (OR = 0.49 [0.13-1.85], p = 0.29).Our study suggests the immune response to the 7.5 µg MF59-adjuvanted Focetria® H1N1pnd09 vaccine in pregnant women may be diminished compared with non-pregnant women.ClinicalTrials.gov NCT01012557.
BibTeX:
@article{,
  author = {Bischoff, Anne Louise and Følsgaard, Nilofar Vahman and Carson, Charlotte Giwercman and Stokholm, Jakob and Pedersen, Louise and Holmberg, Maria and Bisgaard, Amalie and Birch, Sune and Tsai, Theodore F. and Bisgaard, Hans},
  title = {Altered response to A(H1N1)pnd09 vaccination in pregnant women: a single blinded randomized controlled trial.},
  journal = {PLoS One},
  school = {Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Health Sciences, University of Copenhagen, Copenhagen University Hospital, Gentofte, Denmark.},
  year = {2013},
  volume = {8},
  number = {4},
  pages = {e56700},
  url = {http://dx.doi.org/10.1371/journal.pone.0056700},
  doi = {https://doi.org/10.1371/journal.pone.0056700}
}
Stensballe, L.G. Bisgaard, H. Use of antibiotics during pregnancy increases the risk of asthma in early childhood. 2013 J Pediatr 23140881 3,874 92
Authors: Stensballe, L.G., Simonsen, J., Jensen, S.M., Bønnelykke, K. and Bisgaard, H.
Abstract: To investigate the hypothesis that mother's use of antibiotics in pregnancy could influence asthma and eczema in early life.Subjects were included from the Copenhagen Prospective Study on Asthma in Childhood cohort of children born of mothers with asthma (N = 411). Severe asthma exacerbations and eczema were diagnosed by research unit physicians. Replication was sought in children from the Danish National Birth Cohort (N = 30 675). Asthma outcomes were hospitalization and use of inhaled corticosteroids. Eczema was defined by an algorithm developed from cases of clinically verified eczema. All children were followed to age 5 years in a cohort study design.The Copenhagen Prospective Study on Asthma in Childhood data showed increased risk of asthma exacerbation (hazard ratio 1.98 [95% CI 1.08-3.63]) if mothers had used antibiotics during third trimester. The Danish National Birth Cohort confirmed increased risk of asthma hospitalization (hazard ratio 1.17 [1.00-1.36]), and inhaled corticosteroids (1.18 [1.10-1.27]) in the children if mothers used antibiotics any time during pregnancy. In the subgroup of mothers using antibiotics for nonrespiratory infection, the children also had increased risk of asthma.We found increased risk of asthma associated with maternal antibiotic use in a clinical study of a birth cohort with increased risk of asthma and replicated this finding in an unselected national birth cohort, and in a subgroup using antibiotics for nonrespiratory infections. This supports a role for bacterial ecology in pre- or perinatal life for the development of asthma.
BibTeX:
@article{,
  author = {Stensballe, Lone Graff and Simonsen, Jacob and Jensen, Signe M. and Bønnelykke, Klaus and Bisgaard, Hans},
  title = {Use of antibiotics during pregnancy increases the risk of asthma in early childhood.},
  journal = {J Pediatr},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health Sciences, University of Copenhagen, and The Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark. LGN@ssi.dk},
  year = {2013},
  volume = {162},
  number = {4},
  pages = {832--838.e3},
  url = {http://dx.doi.org/10.1016/j.jpeds.2012.09.049},
  doi = {https://doi.org/10.1016/j.jpeds.2012.09.049}
}
von Linstow, M.-L. Bisgaard, H. Neonatal airway colonization is associated with troublesome lung symptoms in infants. 2013 Am J Respir Crit Care Med 24127810 13,204 10
Authors: von Linstow, M.-L., Schønning, K., Hoegh, A.M., Sevelsted, A., Vissing, N.H. and Bisgaard, H.
BibTeX:
@article{,
  author = {von Linstow, Marie-Louise and Schønning, Kristian and Hoegh, Anne M. and Sevelsted, Astrid and Vissing, Nadja H. and Bisgaard, Hans},
  title = {Neonatal airway colonization is associated with troublesome lung symptoms in infants.},
  journal = {Am J Respir Crit Care Med},
  school = {1 Departments of Pediatrics and Clinical Microbiology Copenhagen University Hospital Hvidovre, Denmark.},
  year = {2013},
  volume = {188},
  number = {8},
  pages = {1041--1042},
  url = {http://dx.doi.org/10.1164/rccm.201302-0395LE},
  doi = {https://doi.org/10.1164/rccm.201302-0395LE}
}
Vissing, N.H. Bisgaard, H. Public hygiene campaign in denmark during the 2009 H1N1 pandemic had no effect on hospitalization rate of communicable diseases in children. 2013 PLoS One 23936255 2,806 0
Authors: Vissing, N.H., Sevelsted, A. and Bisgaard, H.
Abstract: During the 2009 H1N1 pandemic the Danish National board of Health carried out massive public hygiene campaigns to limit spread of disease. We aimed to investigate whether this resulted in lower incidences of communicable diseases in the paediatric population.The study compared annual hospitalization rates for childhood infections from 2005 to 2011.Admission rates for infections were higher during the year of the pandemic compared to the rest of the period.There were no indications of a preventive effect by the hygiene campaign on incidence of severe common childhood infections.
BibTeX:
@article{,
  author = {Vissing, Nadja Hawwa and Sevelsted, Astrid and Bisgaard, Hans},
  title = {Public hygiene campaign in denmark during the 2009 H1N1 pandemic had no effect on hospitalization rate of communicable diseases in children.},
  journal = {PLoS One},
  school = {COPSAC, The Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital, Gentofte, Denmark.},
  year = {2013},
  volume = {8},
  number = {7},
  pages = {e70946},
  url = {http://dx.doi.org/10.1371/journal.pone.0070946},
  doi = {https://doi.org/10.1371/journal.pone.0070946}
}
Vissing, N.H. Bisgaard, H. Increased risk of pneumonia and bronchiolitis after bacterial colonization of the airways as neonates. 2013 Am J Respir Crit Care Med 24090102 13,204 52
Authors: Vissing, N.H., Chawes, B.L.K. and Bisgaard, H.
Abstract: The frequency of pneumonia and bronchiolitis exhibits considerable variation in otherwise healthy children, and suspected risk factors explain only a minor proportion of the variation. We hypothesized that alterations in the airway microbiome in early life may be associated with susceptibility to pneumonia and bronchiolitis in young children.To investigate the relation between neonatal airway colonization and pneumonia and bronchiolitis during the first 3 years of life.Participants comprised children of the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) cohort, a prospective birth cohort study of 411 children born to mothers with asthma. Aspirates from the hypopharynx at age 4 weeks were cultured for Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus. Clinical information on pneumonia and bronchiolitis within the first 3 years of life was prospectively collected by the research physicians at the center. Analyses were adjusted for covariates associated with pneumonia and bronchiolitis and bacterial airway colonization.Hypopharyngeal aspirates and full clinical follow-up until 3 years of age were available for 265 children. Of these, 56 (21 neonates were colonized with S. pneumoniae, H. influenzae, and/or M. catarrhalis at 4 weeks of age. Colonization with at least one of these microorganisms (but not S. aureus) was significantly associated with increased incidence of pneumonia and bronchiolitis (adjusted incidence rate ratio, 1.79 [1.29-2.48]; P < 0.005) independently of concurrent or later asthma.Neonatal airway colonization with S. pneumoniae, H. influenzae, or M. catarrhalis is associated with increased risk of pneumonia and bronchiolitis in early life independently of asthma. This suggests a role of pathogenic bacterial colonization of the airways in neonates for subsequent susceptibly to pneumonia and bronchiolitis.
BibTeX:
@article{,
  author = {Vissing, Nadja H. and Chawes, Bo L K. and Bisgaard, Hans},
  title = {Increased risk of pneumonia and bronchiolitis after bacterial colonization of the airways as neonates.},
  journal = {Am J Respir Crit Care Med},
  school = {1 Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen and Copenhagen University Hospital, Gentofte, Copenhagen, Denmark.},
  year = {2013},
  volume = {188},
  number = {10},
  pages = {1246--1252},
  url = {http://dx.doi.org/10.1164/rccm.201302-0215OC},
  doi = {https://doi.org/10.1164/rccm.201302-0215OC}
}
Stokholm, J. Bisgaard, H. Prevalence and predictors of antibiotic administration during pregnancy and birth. 2013 PLoS One 24340068 2,806 16
Authors: Stokholm, J., Schjørring, S., Pedersen, L., Bischoff, A.L., Følsgaard, N., Carson, C.G., Chawes, B.L.K., Bønnelykke, K., Mølgaard, A., Krogfelt, K.A. and Bisgaard, H.
Abstract: Antibiotic treatment during pregnancy and birth is very common. In this study, we describe the estimated prevalence of antibiotic administration during pregnancy and birth in the COPSAC2010 pregnancy cohort, and analyze dependence on social and lifestyle-related factors.706 pregnant women from the novel unselected Copenhagen Prospective Study on Asthma in Childhood (COPSAC2010) pregnancy cohort participated in this analysis. Detailed information on oral antibiotic prescriptions during pregnancy filled at the pharmacy was obtained and verified longitudinally. Information on intrapartum antibiotics, social, and lifestyle-factors was obtained by personal interviews.The prevalence of antibiotic use was 37% during pregnancy and 33% intrapartum. Lower maternal age at birth; adjusted odds ratio (aOR) 0.94, 95% CI, [0.90-0.98], p = 0.003 and maternal smoking; aOR 1.97, 95% CI, [1.07-3.63], p = 0.030 were associated with use of antibiotics for urinary tract infection during pregnancy. Maternal educational level (low vs. high), aOR 2.32, 95% CI, [1.24-4.35], p = 0.011, maternal asthma; aOR 1.99, 95% CI, [1.33-2.98], p < 0.001 and previous childbirth; aOR 1.80, 95% CI, [1.21-2.66], p = 0.004 were associated with use of antibiotics for respiratory tract infection during pregnancy. Lower gestational age; aOR 0.72, 95% CI, [0.61-0.85], p < 0.001, maternal smoking; aOR 2.84, 95% CI, [1.33-6.06], p = 0.007, and nulliparity; aOR 1.79, 95% CI, [1.06-3.02], p = 0.030 were associated with administration of intrapartum antibiotics in women giving birth vaginally.Antibiotic administration during pregnancy and birth may be influenced by social and lifestyle-factors. Understanding such risk factors may guide preventive strategies in order to avoid unnecessary use of antibiotics.
BibTeX:
@article{,
  author = {Stokholm, Jakob and Schjørring, Susanne and Pedersen, Louise and Bischoff, Anne Louise and Følsgaard, Nilofar and Carson, Charlotte G. and Chawes, Bo L K. and Bønnelykke, Klaus and Mølgaard, Anne and Krogfelt, Karen A. and Bisgaard, Hans},
  title = {Prevalence and predictors of antibiotic administration during pregnancy and birth.},
  journal = {PLoS One},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen, Naestved Hospital, Naestved, Denmark ; Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark.},
  year = {2013},
  volume = {8},
  number = {12},
  pages = {e82932},
  url = {http://dx.doi.org/10.1371/journal.pone.0082932},
  doi = {https://doi.org/10.1371/journal.pone.0082932}
}
Horikoshi, M. Freathy, R.M. New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism. 2013 Nat Genet 23202124 27,959 125
Authors: Horikoshi, M., Yaghootkar, H., Mook-Kanamori, D.O., Sovio, U., Taal, H.R., Hennig, B.J., Bradfield, J.P., St Pourcain, B., Evans, D.M., Charoen, P., Kaakinen, M., Cousminer, D.L., Lehtimäki, T., Kreiner-Møller, E., Warrington, N.M., Bustamante, M., Feenstra, B., Berry, D.J., Thiering, E., Pfab, T., Barton, S.J., Shields, B.M., Kerkhof, M., van Leeuwen, E.M., Fulford, A.J., Kutalik, Z., Zhao, J.H., den Hoed, M., Mahajan, A., Lindi, V., Goh, L.-K., Hottenga, J.-J., Wu, Y., Raitakari, O.T., Harder, M.N., Meirhaeghe, A., Ntalla, I., Salem, R.M., Jameson, K.A., Zhou, K., Monies, D.M., Lagou, V., Kirin, M., Heikkinen, J., Adair, L.S., Alkuraya, F.S., Al-Odaib, A., Amouyel, P., Andersson, E.A., Bennett, A.J., Blakemore, A.I.F., Buxton, J.L., Dallongeville, J., Das, S., de Geus, E.J.C., Estivill, X., Flexeder, C., Froguel, P., Geller, F., Godfrey, K.M., Gottrand, F., Groves, C.J., Hansen, T., Hirschhorn, J.N., Hofman, A., Hollegaard, M.V., Hougaard, D.M., Hyppönen, E., Inskip, H.M., Isaacs, A., Jørgensen, T., Kanaka-Gantenbein, C., Kemp, J.P., Kiess, W., Kilpeläinen, T.O., Klopp, N., Knight, B.A., Kuzawa, C.W., McMahon, G., Newnham, J.P., Niinikoski, H., Oostra, B.A., Pedersen, L., Postma, D.S., Ring, S.M., Rivadeneira, F., Robertson, N.R., Sebert, S., Simell, O., Slowinski, T., Tiesler, C.M.T., Tönjes, A., Vaag, A., Viikari, J.S., Vink, J.M., Vissing, N.H., Wareham, N.J., Willemsen, G., Witte, D.R., Zhang, H., Zhao, J., , M.-A.o.G., traits Consortium (MAGIC), I.-r., Wilson, J.F., Stumvoll, M., Prentice, A.M., Meyer, B.F., Pearson, E.R., Boreham, C.A.G., Cooper, C., Gillman, M.W., Dedoussis, G.V., Moreno, L.A., Pedersen, O., Saarinen, M., Mohlke, K.L., Boomsma, D.I., Saw, S.-M., Lakka, T.A., Körner, A., Loos, R.J.F., Ong, K.K., Vollenweider, P., van Duijn, C.M., Koppelman, G.H., Hattersley, A.T., Holloway, J.W., Hocher, B., Heinrich, J., Power, C., Melbye, M., Guxens, M., Pennell, C.E., Bønnelykke, K., Bisgaard, H., Eriksson, J.G., Widén, E., Hakonarson, H., Uitterlinden, A.G., Pouta, A., Lawlor, D.A., Smith, G.D., Frayling, T.M., McCarthy, M.I., Grant, S.F.A., Jaddoe, V.W.V., Jarvelin, M.-R., Timpson, N.J., Prokopenko, I., Freathy, R.M. and , E.G.G.(E.G.G.C.
Abstract: Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
BibTeX:
@article{,
  author = {Horikoshi, Momoko and Yaghootkar, Hanieh and Mook-Kanamori, Dennis O. and Sovio, Ulla and Taal, H Rob and Hennig, Branwen J. and Bradfield, Jonathan P. and St Pourcain, Beate and Evans, David M. and Charoen, Pimphen and Kaakinen, Marika and Cousminer, Diana L. and Lehtimäki, Terho and Kreiner-Møller, Eskil and Warrington, Nicole M. and Bustamante, Mariona and Feenstra, Bjarke and Berry, Diane J. and Thiering, Elisabeth and Pfab, Thiemo and Barton, Sheila J. and Shields, Beverley M. and Kerkhof, Marjan and van Leeuwen, Elisabeth M. and Fulford, Anthony J. and Kutalik, Zoltán and Zhao, Jing Hua and den Hoed, Marcel and Mahajan, Anubha and Lindi, Virpi and Goh, Liang-Kee and Hottenga, Jouke-Jan and Wu, Ying and Raitakari, Olli T. and Harder, Marie N. and Meirhaeghe, Aline and Ntalla, Ioanna and Salem, Rany M. and Jameson, Karen A. and Zhou, Kaixin and Monies, Dorota M. and Lagou, Vasiliki and Kirin, Mirna and Heikkinen, Jani and Adair, Linda S. and Alkuraya, Fowzan S. and Al-Odaib, Ali and Amouyel, Philippe and Andersson, Ehm Astrid and Bennett, Amanda J. and Blakemore, Alexandra I F. and Buxton, Jessica L. and Dallongeville, Jean and Das, Shikta and de Geus, Eco J C. and Estivill, Xavier and Flexeder, Claudia and Froguel, Philippe and Geller, Frank and Godfrey, Keith M. and Gottrand, Frédéric and Groves, Christopher J. and Hansen, Torben and Hirschhorn, Joel N. and Hofman, Albert and Hollegaard, Mads V. and Hougaard, David M. and Hyppönen, Elina and Inskip, Hazel M. and Isaacs, Aaron and Jørgensen, Torben and Kanaka-Gantenbein, Christina and Kemp, John P. and Kiess, Wieland and Kilpeläinen, Tuomas O. and Klopp, Norman and Knight, Bridget A. and Kuzawa, Christopher W. and McMahon, George and Newnham, John P. and Niinikoski, Harri and Oostra, Ben A. and Pedersen, Louise and Postma, Dirkje S. and Ring, Susan M. and Rivadeneira, Fernando and Robertson, Neil R. and Sebert, Sylvain and Simell, Olli and Slowinski, Torsten and Tiesler, Carla M T. and Tönjes, Anke and Vaag, Allan and Viikari, Jorma S. and Vink, Jacqueline M. and Vissing, Nadja Hawwa and Wareham, Nicholas J. and Willemsen, Gonneke and Witte, Daniel R. and Zhang, Haitao and Zhao, Jianhua and , Meta-Analyses of Glucose- and Insulin-related traits Consortium (MAGIC) and Wilson, James F. and Stumvoll, Michael and Prentice, Andrew M. and Meyer, Brian F. and Pearson, Ewan R. and Boreham, Colin A G. and Cooper, Cyrus and Gillman, Matthew W. and Dedoussis, George V. and Moreno, Luis A. and Pedersen, Oluf and Saarinen, Maiju and Mohlke, Karen L. and Boomsma, Dorret I. and Saw, Seang-Mei and Lakka, Timo A. and Körner, Antje and Loos, Ruth J F. and Ong, Ken K. and Vollenweider, Peter and van Duijn, Cornelia M. and Koppelman, Gerard H. and Hattersley, Andrew T. and Holloway, John W. and Hocher, Berthold and Heinrich, Joachim and Power, Chris and Melbye, Mads and Guxens, Mònica and Pennell, Craig E. and Bønnelykke, Klaus and Bisgaard, Hans and Eriksson, Johan G. and Widén, Elisabeth and Hakonarson, Hakon and Uitterlinden, André G. and Pouta, Anneli and Lawlor, Debbie A. and Smith, George Davey and Frayling, Timothy M. and McCarthy, Mark I. and Grant, Struan F A. and Jaddoe, Vincent W V. and Jarvelin, Marjo-Riitta and Timpson, Nicholas J. and Prokopenko, Inga and Freathy, Rachel M. and , Early Growth Genetics (E. G. G) Consortium},
  title = {New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.},
  journal = {Nat Genet},
  school = {Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.},
  year = {2013},
  volume = {45},
  number = {1},
  pages = {76--82}
}
Kreiner-Møller, E. Bønnelykke, K. VEGFA variants are associated with pre-school lung function, but not neonatal lung function. 2013 Clin Exp Allergy 24152156 5,264 9
Authors: Kreiner-Møller, E., Chawes, B.L.K., Vissing, N.H., Koppelman, G.H., Postma, D.S., Madsen, J.S., Olsen, D.A., Baty, F., Vonk, J.M., Kerkhof, M., Sleiman, P., Hakonarsson, H., Mortensen, L.J., Poorisrisak, P., Bisgaard, H. and Bønnelykke, K.
Abstract: Vascular endothelial growth factor (VEGF) is implicated in airway remodelling and asthma development. We studied VEGFA gene variants and plasma levels and the development of lung function, bronchial hyperresponsiveness and asthma in childhood.We analysed 13 SNPs in the VEGFA gene in 411 children from the COPSAC2000 high-risk birth cohort. Asthma was diagnosed prospectively, and lung function measurements were obtained at birth and 6 years of age. Plasma VEGF levels were measured at 18 months of age. We used a Bonferroni adjusted significance level. Findings were replicated in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort at age 8.At age six, three SNPs from the same linkage block were associated with FEV1 (rs699947, P = 1.31E-05), independent of asthma, and there were suggestive associations between FEV1/FVC ratio and rs833052 and maximal mid-expiratory flow and rs6900017. Replication in the PIAMA cohort showed borderline association between FEV1 and rs699947 and significant meta-analysis result. SNPs upstream and nearby rs699947 were nominally associated with VEGF plasma levels. VEGF levels were not associated with asthmatic symptoms or lung function measures.VEGF gene variants are associated with lung function at school age, but not at birth, suggesting a role of VEGF in post-natal lung function development.
BibTeX:
@article{,
  author = {Kreiner-Møller, E. and Chawes, B L K. and Vissing, N. H. and Koppelman, G. H. and Postma, D. S. and Madsen, J. S. and Olsen, D. A. and Baty, F. and Vonk, J. M. and Kerkhof, M. and Sleiman, P. and Hakonarsson, H. and Mortensen, L. J. and Poorisrisak, P. and Bisgaard, H. and Bønnelykke, K.},
  title = {VEGFA variants are associated with pre-school lung function, but not neonatal lung function.},
  journal = {Clin Exp Allergy},
  school = {COPSAC: Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital, Gentofte, Denmark; The Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark.},
  year = {2013},
  volume = {43},
  number = {11},
  pages = {1236--1245},
  url = {http://dx.doi.org/10.1111/cea.12188},
  doi = {https://doi.org/10.1111/cea.12188}
}
Følsgaard, N.V. Bisgaard, H. Pathogenic bacteria colonizing the airways in asymptomatic neonates stimulates topical inflammatory mediator release. 2013 Am J Respir Crit Care Med 23370914 13,204 55
Authors: Følsgaard, N.V., Schjørring, S., Chawes, B.L., Rasmussen, M.A., Krogfelt, K.A., Brix, S. and Bisgaard, H.
Abstract: Bacterial colonization of neonatal airways with the pathogenic bacterial species, Moraxella catarrhalis, Streptococcus pneumoniae, and Haemophilus influenzae, is associated with later development of childhood asthma.To study a possible association between colonization with pathogenic bacterial strains and the immune signature of the upper airways in healthy neonates.A total of 20 cytokines and chemokines were quantified in vivo in the airway mucosal lining fluid of 662 neonates from the Copenhagen Prospective Study of Asthma in Childhood 2010 birth cohort. Colonization of the hypopharynx with M. catarrhalis, S. pneumoniae, H. influenzae, and Staphylococcus aureus was assessed simultaneously. The association between immune signatures and bacterial colonization or noncolonized controls was analyzed using conventional statistical methods supplemented by a multivariate approach for pattern identification.Colonization with M. catarrhalis and H. influenzae induced a mixed T helper cell (Th) type 1/Th2/Th17 response with high levels of IL-1β (M. catarrhalis, P = 2.2 × 10(-12); H. influenzae, P = 7.1 × 10(-10)), TNF-α (M. catarrhalis, P = 1.5 × 10(-9); H. influenzae, P = 5.9 × 10(-7)), and macrophage inflammatory protein-1β (M. catarrhalis, P = 1.6 × 10(-11); H. influenzae, P = 2.7 × 10(-7)). S. aureus colonization demonstrated a Th17-promoting profile with elevated IL-17 levels (P = 1.6 × 10(-24)). S. pneumoniae colonization was not significantly associated with any of the mediators.M. catarrhalis and H. influenzae colonization of the airways of asymptomatic neonates is associated with an inflammatory immune response of the airway mucosa, which may result in chronic inflammation.
BibTeX:
@article{,
  author = {Følsgaard, Nilofar V. and Schjørring, Susanne and Chawes, Bo L. and Rasmussen, Morten A. and Krogfelt, Karen A. and Brix, Susanne and Bisgaard, Hans},
  title = {Pathogenic bacteria colonizing the airways in asymptomatic neonates stimulates topical inflammatory mediator release.},
  journal = {Am J Respir Crit Care Med},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital, Gentofte, Ledreborg Allé 34, Gentofte, Copenhagen, Denmark.},
  year = {2013},
  volume = {187},
  number = {6},
  pages = {589--595},
  url = {http://dx.doi.org/10.1164/rccm.201207-1297OC},
  doi = {https://doi.org/10.1164/rccm.201207-1297OC}
}
Cousminer, D.L. Widén, E. Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity. 2013 Hum Mol Genet 23449627 5,340 56
Authors: Cousminer, D.L., Berry, D.J., Timpson, N.J., Ang, W., Thiering, E., Byrne, E.M., Taal, H.R., Huikari, V., Bradfield, J.P., Kerkhof, M., Groen-Blokhuis, M.M., Kreiner-Møller, E., Marinelli, M., Holst, C., Leinonen, J.T., Perry, J.R.B., Surakka, I., Pietiläinen, O., Kettunen, J., Anttila, V., Kaakinen, M., Sovio, U., Pouta, A., Das, S., Lagou, V., Power, C., Prokopenko, I., Evans, D.M., Kemp, J.P., St Pourcain, B., Ring, S., Palotie, A., Kajantie, E., Osmond, C., Lehtimäki, T., Viikari, J.S., Kähönen, M., Warrington, N.M., Lye, S.J., Palmer, L.J., Tiesler, C.M.T., Flexeder, C., Montgomery, G.W., Medland, S.E., Hofman, A., Hakonarson, H., Guxens, M., Bartels, M., Salomaa, V., , R.C., Murabito, J.M., Kaprio, J., Sørensen, T.I.A., Ballester, F., Bisgaard, H., Boomsma, D.I., Koppelman, G.H., Grant, S.F.A., Jaddoe, V.W.V., Martin, N.G., Heinrich, J., Pennell, C.E., Raitakari, O.T., Eriksson, J.G., Smith, G.D., Hyppönen, E., Järvelin, M.-R., McCarthy, M.I., Ripatti, S., Widén, E. and , E.G.G.(E.G.G.C.
Abstract: The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 10(-8)) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.
BibTeX:
@article{,
  author = {Cousminer, Diana L. and Berry, Diane J. and Timpson, Nicholas J. and Ang, Wei and Thiering, Elisabeth and Byrne, Enda M. and Taal, H Rob and Huikari, Ville and Bradfield, Jonathan P. and Kerkhof, Marjan and Groen-Blokhuis, Maria M. and Kreiner-Møller, Eskil and Marinelli, Marcella and Holst, Claus and Leinonen, Jaakko T. and Perry, John R B. and Surakka, Ida and Pietiläinen, Olli and Kettunen, Johannes and Anttila, Verneri and Kaakinen, Marika and Sovio, Ulla and Pouta, Anneli and Das, Shikta and Lagou, Vasiliki and Power, Chris and Prokopenko, Inga and Evans, David M. and Kemp, John P. and St Pourcain, Beate and Ring, Susan and Palotie, Aarno and Kajantie, Eero and Osmond, Clive and Lehtimäki, Terho and Viikari, Jorma S. and Kähönen, Mika and Warrington, Nicole M. and Lye, Stephen J. and Palmer, Lyle J. and Tiesler, Carla M T. and Flexeder, Claudia and Montgomery, Grant W. and Medland, Sarah E. and Hofman, Albert and Hakonarson, Hakon and Guxens, Mònica and Bartels, Meike and Salomaa, Veikko and , ReproGen Consortium and Murabito, Joanne M. and Kaprio, Jaakko and Sørensen, Thorkild I A. and Ballester, Ferran and Bisgaard, Hans and Boomsma, Dorret I. and Koppelman, Gerard H. and Grant, Struan F A. and Jaddoe, Vincent W V. and Martin, Nicholas G. and Heinrich, Joachim and Pennell, Craig E. and Raitakari, Olli T. and Eriksson, Johan G. and Smith, George Davey and Hyppönen, Elina and Järvelin, Marjo-Riitta and McCarthy, Mark I. and Ripatti, Samuli and Widén, Elisabeth and , Early Growth Genetics (E. G. G) Consortium},
  title = {Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity.},
  journal = {Hum Mol Genet},
  school = {Institute for Molecular Medicine, and Department of Public Health, University of Helsinki, Helsinki, Finland.},
  year = {2013},
  volume = {22},
  number = {13},
  pages = {2735--2747},
  url = {http://dx.doi.org/10.1093/hmg/ddt104},
  doi = {https://doi.org/10.1093/hmg/ddt104}
}
Chawes, B.L.K. Bisgaard, H. Pharmacokinetic comparison of inhaled fixed combination vs. the free combination of beclomethasone and formoterol pMDIs in asthmatic children. 2013 Br J Clin Pharmacol 22978252 3,493 6
Authors: Chawes, B.L.K., Piccinno, A., Kreiner-Møller, E., Vissing, N.H., Poorisrisak, P., Mortensen, L., Nilson, E., Bisgaard, A., Dossing, A., Deleuran, M., Skytt, N.L., Samandari, N., Sergio, F., Ciurlia, G., Poli, G., Acerbi, D. and Bisgaard, H.
Abstract: The fixed combination of beclomethasone (BDP) and formoterol pressurized metered dose inhaler (pMDI) (Foster®, Chiesi Farmaceutici) is being developed in the lower strength (BDP/formoterol: 50/6 μg) to provide an appropriate dosage for children with asthma. The aim of this work was to investigate the systemic bioavailability of beclomethasone-17-monoproprionate (B17MP, the active metabolite of BDP) and formoterol after single inhalation of Foster® pMDI 50/6 μg vs. the free combination of BDP and formoterol pMDIs in asthmatic children.Children aged 5-11 years old inhaled BDP 200 μg and formoterol 24 μg as fixed vs. free combination in an open label, randomized, two way crossover single dose study. Blood was collected pre-dose up to 8 h post-dose for pharmacokinetic evaluation (AUC(0,t), AUC(0,∞), AUC(0,0.5 h, Cmax , tmax , t1/2 ). Pharmacodynamics included heart rate, plasma potassium, urinary glucose and cortisol excretion. Peak expiratory flow and adverse events were monitored.Twenty subjects were evaluable. The systemic exposure of B17MP and formoterol administered as fixed combination did not exceed the free combination: B17MP AUC(0,t) (pg ml(-1)  h) ratio test : reference (90% CI), 0.81 (0.697, 0.948) and formoterol AUC(0,t) (pg ml(-1)  h) ratio test : reference 0.97 (0.85, 1.10). All pharmacokinetic and pharmacodynamic end points showed non-superiority in favour of the test drug. One adverse event (vertigo) occurred but was not considered treatment-related.BDP and formoterol pharmacokinetic and pharmacodynamic effects are non-superior after administration of the two actives as fixed vs. the free combination in 5-11-year-old asthmatic children.
BibTeX:
@article{,
  author = {Chawes, Bo L K. and Piccinno, Annalisa and Kreiner-Møller, Eskil and Vissing, Nadja H. and Poorisrisak, Porntiva and Mortensen, Li and Nilson, Erik and Bisgaard, Amalie and Dossing, Anna and Deleuran, Maja and Skytt, Nanna L. and Samandari, Nasim and Sergio, Francesco and Ciurlia, Giorgia and Poli, Gianluigi and Acerbi, Daniela and Bisgaard, Hans},
  title = {Pharmacokinetic comparison of inhaled fixed combination vs. the free combination of beclomethasone and formoterol pMDIs in asthmatic children.},
  journal = {Br J Clin Pharmacol},
  school = { Danish Pediatric Asthma Center, Gentofte, Denmark.},
  year = {2013},
  volume = {75},
  number = {4},
  pages = {1081--1088},
  url = {http://dx.doi.org/10.1111/j.1365-2125.2012.04459.x},
  doi = {https://doi.org/10.1111/j.1365-2125.2012.04459.x}
}
Carlsen, K. Bisgaard, H. Association between whole-blood polyunsaturated fatty acids in pregnant women and early fetal weight. 2013 Eur J Clin Nutr 23756387 3,057 2
Authors: Carlsen, K., Pedersen, L., Bønnelykke, K., Stark, K.D., Lauritzen, L. and Bisgaard, H.
Abstract: Studies suggest that intake of marine n-3 polyunsaturated fatty acids (n-3 PUFA) in pregnancy have an impact on birth weight, but only few have investigated the effect on early fetal growth. The objective of the study was to investigate the association between levels of PUFA in maternal blood in gestational week 24 and biometric measures and estimated fetal weight in gestational week 20.In the COPSAC2010 cohort, whole-blood fatty acid composition (a biomarker of PUFA intake) from 583 women in week 24 was analyzed by gas chromatography. Biometric data (head circumference, abdominal circumference and femur length) were collected by ultra sound in week 20 and fetal weight was estimated. Associations between whole-blood PUFA (docosahexaenoic acid (DHA), total n-3 PUFA, n-6/n-3 PUFA, total n-6 PUFA) and fetal weight and biometrics measures were analyzed by multivariable-adjusted linear regression analyses.There was a wide range in maternal blood DHA, which varied from 1.8 to 6.9% depending on socioeconomic status, smoking and body mass index. After adjusting for these variables, no association was observed between any of the assessed PUFA components and the circumference of head or abdomen or fetal weight. However, an inverse association was established between DHA and total n-3 PUFA and femur length (P<0.02).Maternal whole-blood PUFA composition, specifically her n-3 PUFA status, in gestational week 24 was not associated with overall early fetal weight gain, but this study indicates that it may decrease the length of femur.
BibTeX:
@article{,
  author = {Carlsen, K. and Pedersen, L. and Bønnelykke, K. and Stark, K. D. and Lauritzen, L. and Bisgaard, H.},
  title = {Association between whole-blood polyunsaturated fatty acids in pregnant women and early fetal weight.},
  journal = {Eur J Clin Nutr},
  school = {Copenhagen University Hospital Gentofte, Gentofte, Denmark. katrinec@gmail.com},
  year = {2013},
  volume = {67},
  number = {9},
  pages = {978--983},
  url = {http://dx.doi.org/10.1038/ejcn.2013.108},
  doi = {https://doi.org/10.1038/ejcn.2013.108}
}
Calışkan, M. Ober, C. Rhinovirus wheezing illness and genetic risk of childhood-onset asthma. 2013 N Engl J Med 23534543 72,406 176
Authors: Calışkan, M., Bochkov, Y.A., Kreiner-Møller, E., Bønnelykke, K., Stein, M.M., Du, G., Bisgaard, H., Jackson, D.J., Gern, J.E., Lemanske Jr, R.F., Nicolae, D.L. and Ober, C.
Abstract: Both genetic variation at the 17q21 locus and virus-induced respiratory wheezing illnesses are associated with the development of asthma. Our aim was to determine the effects of these two factors on the risk of asthma in the Childhood Origins of Asthma (COAST) and the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohorts.We tested genotypes at the 17q21 locus for associations with asthma and with human rhinovirus (HRV) and respiratory syncytial virus (RSV) wheezing illnesses and tested for interactions between 17q21 genotypes and HRV and RSV wheezing illnesses with respect to the risk of asthma. Finally, we examined genotype-specific expression of 17q21 genes in unstimulated and HRV-stimulated peripheral-blood mononuclear cells (PBMCs).The 17q21 variants were associated with HRV wheezing illnesses in early life, but not with RSV wheezing illnesses. The associations of 17q21 variants with asthma were restricted to children who had had HRV wheezing illnesses, resulting in a significant interaction effect with respect to the risk of asthma. Moreover, the expression levels of ORMDL3 and of GSDMB were significantly increased in HRV-stimulated PBMCs, as compared with unstimulated PBMCs. The expression of these genes was associated with 17q21 variants in both conditions, although the increase with exposure to HRV was not genotype-specific.Variants at the 17q21 locus were associated with asthma in children who had had HRV wheezing illnesses and with expression of two genes at this locus. The expression levels of both genes increased in response to HRV stimulation, although the relative increase was not associated with the 17q21 genotypes. (Funded by the National Institutes of Health.).
BibTeX:
@article{,
  author = {Calışkan, Minal and Bochkov, Yury A. and Kreiner-Møller, Eskil and Bønnelykke, Klaus and Stein, Michelle M. and Du, Gaixin and Bisgaard, Hans and Jackson, Daniel J. and Gern, James E. and Lemanske, Jr, Robert F and Nicolae, Dan L. and Ober, Carole},
  title = {Rhinovirus wheezing illness and genetic risk of childhood-onset asthma.},
  journal = {N Engl J Med},
  school = {Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA. caliskan@uchicago.edu},
  year = {2013},
  volume = {368},
  number = {15},
  pages = {1398--1407},
  url = {http://dx.doi.org/10.1056/NEJMoa1211592},
  doi = {https://doi.org/10.1056/NEJMoa1211592}
}
Brasholt, M. Bisgaard, H. Objective assessment of levels and patterns of physical activity in preschool children. 2013 Pediatr Res 23770920 2,882 14
Authors: Brasholt, M., Chawes, B., Kreiner-Møller, E., Vahlkvist, S., Sinding, M. and Bisgaard, H.
Abstract: The aim of this study was to examine in detail levels and patterns of physical activity in preschool children and the effects of gender and BMI on this activity.Two hundred and fifty-three children aged 5 y participating in the Copenhagen Prospective Studies on Asthma in Childhood wore an accelerometer day and night over a 4-wk period. The main outcome measure was level of physical activity using the raw data. A secondary measure was time spent in moderate to vigorous physical activity (MVPA). A Fourier series analysis was applied to study in detail patterns over time.Activity profiles throughout the year were unique for each sex, with boys being overall more active than girls except for winter months. Preschool children also showed distinct patterns of physical activity during weekdays as compared with weekends and were most active during weekdays. Preschool children in the highest tertile of BMI had a flat yearly activity profile and tended to be less active as compared with those in the lowest tertile.Preschool children showed significant gender differences in physical activity, with distinct patterns throughout the year as well as between weekdays and weekends. A high BMI tended to be associated with lower levels of physical activity.
BibTeX:
@article{,
  author = {Brasholt, Martin and Chawes, Bo and Kreiner-Møller, Eskil and Vahlkvist, Signe and Sinding, Marianne and Bisgaard, Hans},
  title = {Objective assessment of levels and patterns of physical activity in preschool children.},
  journal = {Pediatr Res},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Danish Pediatric Asthma Center, Faculty of Health Sciences, Copenhagen University Hospital Gentofte, Gentofte, Denmark. mbrasholt@hotmail.com},
  year = {2013},
  volume = {74},
  number = {3},
  pages = {333--338},
  url = {http://dx.doi.org/10.1038/pr.2013.99},
  doi = {https://doi.org/10.1038/pr.2013.99}
}
Bisgaard, H. Bønnelykke, K. Deep phenotyping of the unselected COPSAC2010 birth cohort study. 2013 Clin Exp Allergy 24118234 5,264 25
Authors: Bisgaard, H., Vissing, N.H., Carson, C.G., Bischoff, A.L., Følsgaard, N.V., Kreiner-Møller, E., Chawes, B.L.K., Stokholm, J., Pedersen, L., Bjarnadóttir, E., Thysen, A.H., Nilsson, E., Mortensen, L.J., Olsen, S.F., Schjørring, S., Krogfelt, K.A., Lauritzen, L., Brix, S. and Bønnelykke, K.
Abstract: We hypothesize that perinatal exposures, in particular the human microbiome and maternal nutrition during pregnancy, interact with the genetic predisposition to cause an abnormal immune modulation in early life towards a trajectory to chronic inflammatory diseases such as asthma and others.The aim of this study is to explore these interactions by conducting a longitudinal study in an unselected cohort of pregnant women and their offspring with emphasis on deep clinical phenotyping, exposure assessment, and biobanking. Exposure assessments focus on the human microbiome. Nutritional intervention during pregnancy in randomized controlled trials are included in the study to prevent disease and to be able to establish causal relationships.Pregnant women from eastern Denmark were invited during 2008-2010 to a novel unselected 'COPSAC2010 ' cohort. The women visited the clinic during pregnancy weeks 24 and 36. Their children were followed at the clinic with deep phenotyping and collection of biological samples at nine regular visits until the age of 3 and at acute symptoms. Randomized controlled trials of high-dose vitamin D and fish oil supplements were conducted during pregnancy, and a trial of azithromycin for acute lung symptoms was conducted in the children with recurrent wheeze.Seven hundred and thirty-eight mothers were recruited from week 24 of gestation, and 700 of their children were included in the birth cohort. The cohort has an over-representation of atopic parents. The participant satisfaction was high and the adherence equally high with 685 children (98 attending the 1 year clinic visit and 667 children (95 attending the 2 year clinic visit.The COPSAC2010 birth cohort study provides longitudinal clinical follow-up with highly specific end-points, exposure assessments, and biobanking. The cohort has a high adherence rate promising strong data to elucidate the interaction between genomics and the exposome in perinatal life leading to lifestyle-related chronic inflammatory disorders such as asthma.
BibTeX:
@article{,
  author = {Bisgaard, H. and Vissing, N. H. and Carson, C. G. and Bischoff, A. L. and Følsgaard, N. V. and Kreiner-Møller, E. and Chawes, B L K. and Stokholm, J. and Pedersen, L. and Bjarnadóttir, E. and Thysen, A. H. and Nilsson, E. and Mortensen, L. J. and Olsen, S. F. and Schjørring, S. and Krogfelt, K. A. and Lauritzen, L. and Brix, S. and Bønnelykke, K.},
  title = {Deep phenotyping of the unselected COPSAC2010 birth cohort study.},
  journal = {Clin Exp Allergy},
  school = { Naestved, Denmark; Health Sciences, University of Copenhagen, Copenhagen, Denmark.},
  year = {2013},
  volume = {43},
  number = {12},
  pages = {1384--1394},
  url = {http://dx.doi.org/10.1111/cea.12213},
  doi = {https://doi.org/10.1111/cea.12213}
}
Bønnelykke, K. Bisgaard, H. [Childhood asthma: Danish guidelines for diagnosis and treatment]. 2013 Ugeskr Laeger 23937873 0 1
Authors: Bønnelykke, K., Pedersen, S., Rubak, S.L.M., Schiøtz, O. and Bisgaard, H.
Abstract: These clinical guidelines were developed by the Danish Pediatric Asthma Center in collaboration with the Danish Paediatric Society. Key messages in the guidelines are: 1) Inhaled steroids are the most effective preventive medication and are first choice in children with persistent symptoms. 2) There is rarely indication for more than low to moderate doses of inhaled steroids as preventive medication. 3) There is insufficient evidence for preventive medication in pre-school children with intermittent asthma; a trial of leukotriene-receptor-antagonists or inhaled steroids could be done.
BibTeX:
@article{,
  author = {Bønnelykke, Klaus and Pedersen, Søren and Rubak, Sune L M. and Schiøtz, Oluf and Bisgaard, Hans},
  title = {[Childhood asthma: Danish guidelines for diagnosis and treatment].},
  journal = {Ugeskr Laeger},
  school = {Dansk BørneAstma Center, Gentofte Hospital, Ledreborg Alle 34, 2820 Gentofte, Denmark.},
  year = {2013},
  volume = {175},
  number = {33},
  pages = {1863--1867}
}
Bønnelykke, K. Henderson, A.J. Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization. 2013 Nat Genet 23817571 27,959 106
Authors: Bønnelykke, K., Matheson, M.C., Pers, T.H., Granell, R., Strachan, D.P., Alves, A.C., Linneberg, A., Curtin, J.A., Warrington, N.M., Standl, M., Kerkhof, M., Jonsdottir, I., Bukvic, B.K., Kaakinen, M., Sleimann, P., Thorleifsson, G., Thorsteinsdottir, U., Schramm, K., Baltic, S., Kreiner-Møller, E., Simpson, A., St Pourcain, B., Coin, L., Hui, J., Walters, E.H., Tiesler, C.M.T., Duffy, D.L., Jones, G., , A.A.G.C., Ring, S.M., McArdle, W.L., Price, L., Robertson, C.F., Pekkanen, J., Tang, C.S., Thiering, E., Montgomery, G.W., Hartikainen, A.-L., Dharmage, S.C., Husemoen, L.L., Herder, C., Kemp, J.P., Elliot, P., James, A., Waldenberger, M., Abramson, M.J., Fairfax, B.P., Knight, J.C., Gupta, R., Thompson, P.J., Holt, P., Sly, P., Hirschhorn, J.N., Blekic, M., Weidinger, S., Hakonarsson, H., Stefansson, K., Heinrich, J., Postma, D.S., Custovic, A., Pennell, C.E., Jarvelin, M.-R., Koppelman, G.H., Timpson, N., Ferreira, M.A., Bisgaard, H. and Henderson, A.J.
Abstract: Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk-associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide new insights into the etiology of allergic disease.
BibTeX:
@article{,
  author = {Bønnelykke, Klaus and Matheson, Melanie C. and Pers, Tune H. and Granell, Raquel and Strachan, David P. and Alves, Alexessander Couto and Linneberg, Allan and Curtin, John A. and Warrington, Nicole M. and Standl, Marie and Kerkhof, Marjan and Jonsdottir, Ingileif and Bukvic, Blazenka K. and Kaakinen, Marika and Sleimann, Patrick and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Schramm, Katharina and Baltic, Svetlana and Kreiner-Møller, Eskil and Simpson, Angela and St Pourcain, Beate and Coin, Lachlan and Hui, Jennie and Walters, Eugene H. and Tiesler, Carla M T. and Duffy, David L. and Jones, Graham and , A. A. G. C. and Ring, Susan M. and McArdle, Wendy L. and Price, Loren and Robertson, Colin F. and Pekkanen, Juha and Tang, Clara S. and Thiering, Elisabeth and Montgomery, Grant W. and Hartikainen, Anna-Liisa and Dharmage, Shyamali C. and Husemoen, Lise L. and Herder, Christian and Kemp, John P. and Elliot, Paul and James, Alan and Waldenberger, Melanie and Abramson, Michael J. and Fairfax, Benjamin P. and Knight, Julian C. and Gupta, Ramneek and Thompson, Philip J. and Holt, Patrick and Sly, Peter and Hirschhorn, Joel N. and Blekic, Mario and Weidinger, Stephan and Hakonarsson, Hakon and Stefansson, Kari and Heinrich, Joachim and Postma, Dirkje S. and Custovic, Adnan and Pennell, Craig E. and Jarvelin, Marjo-Riitta and Koppelman, Gerard H. and Timpson, Nicholas and Ferreira, Manuel A. and Bisgaard, Hans and Henderson, A John},
  title = {Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization.},
  journal = {Nat Genet},
  school = {School of Social and Community Medicine, University of Bristol, Bristol, UK.},
  year = {2013},
  volume = {45},
  number = {8},
  pages = {902--906},
  url = {http://dx.doi.org/10.1038/ng.2694},
  doi = {https://doi.org/10.1038/ng.2694}
}
Bønnelykke, K. Bisgaard, H. Aerosol particle size does not predict pharmacokinetic determined lung dose in children. 2013 J Clin Pharmacol 23553595 2,812 1
Authors: Bønnelykke, K., Chawes, B.L.K., Vindfeld, S., Moore, A.C. and Bisgaard, H.
Abstract: In vitro measures of aerosol particles size, such as the fine particle mass, play a pivotal role for approval of inhaled anti-asthmatic drugs. However, the validity as a measure of dose to the lungs in children lacks evidence. In this study we investigated for the first time the association between an in vivo estimate of lung dose of inhaled drug in children and the corresponding particle size segments assessed ex vivo. Lung dose of fluticasone propionate after inhalation from a dry powder inhaler (Diskus®) was studied in 23 children aged 4-7 and 12-15 years with mild asthma. Six-hour pharmacokinetics was assessed after single inhalation. The corresponding emitted mass of drug in segments of aerosol particle size was assessed ex vivo by replicating the inhalation flows recorded by transducers built into the Diskus® inhaler and re-playing them in a breathing simulator. There was no correlation between any inhaled particle size segment and lung dose assessed by pharmacokinetics and adjusted for age and body size. Measures of particles size segments were not related to lung dose in children. Until further evidence is provided it may be warranted to emphasize pharmacokinetic or pharmacodynamic assessments of drug delivery to the lung.
BibTeX:
@article{,
  author = {Bønnelykke, Klaus and Chawes, Bo L K. and Vindfeld, Signe and Moore, Alison C. and Bisgaard, Hans},
  title = {Aerosol particle size does not predict pharmacokinetic determined lung dose in children.},
  journal = {J Clin Pharmacol},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Danish Pediatric Asthma Center, Health Sciences, University of Copenhagen, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark.},
  year = {2013},
  volume = {53},
  number = {5},
  pages = {517--522},
  url = {http://dx.doi.org/10.1002/jcph.74},
  doi = {https://doi.org/10.1002/jcph.74}
}
Stokholm, J. Bisgaard, H. Living with cat and dog increases vaginal colonization with E. coli in pregnant women. 2012 PLoS One 23049986 2,806 13
Authors: Stokholm, J., Schjørring, S., Pedersen, L., Bischoff, A.L., Følsgaard, N., Carson, C.G., Chawes, B., Bønnelykke, K., Mølgaard, A., Krogfelt, K.A. and Bisgaard, H.
Abstract: Furred pets in the household are known reservoirs for pathogenic bacteria, but it is not known if transmission of bacteria between pet and owner leads to significantly increased rate of infections. We studied whether cats and dogs living in the household of pregnant women affect the commensal vaginal flora, and furthermore the need for oral antibiotics and rate of urinary tract infections during pregnancy.The novel unselected Copenhagen Prospective Study on Asthma in Childhood (COPSAC(2010)) pregnancy cohort of 709 women participated in this analysis. Detailed information on pet exposure, oral antibiotic prescriptions filled at pharmacy and urinary tract infection during pregnancy was obtained and verified prospectively during clinic visits. Vaginal cultures were obtained at pregnancy week 36.Women, who had cat or dog in the home during pregnancy, had a different vaginal flora, in particular with increased Escherichia coli (E. coli) colonization; odds ratio after adjustment for lifestyle confounders and antibiotics 2.20, 95% CI, [1.27-3.80], p=0.005. 43% of women living with cat and/or dog in the home used oral antibiotics compared to 33% of women with no cat or dog; adjusted odds ratio 1.51, 95% CI, [1.08-2.12], p=0.016. Women living with cat had increased frequency of self-reported urinary tract infection; adjusted odds ratio 1.57, 95% CI, [1.02-2.43], p=0.042.The increased vaginal E. coli colonization in women living with cat or dog suggests a clinically important transmission of pathogenic bacteria from pet to owner substantiated by increased rate of antibiotic use and urinary tract infections which, which is of particular concern during pregnancy.
BibTeX:
@article{,
  author = {Stokholm, Jakob and Schjørring, Susanne and Pedersen, Louise and Bischoff, Anne Louise and Følsgaard, Nilofar and Carson, Charlotte G. and Chawes, Bo and Bønnelykke, Klaus and Mølgaard, Anne and Krogfelt, Karen A. and Bisgaard, Hans},
  title = {Living with cat and dog increases vaginal colonization with E. coli in pregnant women.},
  journal = {PLoS One},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen, Naestved Hospital, Naestved, Denmark.},
  year = {2012},
  volume = {7},
  number = {9},
  pages = {e46226},
  url = {http://dx.doi.org/10.1371/journal.pone.0046226},
  doi = {https://doi.org/10.1371/journal.pone.0046226}
}
Vissing, N.H. Bisgaard, H. Validity of information on atopic disease and other illness in young children reported by parents in a prospective birth cohort study. 2012 BMC Med Res Methodol 23088330 3,295 19
Authors: Vissing, N.H., Jensen, S.M. and Bisgaard, H.
Abstract: The longitudinal birth cohort study is the preferred design for studies of childhood health, particularly atopic disease. Still, prospective data collection depends on recollection of the medical history since the previous visit representing a potential recall-bias. We aimed to ascertain the quality of information on atopic disease and other health symptoms reported by parental interview in a closely monitored birth cohort study. Possible bias from symptom severity and socioeconomics were sought.Copenhagen study on Asthma in Childhood (COPSAC) is a clinical birth cohort study of 411 children born of asthmatic mothers from 1999 to 2001. Child health is monitored at six-monthly visits with particular emphasis on atopic symptoms and infections. Data from the first three study years on 260 children was compared with records from their family practitioner as an external reference.A total of 6134 medical events were reported at the COPSAC interviews. Additional 586 medical events were recorded by family practitioners but not reported at the interview. There were no missed events related to asthma, eczema or allergy. Respiratory, infectious and skin related symptoms showed completeness above 90 other diseases showed lower completeness around 77%. There was no meaningful influence from concurrent asthma or socioeconomics.The COPSAC study exhibited full sensitivity to the main study objectives, atopic disease, and high sensitivity to respiratory, infectious and skin related illness. Our findings support the validity of parental interviews in longitudinal cohort studies investigating atopic disease and illness in childhood.
BibTeX:
@article{,
  author = {Vissing, Nadja Hawwa and Jensen, Signe Marie and Bisgaard, Hans},
  title = {Validity of information on atopic disease and other illness in young children reported by parents in a prospective birth cohort study.},
  journal = {BMC Med Res Methodol},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, The Danish Pediatric Asthma Center, Health Sciences, University of Copenhagen, Copenhagen University Hospital, Gentofte, Ledreborg Alle 34 2900 Hellerup, Copenhagen, Denmark. nadja.vissing@dbac.dk},
  year = {2012},
  volume = {12},
  pages = {160},
  url = {http://dx.doi.org/10.1186/1471-2288-12-160},
  doi = {https://doi.org/10.1186/1471-2288-12-160}
}
Skytt, N. Bisgaard, H. "To wheeze or not to wheeze": That is not the question. 2012 J Allergy Clin Immunol 22766098 13,081 27
Authors: Skytt, N., Bønnelykke, K. and Bisgaard, H.
Abstract: The diagnosis of asthma in young children is difficult and based on clinical assessment of symptoms and results of physical examination. Respiratory wheeze has traditionally been used to define asthma in young children.We sought to compare the qualitative diagnosis of wheeze with a quantitative global assessment of significant troublesome lung symptoms during the first 3 years of life as a predictor of asthma by age 7 years.Children born to asthmatic mothers (n= 411) were followed prospectively to age 7 years. Parents were instructed to visit the research clinic during the first 3 years of life each time the child had significant troublesome lung symptoms for 3 days. At the clinic, a research physician performed a physical examination, including auscultation for wheeze and excluding differential diagnoses. We tested whether wheeze was independently associated with asthma at age 7 years after adjusting for the total number of episodes.Three hundred thirteen children had full follow-up by age 7 years. In a multivariable analysis the total number of acute clinic visits for asthma symptom was significantly associated with later asthma (P< .0001), whereas the presence of wheeze at these visits was not (P= .5). The total number of acute clinic visits for significant troublesome lung symptoms was also significantly associated with later asthma in children who had never presented with any wheeze (P= .03).A quantitative global assessment of significant troublesome lung symptoms in the first 3 years of life is a better predictor of asthma than assessment of wheeze. Doctor-diagnosed wheeze is not a prerequisite for the diagnosis of asthma, and relying on the symptom of wheeze will likely be an important cause of undertreatment.
BibTeX:
@article{,
  author = {Skytt, Nanna and Bønnelykke, Klaus and Bisgaard, Hans},
  title = {"To wheeze or not to wheeze": That is not the question.},
  journal = {J Allergy Clin Immunol},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen, Copenhagen, Denmark.},
  year = {2012},
  volume = {130},
  number = {2},
  pages = {403--7.e5},
  url = {http://dx.doi.org/10.1016/j.jaci.2012.04.043},
  doi = {https://doi.org/10.1016/j.jaci.2012.04.043}
}
Thyssen, J.P. Linneberg, A. Skin barrier abnormality caused by filaggrin (FLG) mutations is associated with increased serum 25-hydroxyvitamin D concentrations. 2012 J Allergy Clin Immunol 22921868 13,081 36
Authors: Thyssen, J.P., Thuesen, B., Huth, C., Standl, M., Carson, C.G., Heinrich, J., Krämer, U., Kratzsch, J., Berg, N.D., Menné, T., Johansen, J.D., Carlsen, B.C., Schwab, S., Thorand, B., Munk, M., Wallaschofski, H., Heickendorff, L., Meldgaard, M., Szecsi, P.B., Stender, S., Bønnelykke, K., Weidinger, S., Bisgaard, H. and Linneberg, A.
BibTeX:
@article{,
  author = {Thyssen, Jacob P. and Thuesen, Betina and Huth, Cornelia and Standl, Marie and Carson, Charlotte G. and Heinrich, Joachim and Krämer, Ursula and Kratzsch, Jürgen and Berg, Nikolaj D. and Menné, Torkil and Johansen, Jeanne D. and Carlsen, Berit C. and Schwab, Sigrid and Thorand, Barbara and Munk, Marianne and Wallaschofski, Henri and Heickendorff, Lene and Meldgaard, Michael and Szecsi, Pal B. and Stender, Steen and Bønnelykke, Klaus and Weidinger, Stephan and Bisgaard, Hans and Linneberg, Allan},
  title = {Skin barrier abnormality caused by filaggrin (FLG) mutations is associated with increased serum 25-hydroxyvitamin D concentrations.},
  journal = {J Allergy Clin Immunol},
  year = {2012},
  volume = {130},
  number = {5},
  pages = {1204--1207.e2},
  url = {http://dx.doi.org/10.1016/j.jaci.2012.06.046},
  doi = {https://doi.org/10.1016/j.jaci.2012.06.046}
}
Thyssen, J.P. Menné, T. Filaggrin loss-of-function mutation R501X and 2282del4 carrier status is associated with fissured skin on the hands: results from a cross-sectional population study. 2012 Br J Dermatol 21777221 4,706 25
Authors: Thyssen, J.P., Ross-Hansen, K., Johansen, J.D., Zachariae, C., Carlsen, B.C., Linneberg, A., Bisgaard, H., Carson, C.G., Nielsen, N.H., Meldgaard, M., Szecsi, P.B., Stender, S. and Menné, T.
Abstract: Filaggrin metabolites act as osmolytes and are important for skin hydration. Carriers of filaggrin loss-of-function mutations have a higher prevalence of atopic dermatitis and dry skin. There is also evidence to suggest that filaggrin mutations increase the risk of hand eczema in atopic individuals. In our clinic, we have observed a distinct phenotype of hand eczema in patients with filaggrin mutation carrier status, characterized by fissured dermatitis on the dorsal aspect of the hands and with only sparse involvement of the palms including fine scaling.To investigate whether filaggrin loss-of-function mutations are associated with skin fissures on the hands and/or fingers in the general population.Participants in a population-based study were questioned about skin symptoms, genotyped for filaggrin mutation, patch tested for nickel allergy and skin prick tested.In an adjusted logistic regression analysis, filaggrin mutation status was significantly associated with fissured skin on the hands and/or fingers in adults (odds ratio 1·93, 95% confidence interval 1·05-3·55) and showed a nearly significant negative interaction with atopic dermatitis (P=0·055), suggesting that the effect was predominantly in subjects without atopic dermatitis.Filaggrin loss-of-function mutations seem not only to increase the risk of atopic dermatitis and dry skin but also the risk of fissures on the hands and/or fingers in subjects without atopic dermatitis. Prophylactic emollient therapy should be particularly encouraged in filaggrin loss-of-function mutation carriers.
BibTeX:
@article{,
  author = {Thyssen, J. P. and Ross-Hansen, K. and Johansen, J. D. and Zachariae, C. and Carlsen, B. C. and Linneberg, A. and Bisgaard, H. and Carson, C. G. and Nielsen, N. H. and Meldgaard, M. and Szecsi, P. B. and Stender, S. and Menné, T.},
  title = {Filaggrin loss-of-function mutation R501X and 2282del4 carrier status is associated with fissured skin on the hands: results from a cross-sectional population study.},
  journal = {Br J Dermatol},
  school = {National Allergy Research Centre, Department of Dermato-Allergology, Copenhagen University Hospital Gentofte, University of Copenhagen, Niels Andersens Vej 65, 2900 Hellerup, Denmark. jacpth01@geh.regionh.dk},
  year = {2012},
  volume = {166},
  number = {1},
  pages = {46--53},
  url = {http://dx.doi.org/10.1111/j.1365-2133.2011.10530.x},
  doi = {https://doi.org/10.1111/j.1365-2133.2011.10530.x}
}
Thyssen, J.P. Menné, T. Individuals who are homozygous for the 2282del4 and R501X filaggrin null mutations do not always develop dermatitis and complete long-term remission is possible. 2012 J Eur Acad Dermatol Venereol 21501248 3,528 11
Authors: Thyssen, J.P., Carlsen, B.C., Bisgaard, H., Giwercman, C., Johansen, J.D., Linneberg, A., Meldgaard, M., Szecsi, P.B., Stender, S. and Menné, T.
Abstract: About 8-10% of the general population in Europe carry a null mutation in the filaggrin gene which is associated with early onset of atopic dermatitis as well as persistence into adulthood. No studies have investigated whether individuals with the homozygous filaggrin null genotype always develop dermatitis.The aim of this study was to describe the natural history of individuals with no filaggrin expression.Three study populations were included: (i) a random sample of 3335 subjects aged 18-69 years from the general population in Copenhagen who underwent general health examination; (ii) a total of 499 patients seen in our dermatitis clinic since 2009 and who were filaggrin genotyped as a part of the routine diagnostic work up; and (iii) a prospective, longitudinal, birth cohort study of 411 children born to mothers with a history of asthma. Filaggrin genotyping was performed for the 2282del4 and R501X mutations.Filaggrin homozygous/compound heterozygous individuals accounted for 0.3% of adults, 3% of dermatitis patients and 0.7% of children. Respectively, one of nine adults and one of three children never experienced dermatitis until now. All hospital patients had atopic dermatitis with onset during (early) childhood. Year-long complete remission was observed in half of patients.The natural history of individuals with the filaggrin null genotype is fairly good in the sense that they may not develop dermatitis at all, and if they do, they may experience complete remission.
BibTeX:
@article{,
  author = {Thyssen, J. P. and Carlsen, B. C. and Bisgaard, H. and Giwercman, C. and Johansen, J. D. and Linneberg, A. and Meldgaard, M. and Szecsi, P. B. and Stender, S. and Menné, T.},
  title = {Individuals who are homozygous for the 2282del4 and R501X filaggrin null mutations do not always develop dermatitis and complete long-term remission is possible.},
  journal = {J Eur Acad Dermatol Venereol},
  school = {National Allergy Research Centre, Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, Denmark. jacpth01@geh.regionh.dk},
  year = {2012},
  volume = {26},
  number = {3},
  pages = {386--389},
  url = {http://dx.doi.org/10.1111/j.1468-3083.2011.04073.x},
  doi = {https://doi.org/10.1111/j.1468-3083.2011.04073.x}
}
Sevelsted, A. Bisgaard, H. Neonatal size in term children is associated with asthma at age 7, but not with atopic dermatitis or allergic sensitization. 2012 Allergy 22381045 7,361 0
Authors:
Abstract: We hypothesized that anthropometrics in the newborn is associated with development of asthma later in life.The study included a prospective, longitudinal clinical study of a birth cohort of 411 Danish neonates born at term of mothers with a history of asthma. The primary endpoint was physician-diagnosed asthma at age 7 years. Allergic sensitization and atopic dermatitis (AD) were also investigated. Infant size was measured at the research clinic on four occasions during the first year of life. Risk for asthma, AD, and allergic sensitization at age 6-7 were estimated from logistic regression. Time to first asthma and AD were investigated by Cox regression. Multivariate models were adjusted for gender, gestational age, and mothers smoking during pregnancy.Neonatal weight, length, body mass index and head circumference (z-score) were all significantly associated with asthma at age 7. Adjusted odds ratio for asthma by estimated birth weight z-score: 1.87 [1.23-2.84]; P = 0.004. Adjusted HR for onset of asthma by neonatal weight z-score: 1.46 [1.08-1.96]; P = 0.013. Neonatal size did not associate with AD or allergic sensitization.Increased neonatal size was significantly associated with asthma at age 7 but not AD or allergic sensitization in at-risk children born at term. The findings suggest some common prenatal mechanisms linking body size and asthma.
BibTeX:
@article{,
  author = {Sevelsted, A. and Bisgaard, H.},
  title = {Neonatal size in term children is associated with asthma at age 7, but not with atopic dermatitis or allergic sensitization.},
  journal = {Allergy},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health Sciences, University of Copenhagen, Gentofte, Copenhagen, Denmark.},
  year = {2012},
  volume = {67},
  number = {5},
  pages = {670--675},
  url = {http://dx.doi.org/10.1111/j.1398-9995.2012.02805.x},
  doi = {https://doi.org/10.1111/j.1398-9995.2012.02805.x}
}
Schoos, A.-M.M. Bisgaard, H. Fraction of exhaled nitric oxide and bronchial responsiveness are associated and continuous traits in young children independent of asthma. 2012 Chest 23187857 6,044 6
Authors: Schoos, A.-M.M., Chawes, B.L.K., Bønnelykke, K. and Bisgaard, H.
BibTeX:
@article{,
  author = {Schoos, Ann-Marie Malby and Chawes, Bo Lund Krogsgaard and Bønnelykke, Klaus and Bisgaard, Hans},
  title = {Fraction of exhaled nitric oxide and bronchial responsiveness are associated and continuous traits in young children independent of asthma.},
  journal = {Chest},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health Sciences, University of Copenhagen, and Copenhagen University Hospital Gentofte, Copenhagen, Denmark. Electronic address: bisgaard@copsac.com.},
  year = {2012},
  volume = {142},
  number = {6},
  pages = {1562--1568},
  url = {http://dx.doi.org/10.1378/chest.12-0658},
  doi = {https://doi.org/10.1378/chest.12-0658}
}
Taal, H.R. Jaddoe, V.W.V. Common variants at 12q15 and 12q24 are associated with infant head circumference. 2012 Nat Genet 22504419 27,959 55
Authors: Taal, H.R., Pourcain, B.S., Thiering, E., Das, S., Mook-Kanamori, D.O., Warrington, N.M., Kaakinen, M., Kreiner-Møller, E., Bradfield, J.P., Freathy, R.M., Geller, F., Guxens, M., Cousminer, D.L., Kerkhof, M., Timpson, N.J., Ikram, M.A., Beilin, L.J., Bønnelykke, K., Buxton, J.L., Charoen, P., Chawes, B.L.K., Eriksson, J., Evans, D.M., Hofman, A., Kemp, J.P., Kim, C.E., Klopp, N., Lahti, J., Lye, S.J., McMahon, G., Mentch, F.D., Müller, M., O'Reilly, P.F., Prokopenko, I., Rivadeneira, F., Steegers, E.A.P., Sunyer, J., Tiesler, C., Yaghootkar, H., , C.f.H., in Genetic Epidemiology (CHARGE) Consortium, A.R., Breteler, M.M.B., Debette, S., Fornage, M., Gudnason, V., Launer, L.J., van der Lugt, A., Mosley, T.H., Seshadri, S., Smith, A.V., Vernooij, M.W., , E.G.&.L.E.(E.A.G.L.E.c., Blakemore, A.I., Chiavacci, R.M., Feenstra, B., Fernandez-Benet, J., Grant, S.F.A., Hartikainen, A.-L., van der Heijden, A.J., Iñiguez, C., Lathrop, M., McArdle, W.L., Mølgaard, A., Newnham, J.P., Palmer, L.J., Palotie, A., Pouta, A., Ring, S.M., Sovio, U., Standl, M., Uitterlinden, A.G., Wichmann, H.-E., Vissing, N.H., DeCarli, C., van Duijn, C.M., McCarthy, M.I., Koppelman, G.H., Estivill, X., Hattersley, A.T., Melbye, M., Bisgaard, H., Pennell, C.E., Widen, E., Hakonarson, H., Smith, G.D., Heinrich, J., Jarvelin, M.-R., , E.G.G.(E.G.G.C. and Jaddoe, V.W.V.
Abstract: To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 × 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 × 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height, their effects on infant head circumference were largely independent of height (P = 3.8 × 10(-7) for rs7980687 and P = 1.3 × 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 × 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume, Parkinson's disease and other neurodegenerative diseases, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
BibTeX:
@article{,
  author = {Taal, H Rob and Pourcain, Beate St and Thiering, Elisabeth and Das, Shikta and Mook-Kanamori, Dennis O. and Warrington, Nicole M. and Kaakinen, Marika and Kreiner-Møller, Eskil and Bradfield, Jonathan P. and Freathy, Rachel M. and Geller, Frank and Guxens, Mònica and Cousminer, Diana L. and Kerkhof, Marjan and Timpson, Nicholas J. and Ikram, M Arfan and Beilin, Lawrence J. and Bønnelykke, Klaus and Buxton, Jessica L. and Charoen, Pimphen and Chawes, Bo Lund Krogsgaard and Eriksson, Johan and Evans, David M. and Hofman, Albert and Kemp, John P. and Kim, Cecilia E. and Klopp, Norman and Lahti, Jari and Lye, Stephen J. and McMahon, George and Mentch, Frank D. and Müller, Martina and O'Reilly, Paul F. and Prokopenko, Inga and Rivadeneira, Fernando and Steegers, Eric A P. and Sunyer, Jordi and Tiesler, Carla and Yaghootkar, Hanieh and , Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium and Breteler, Monique M B. and Debette, Stephanie and Fornage, Myriam and Gudnason, Vilmundur and Launer, Lenore J. and van der Lugt, Aad and Mosley, Thomas H. and Seshadri, Sudha and Smith, Albert V. and Vernooij, Meike W. and , Early Genetics & Lifecourse Epidemiology (E. A. G. L. E) consortium and Blakemore, Alexandra If and Chiavacci, Rosetta M. and Feenstra, Bjarke and Fernandez-Benet, Julio and Grant, Struan F A. and Hartikainen, Anna-Liisa and van der Heijden, Albert J. and Iñiguez, Carmen and Lathrop, Mark and McArdle, Wendy L. and Mølgaard, Anne and Newnham, John P. and Palmer, Lyle J. and Palotie, Aarno and Pouta, Annneli and Ring, Susan M. and Sovio, Ulla and Standl, Marie and Uitterlinden, Andre G. and Wichmann, H-Erich and Vissing, Nadja Hawwa and DeCarli, Charles and van Duijn, Cornelia M. and McCarthy, Mark I. and Koppelman, Gerard H. and Estivill, Xavier and Hattersley, Andrew T. and Melbye, Mads and Bisgaard, Hans and Pennell, Craig E. and Widen, Elisabeth and Hakonarson, Hakon and Smith, George Davey and Heinrich, Joachim and Jarvelin, Marjo-Riitta and , Early Growth Genetics (E. G. G) Consortium and Jaddoe, Vincent W V.},
  title = {Common variants at 12q15 and 12q24 are associated with infant head circumference.},
  journal = {Nat Genet},
  school = {The Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands.},
  year = {2012},
  volume = {44},
  number = {5},
  pages = {532--538},
  url = {http://dx.doi.org/10.1038/ng.2238},
  doi = {https://doi.org/10.1038/ng.2238}
}
Pedersen, L. Bisgaard, H. Polyunsaturated fatty acid content of mother's milk is associated with childhood body composition. 2012 Pediatr Res 23007033 2,882 25
Authors: Pedersen, L., Lauritzen, L., Brasholt, M., Buhl, T. and Bisgaard, H.
Abstract: The consumption of polyunsaturated fatty acids has changed, and the prevalence of adiposity has increased over the past 30 y. A decrease of n-3 polyunsaturated fatty acid content in breast milk has been suggested to be a contributing factor. The objective of this study was to investigate the relationship between docosahexaenoic acid (DHA) content and n-6/n-3 polyunsaturated fatty acid ratio in breast milk, body composition, and timing of adiposity rebound in children.In the Copenhagen Prospective Study on Asthma in Childhood birth cohort, breast milk fatty acid profile was determined in 281 mothers and BMI development was prospectively followed up to the age of 7 y in 222 children. Age and BMI at adiposity rebound were registered. Furthermore, fat mass determination by dual energy X-ray absorptiometry was performed in 207 children at 6-9 y of age.There was a significant association between breast milk DHA and BMI from 2 to 7 y, fat mass, and, for the girls, age at adiposity rebound. No associations were found between the breast milk n-6/n-3 polyunsaturated fatty acid ratio and body composition.Early intake of DHA may have an effect on body composition. Dietary habits of lactating mothers could contribute to the increased prevalence of obesity in Western societies.
BibTeX:
@article{,
  author = {Pedersen, Louise and Lauritzen, Lotte and Brasholt, Martin and Buhl, Thora and Bisgaard, Hans},
  title = {Polyunsaturated fatty acid content of mother's milk is associated with childhood body composition.},
  journal = {Pediatr Res},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen, Naestved Hospital, Copenhagen, Denmark.},
  year = {2012},
  volume = {72},
  number = {6},
  pages = {631--636},
  url = {http://dx.doi.org/10.1038/pr.2012.127},
  doi = {https://doi.org/10.1038/pr.2012.127}
}
Iskandar, A. Bisgaard, H. Coarse and fine particles but not ultrafine particles in urban air trigger hospital admission for asthma in children. 2012 Thorax 22156960 8,272 64
Authors: Iskandar, A., Andersen, Z.J., Bønnelykke, K., Ellermann, T., Andersen, K.K. and Bisgaard, H.
BibTeX:
@article{,
  author = {Iskandar, Amne and Andersen, Zorana Jovanovic and Bønnelykke, Klaus and Ellermann, Thomas and Andersen, Klaus Kaae and Bisgaard, Hans},
  title = {Coarse and fine particles but not ultrafine particles in urban air trigger hospital admission for asthma in children.},
  journal = {Thorax},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen, Copenhagen University Hospital, Ledreborg Allé 34, 2820 Gentofte, Denmark.},
  year = {2012},
  volume = {67},
  number = {3},
  pages = {252--257},
  url = {http://dx.doi.org/10.1136/thoraxjnl-2011-200324},
  doi = {https://doi.org/10.1136/thoraxjnl-2011-200324}
}
Kreiner-Møller, E. Bisgaard, H. Infant acetaminophen use associates with early asthmatic symptoms independently of respiratory tract infections: the Copenhagen Prospective Study on Asthma in Childhood 2000 (COPSAC(2000)) cohort. 2012 J Allergy Clin Immunol 23102919 13,081 21
Authors: Kreiner-Møller, E., Sevelsted, A., Vissing, N.H., Schoos, A.-M.M. and Bisgaard, H.
BibTeX:
@article{,
  author = {Kreiner-Møller, Eskil and Sevelsted, Astrid and Vissing, Nadja Hawwa and Schoos, Ann-Marie Malby and Bisgaard, Hans},
  title = {Infant acetaminophen use associates with early asthmatic symptoms independently of respiratory tract infections: the Copenhagen Prospective Study on Asthma in Childhood 2000 (COPSAC(2000)) cohort.},
  journal = {J Allergy Clin Immunol},
  year = {2012},
  volume = {130},
  number = {6},
  pages = {1434--1436},
  url = {http://dx.doi.org/10.1016/j.jaci.2012.09.017},
  doi = {https://doi.org/10.1016/j.jaci.2012.09.017}
}
Kreiner-Møller, E. Bisgaard, H. Allergic rhinitis is associated with otitis media with effusion: a birth cohort study. 2012 Clin Exp Allergy 23106661 5,264 20
Authors: Kreiner-Møller, E., Chawes, B.L.K., Caye-Thomasen, P., Bønnelykke, K. and Bisgaard, H.
Abstract: Childhood otitis media with effusion is a common disease and a link to allergic diseases has been suggested.To investigate the association between atopic disease and otitis media with effusion diagnosed according to strict objective case definitions by age 6 years.We evaluated 291 children in the 6th year of life from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) 2000 birth cohort. Otitis media with effusion was diagnosed based on tympanometric and objective evaluation. Asthma, eczema, allergic- and non-allergic rhinitis was diagnosed prospectively by pre-defined algorithms. Nasal mucosal swelling was assessed using acoustic rhinometry and nasal eosinophilia from scrapings. Analyses were performed using logistic regression and adjusted for dog, cat and smoking exposure, paternal atopy, household income, older siblings, gender and number of acute otitis media episodes.Otitis media with effusion was diagnosed in 39% of the cohort and was associated with allergic rhinitis (aOR = 3.36, CI = 1.26-8.96, P = 0.02), but not with nasal mucosal swelling, nasal oeosinophilia, non-allergic rhinitis, asthma or eczema.Otitis media with effusion is closely associated with allergic rhinitis presumably caused by allergic inflammation, but not mechanical nasal mucosal swelling. These findings warrant an increased awareness of otitis media with effusion in children with allergic rhinitis.
BibTeX:
@article{,
  author = {Kreiner-Møller, E. and Chawes, B L K. and Caye-Thomasen, P. and Bønnelykke, K. and Bisgaard, H.},
  title = {Allergic rhinitis is associated with otitis media with effusion: a birth cohort study.},
  journal = {Clin Exp Allergy},
  school = {COPSAC, The Copenhagen Prospective Studies on Asthma in Childhood, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.},
  year = {2012},
  volume = {42},
  number = {11},
  pages = {1615--1620},
  url = {http://dx.doi.org/10.1111/j.1365-2222.2012.04038.x},
  doi = {https://doi.org/10.1111/j.1365-2222.2012.04038.x}
}
Følsgaard, N.V. Bisgaard, H. Cord blood Th2-related chemokine CCL22 levels associate with elevated total-IgE during preschool age. 2012 Clin Exp Allergy 23106659 5,264 12
Authors: Følsgaard, N.V., Chawes, B.L.K., Bønnelykke, K., Jenmalm, M.C. and Bisgaard, H.
Abstract: Early-life immune deviation is suspected in the inception of atopic disease.To investigate the association between cord blood chemokines and the subsequent development of atopic biomarkers and clinical end-points during the first 6 years of life.The Th1-associated chemokines CXCL10 and CXCL11 and the Th2-associated chemokines CCL17 and CCL22 were assessed in cord blood of asymptomatic at-risk newborn children from the Copenhagen Prospective Study on Asthma in Childhood (COPSAC(2000) ) birth cohort and associated with the longitudinal development of biomarkers and clinical end-points of asthma, eczema, and allergic rhinitis during the first 6 years of life.Cord blood CCL22 levels were significantly associated to total-IgE levels measured at four time-points during the first 6 years of life; overall odds ratio, 1.54 [CI, 1.25-1.89; P < 0.0001]. CXCL10 and CXCL11 were not associated with development of any atopic disorders or biomarkers.High cord blood levels of the Th2 related chemokine CCL22 were significantly associated with high total- IgE levels during the first 6 years of life, but not with specific sensitization, asthma, eczema or allergic rhinitis. This suggests an inborn skewing of the immune system in healthy newborns developing elevated total- IgE later in life.
BibTeX:
@article{,
  author = {Følsgaard, N. V. and Chawes, B L K. and Bønnelykke, K. and Jenmalm, M. C. and Bisgaard, H.},
  title = {Cord blood Th2-related chemokine CCL22 levels associate with elevated total-IgE during preschool age.},
  journal = {Clin Exp Allergy},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital, Gentofte, Denmark.},
  year = {2012},
  volume = {42},
  number = {11},
  pages = {1596--1603},
  url = {http://dx.doi.org/10.1111/j.1365-2222.2012.04048.x},
  doi = {https://doi.org/10.1111/j.1365-2222.2012.04048.x}
}
Følsgaard, N.V. Bisgaard, H. Neonatal cytokine profile in the airway mucosal lining fluid is skewed by maternal atopy. 2012 Am J Respir Crit Care Med 22077068 13,204 34
Authors: Følsgaard, N.V., Chawes, B.L., Rasmussen, M.A., Bischoff, A.L., Carson, C.G., Stokholm, J., Pedersen, L., Hansel, T.T., Bønnelykke, K., Brix, S. and Bisgaard, H.
Abstract: Heredity from mother or father may impact differently in complex diseases, such as atopy. Maternal atopy is a stronger risk factor than paternal atopy for the development of atopy in the offspring. We hypothesized that mother's and father's atopy would have a differential imprinting on the cytokines and chemokines in the upper airway mucosal lining fluid of healthy neonates.To study parental atopic imprinting on the cytokines and chemokines in the upper airway mucosal lining fluid of healthy neonates.Eighteen cytokines and chemokines were quantified in nasal mucosal lining fluid in 309 neonates from the novel unselected Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohort.Maternal, but not paternal, atopic status (asthma, hay fever, or eczema with or without sensitization) was associated with general down-regulation of all 18 mediators assessed by principal component analysis (overall P = 0.015).Maternal atopy, but not paternal atopy, showed a strong linkage with a suppressed mucosal cytokine and chemokine signature in asymptomatic neonates, suggesting imprinting by the maternal milieu in utero or perinatal life.
BibTeX:
@article{,
  author = {Følsgaard, Nilofar V. and Chawes, Bo L. and Rasmussen, Morten A. and Bischoff, Anne L. and Carson, Charlotte G. and Stokholm, Jakob and Pedersen, Louise and Hansel, Trevor T. and Bønnelykke, Klaus and Brix, Susanne and Bisgaard, Hans},
  title = {Neonatal cytokine profile in the airway mucosal lining fluid is skewed by maternal atopy.},
  journal = {Am J Respir Crit Care Med},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen, Copenhagen University Hospital, Gentofte, Denmark.},
  year = {2012},
  volume = {185},
  number = {3},
  pages = {275--280},
  url = {http://dx.doi.org/10.1164/rccm.201108-1471OC},
  doi = {https://doi.org/10.1164/rccm.201108-1471OC}
}
Chawes, B.L.K. Bisgaard, H. Neonatal bronchial hyperresponsiveness precedes acute severe viral bronchiolitis in infants. 2012 J Allergy Clin Immunol 22713595 13,081 38
Authors: Chawes, B.L.K., Poorisrisak, P., Johnston, S.L. and Bisgaard, H.
Abstract: Respiratory syncytial virus and other respiratory tract viruses lead to common colds in most infants, whereas a minority develop acute severe bronchiolitis often requiring hospitalization. We hypothesized that such an excessive response to respiratory tract viral infection is caused by host factors reflected in pre-existing increased bronchial responsiveness.We sought to compare bronchial responsiveness and lung function in 1-month-old neonates who later develop acute severe bronchiolitis with those who do not.We measured infant lung function (n=402) and bronchial responsiveness to methacholine (n=363) using the raised-volume rapid thoracoabdominal compression technique before any respiratory symptoms in 1-month-old neonates from the Copenhagen Prospective Study of Asthma in Childhood birth cohort born to mothers with asthma. The children were prospectively monitored for respiratory symptoms and given a diagnosis of acute severe bronchiolitis according to a fixed algorithm.Thirty-four (8.5 infants had acute severe bronchiolitis before 2 years of age, 21 (62 were hospitalized, and 23 (67 of the cases were associated with respiratory syncytial virus. Children who later had acute severe bronchiolitis irrespective of viral species had a 2.5-fold increased responsiveness to methacholine (provocative dose of methacholine producing a 15% decrease in transcutaneous oxygen pressure [PD(15)]) at age 1 month compared with control subjects (median PD(15) in cases vs control subjects, 0.13 vs 0.33 μmol; P=.01), whereas differences in baseline airflow were not significant for forced expiratory volume at 0.5 seconds (mean z score for cases vs control subjects, -0.18 vs -0.01; P=.36) and forced expiratory flow at 50% of forced vital capacity (mean z score for cases vs control subjects, -0.37 vs -0.09; P=.13).Bronchial hyperresponsiveness in at-risk neonates precedes acute severe bronchiolitis in response to infections with respiratory tract virus.
BibTeX:
@article{,
  author = {Chawes, Bo L K. and Poorisrisak, Porntiva and Johnston, Sebastian L. and Bisgaard, Hans},
  title = {Neonatal bronchial hyperresponsiveness precedes acute severe viral bronchiolitis in infants.},
  journal = {J Allergy Clin Immunol},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen and Danish Pediatric Asthma Centre, Copenhagen University Hospital, Gentofte, Denmark.},
  year = {2012},
  volume = {130},
  number = {2},
  pages = {354--61.e3},
  url = {http://dx.doi.org/10.1016/j.jaci.2012.04.045},
  doi = {https://doi.org/10.1016/j.jaci.2012.04.045}
}
Carson, C.G. Bisgaard, H. Clinical presentation of atopic dermatitis by filaggrin gene mutation status during the first 7 years of life in a prospective cohort study. 2012 PLoS One 23166590 2,806 32
Authors: Carson, C.G., Rasmussen, M.A., Thyssen, J.P., Menné, T. and Bisgaard, H.
Abstract: Filaggrin null mutations result in impaired skin barrier functions, increase the risk of early onset atopic dermatitis and lead to a more severe and chronic disease. We aimed to characterize the clinical presentation and course of atopic dermatitis associated with filaggrin mutations within the first 7 years of life.The COPSAC cohort is a prospective, clinical birth cohort study of 411 children born to mothers with a history of asthma followed during their first 7 years of life with scheduled visits every 6 months, as well as visits for acute exacerbations of dermatitis. Atopic dermatitis was defined in accordance with international guidelines and described at every visit using 35 predefined localizations and 10 different characteristics.A total of 170 (43 of 397 Caucasian children developed atopic dermatitis. The R501X and/or 2282del4 filaggrin null mutations were present in 26 (15 of children with atopic dermatitis and were primarily associated with predilection to exposed skin areas (especially the cheeks and back of the hands) and an up-regulation of both acute and chronic dermatitis. Furthermore, we found the filaggrin mutations to be associated with a higher number of unscheduled visits (3.6 vs. 2.7; p=0.04) and more severe (moderate-severe SCORAD 44% vs. 31 p=0.14), and widespread dermatitis (10% vs. 6% of the body area, p<0.001) with an earlier age at onset (246 vs. 473 days, p<0.0001) compared to wild-type.In children, filaggrin mutations seem to define a specific endotype of atopic dermatitis primarily characterized by predilection to exposed areas of the body, in particular hands and cheeks, and an up-regulation in both acute and chronic morphological markers. Secondary, this endotype is characterized by an early onset of dermatitis and a more severe course, with more generalized dermatitis resulting in more frequent medical consultations.
BibTeX:
@article{,
  author = {Carson, Charlotte Giwercman and Rasmussen, Morten Arendt and Thyssen, Jacob P. and Menné, Torkil and Bisgaard, Hans},
  title = {Clinical presentation of atopic dermatitis by filaggrin gene mutation status during the first 7 years of life in a prospective cohort study.},
  journal = {PLoS One},
  school = {Copenhagen Prospective Studies on Asthma in Childhood; COPSAC, Health Sciences, University of Copenhagen, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark.},
  year = {2012},
  volume = {7},
  number = {11},
  pages = {e48678},
  url = {http://dx.doi.org/10.1371/journal.pone.0048678},
  doi = {https://doi.org/10.1371/journal.pone.0048678}
}
Carson, C.G. Bisgaard, H. Alcohol intake in pregnancy increases the child's risk of atopic dermatitis. the COPSAC prospective birth cohort study of a high risk population. 2012 PLoS One 22916148 2,806 12
Authors: Carson, C.G., Halkjaer, L.B., Jensen, S.M. and Bisgaard, H.
Abstract: Atopic dermatitis has increased four-fold over the recent decades in developed countries, indicating that changes in environmental factors associated with lifestyle may play an important role in this epidemic. It has been proposed that alcohol consumption may be one contributing risk factor in this development.To analyze the impact of alcohol intake during pregnancy on the development of atopic dermatitis during the first 7 years of life.The COPSAC cohort is a prospective, longitudinal, birth cohort study of 411 children born to mothers with a history of asthma, followed up for 7 years with scheduled visits every 6 months as well as visits for acute exacerbations of atopic dermatitis. Risk of atopic dermatitis from any alcohol consumption during pregnancy was analyzed as time-to-diagnosis and adjusted for known risk factors.177 of 411 children developed atopic dermatitis before age 7 years. We found a significant effect of alcohol intake during pregnancy on atopic dermatitis development (HR 1.44, 95% CI 1.05-1.99 p=0.024). This conclusion was unaffected after adjustment for smoking, mother's education and mother's atopic dermatitis.The selection of a high-risk cohort, with all mothers suffering from asthma, and all children having a gestational age above 35 weeks with no congenital abnormality, systemic illness, or history of mechanical ventilation or lower airway infection.Alcohol intake by pregnant women with a history of asthma, is significantly associated with an increased risk for the child for developing atopic dermatitis during the first 7 years of life.
BibTeX:
@article{,
  author = {Carson, Charlotte Giwercman and Halkjaer, Liselotte Brydensholt and Jensen, Signe Marie and Bisgaard, Hans},
  title = {Alcohol intake in pregnancy increases the child's risk of atopic dermatitis. the COPSAC prospective birth cohort study of a high risk population.},
  journal = {PLoS One},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark.},
  year = {2012},
  volume = {7},
  number = {8},
  pages = {e42710},
  url = {http://dx.doi.org/10.1371/journal.pone.0042710},
  doi = {https://doi.org/10.1371/journal.pone.0042710}
}
Bradfield, J.P. Grant, S.F.A. A genome-wide association meta-analysis identifies new childhood obesity loci. 2012 Nat Genet 22484627 27,959 173
Authors: Bradfield, J.P., Taal, H.R., Timpson, N.J., Scherag, A., Lecoeur, C., Warrington, N.M., Hypponen, E., Holst, C., Valcarcel, B., Thiering, E., Salem, R.M., Schumacher, F.R., Cousminer, D.L., Sleiman, P.M.A., Zhao, J., Berkowitz, R.I., Vimaleswaran, K.S., Jarick, I., Pennell, C.E., Evans, D.M., St Pourcain, B., Berry, D.J., Mook-Kanamori, D.O., Hofman, A., Rivadeneira, F., Uitterlinden, A.G., van Duijn, C.M., van der Valk, R.J.P., de Jongste, J.C., Postma, D.S., Boomsma, D.I., Gauderman, W.J., Hassanein, M.T., Lindgren, C.M., Mägi, R., Boreham, C.A.G., Neville, C.E., Moreno, L.A., Elliott, P., Pouta, A., Hartikainen, A.-L., Li, M., Raitakari, O., Lehtimäki, T., Eriksson, J.G., Palotie, A., Dallongeville, J., Das, S., Deloukas, P., McMahon, G., Ring, S.M., Kemp, J.P., Buxton, J.L., Blakemore, A.I.F., Bustamante, M., Guxens, M., Hirschhorn, J.N., Gillman, M.W., Kreiner-Møller, E., Bisgaard, H., Gilliland, F.D., Heinrich, J., Wheeler, E., Barroso, I., O'Rahilly, S., Meirhaeghe, A., Sørensen, T.I.A., Power, C., Palmer, L.J., Hinney, A., Widen, E., Farooqi, I.S., McCarthy, M.I., Froguel, P., Meyre, D., Hebebrand, J., Jarvelin, M.-R., Jaddoe, V.W.V., Smith, G.D., Hakonarson, H., Grant, S.F.A. and , E.G.G.C.
Abstract: Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made in establishing genetic influences on common early-onset obesity. We performed a North American, Australian and European collaborative meta-analysis of 14 studies consisting of 5,530 cases (≥95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight newly discovered signals yielding association with P < 5 × 10(-6) in nine independent data sets (2,818 cases and 4,083 controls), we observed two loci that yielded genome-wide significant combined P values near OLFM4 at 13q14 (rs9568856; P = 1.82 × 10(-9); odds ratio (OR) = 1.22) and within HOXB5 at 17q21 (rs9299; P = 3.54 × 10(-9); OR = 1.14). Both loci continued to show association when two extreme childhood obesity cohorts were included (2,214 cases and 2,674 controls). These two loci also yielded directionally consistent associations in a previous meta-analysis of adult BMI(1).
BibTeX:
@article{,
  author = {Bradfield, Jonathan P. and Taal, H Rob and Timpson, Nicholas J. and Scherag, André and Lecoeur, Cecile and Warrington, Nicole M. and Hypponen, Elina and Holst, Claus and Valcarcel, Beatriz and Thiering, Elisabeth and Salem, Rany M. and Schumacher, Fredrick R. and Cousminer, Diana L. and Sleiman, Patrick M A. and Zhao, Jianhua and Berkowitz, Robert I. and Vimaleswaran, Karani S. and Jarick, Ivonne and Pennell, Craig E. and Evans, David M. and St Pourcain, Beate and Berry, Diane J. and Mook-Kanamori, Dennis O. and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, André G. and van Duijn, Cornelia M. and van der Valk, Ralf J P. and de Jongste, Johan C. and Postma, Dirkje S. and Boomsma, Dorret I. and Gauderman, W James and Hassanein, Mohamed T. and Lindgren, Cecilia M. and Mägi, Reedik and Boreham, Colin A G. and Neville, Charlotte E. and Moreno, Luis A. and Elliott, Paul and Pouta, Anneli and Hartikainen, Anna-Liisa and Li, Mingyao and Raitakari, Olli and Lehtimäki, Terho and Eriksson, Johan G. and Palotie, Aarno and Dallongeville, Jean and Das, Shikta and Deloukas, Panos and McMahon, George and Ring, Susan M. and Kemp, John P. and Buxton, Jessica L. and Blakemore, Alexandra I F. and Bustamante, Mariona and Guxens, Mònica and Hirschhorn, Joel N. and Gillman, Matthew W. and Kreiner-Møller, Eskil and Bisgaard, Hans and Gilliland, Frank D. and Heinrich, Joachim and Wheeler, Eleanor and Barroso, Inês and O'Rahilly, Stephen and Meirhaeghe, Aline and Sørensen, Thorkild I A. and Power, Chris and Palmer, Lyle J. and Hinney, Anke and Widen, Elisabeth and Farooqi, I Sadaf and McCarthy, Mark I. and Froguel, Philippe and Meyre, David and Hebebrand, Johannes and Jarvelin, Marjo-Riitta and Jaddoe, Vincent W V. and Smith, George Davey and Hakonarson, Hakon and Grant, Struan F A. and , Early Growth Genetics Consortium},
  title = {A genome-wide association meta-analysis identifies new childhood obesity loci.},
  journal = {Nat Genet},
  school = {Center for Applied Genomics, Abramson Research Center, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.},
  year = {2012},
  volume = {44},
  number = {5},
  pages = {526--531},
  url = {http://dx.doi.org/10.1038/ng.2247},
  doi = {https://doi.org/10.1038/ng.2247}
}
Bisgaard, H. Knorr, B. "To wheeze or not to wheeze": that is not the question--the sequel. 2012 J Allergy Clin Immunol 22365706 13,081 7
Authors: Bisgaard, H., Swern, A.S. and Knorr, B.
BibTeX:
@article{,
  author = {Bisgaard, Hans and Swern, Arlene S. and Knorr, Barbara},
  title = {"To wheeze or not to wheeze": that is not the question--the sequel.},
  journal = {J Allergy Clin Immunol},
  year = {2012},
  volume = {130},
  number = {2},
  pages = {531--532},
  url = {http://dx.doi.org/10.1016/j.jaci.2011.10.047},
  doi = {https://doi.org/10.1016/j.jaci.2011.10.047}
}
Bisgaard, H. Bønnelykke, K. Interaction between asthma and lung function growth in early life. 2012 Am J Respir Crit Care Med 22461370 13,204 112
Authors: Bisgaard, H., Jensen, S.M. and Bønnelykke, K.
Abstract: The causal direction between asthma and lung function deficit is unknown, but important for the focus of preventive measures and research into the origins of asthma.To analyze the interaction between lung function development and asthma from birth to 7 years of age.The Copenhagen Prospective Studies on Asthma in Childhood is a prospective clinical study of a birth cohort of 411 at-risk children. Spirometry was completed in 403 (98 neonates and again by age 7 in 317 children (77.Neonatal spirometry and bronchial responsiveness to methacholine was measured during sedation by forced flow-volume measurements. Asthma was diagnosed prospectively from daily diary cards and clinic visits every 6 months. Children with asthma by age 7 (14 already had a significant airflow deficit as neonates (forced expiratory flow at 50% of vital capacity second in neonates reduced by 0.34 z score by 1 mo; P = 0.03). This deficit progressed significantly during early childhood (forced expiratory flow at 0.5 seconds in neonates at age 7 reduced by 0.82 z score by age 7; P < 0.0001), suggesting that approximately 40% of the airflow deficit associated with asthma is present at birth, whereas 60% develops with clinical disease. Environmental tobacco exposure, but not allergic sensitization, also hampered airflow growth. Bronchial responsiveness to methacholine in the neonates was associated with the development of asthma (P = 0.01).Children developing asthma by age 7 had a lung function deficit and increased bronchial responsiveness as neonates. This lung function deficit progressed to age 7. Therefore, research into the origins and prevention of asthma should consider early life before and after birth.
BibTeX:
@article{,
  author = {Bisgaard, Hans and Jensen, Signe M. and Bønnelykke, Klaus},
  title = {Interaction between asthma and lung function growth in early life.},
  journal = {Am J Respir Crit Care Med},
  school = {Copenhagen Prospective Studies on Asthma in Childhood; Health Sciences, University of Copenhagen, Copenhagen, Denmark. bisgaard@copsac.com},
  year = {2012},
  volume = {185},
  number = {11},
  pages = {1183--1189},
  url = {http://dx.doi.org/10.1164/rccm.201110-1922OC},
  doi = {https://doi.org/10.1164/rccm.201110-1922OC}
}
Bel, E.H. Compton, C.H. Diagnosis and definition of severe refractory asthma: an international consensus statement from the Innovative Medicine Initiative (IMI). 2011 Thorax 21106547 8,272 164
Authors: Bel, E.H., Sousa, A., Fleming, L., Bisgaard, H., Bush, A., Chung, K.F., Versnel, J., Wagener, A.H., Wagers, S.S., Sterk, P.J., Compton, C.H. and Unbiased Biomarkers for the Prediction of Respiratory Disease Outcome (U-B. I. O. P. R. E. D) Consortium, C.G.
Abstract: Patients with severe refractory asthma pose a major healthcare problem. Over the last decade it has become increasingly clear that, for the development of new targeted therapies, there is an urgent need for further characterisation and classification of these patients. The Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) consortium is a pan-European public-private collaboration funded by the European Commission Innovative Medicines Initiative of the European Union. U-BIOPRED aims to subphenotype patients with severe refractory asthma by using an innovative systems biology approach. This paper presents the U-BIOPRED international consensus on the definition and diagnosis of severe asthma, aligning the latest concepts in adults as well as in children. The consensus is based on existing recommendations up to 2010 and will be used for the selection of patients for the upcoming U-BIOPRED study. It includes the differentiation between 'problematic', 'difficult' and 'severe refractory' asthma, and provides a systematic algorithmic approach to the evaluation of patients presenting with chronic severe asthma symptoms for use in clinical research and specialised care.
BibTeX:
@article{,
  author = {Bel, Elisabeth H. and Sousa, Ana and Fleming, Louise and Bush, Andrew and Chung, K Fan and Versnel, Jennifer and Wagener, Ariane H. and Wagers, Scott S. and Sterk, Peter J. and Compton, Chris H. and , Unbiased Biomarkers for the Prediction of Respiratory Disease Outcome (U-B. I. O. P. R. E. D) Consortium, Consensus Generation},
  title = {Diagnosis and definition of severe refractory asthma: an international consensus statement from the Innovative Medicine Initiative (IMI).},
  journal = {Thorax},
  school = {Department of Respiratory Medicine, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. e.h.bel@amc.uva.nl},
  year = {2011},
  volume = {66},
  number = {10},
  pages = {910--917},
  url = {http://dx.doi.org/10.1136/thx.2010.153643},
  doi = {https://doi.org/10.1136/thx.2010.153643}
}
Raaschou-Nielsen, O. Bisgaard, H. Predictors of indoor fine particulate matter in infants' bedrooms in Denmark. 2011 Environ Res 21059467 3,835 9
Authors: Raaschou-Nielsen, O., Sørensen, M., Hertel, O., Chawes, B.L.K., Vissing, N., Bønnelykke, K. and Bisgaard, H.
Abstract: Particulate matter (PM) in ambient air is responsible for adverse health effects in adults and children. Relatively little is known about the concentrations, sources and health effects of PM in indoor air.To identify sources of fine PM in infants' bedrooms.We conducted 1122 measurements of fine PM (PM(2.5) and black smoke) in the bedrooms of 389 infants and registered indoor activities and characteristics of the house. We used mixed models to identify and quantify associations between predictors and concentrations.The concentration of PM(2.5) was 2.8 times (95% confidence interval [CI], 1.4-5.5 times) higher in houses where people smoked; the concentration increased by 19% (95% CI, 15-23 per doubling of the amount of tobacco smoked and decreased by 16% (95% CI, 9-27 per 5-m increase in the distance between the smoking area and the infant's bedroom. Frying without a range hood was associated with a 32% (95% CI, 12-54 higher PM(2.5) concentration per time per day, whereas frying with use of a range hood did not increase the concentration in the infant's bedroom. Use of a fireplace, stove, candles or vacuum-cleaner, interior rebuilding or renovation, local traffic, inner city residence and cold season increased the fine PM concentration. Open windows decreased the PM(2.5) concentration in homes with smokers but increased the concentration in non-smoking homes.We identified several sources of fine PM in infants' bedrooms. The concentrations can be reduced by use of a range hood for frying, by not using candles, a fireplace or a stove, by increasing the distance between the bedroom and the smoking area and by opening windows in houses of smokers. Smoking is a strong predictor of fine PM in infants' bedrooms and should be avoided.
BibTeX:
@article{,
  author = {Raaschou-Nielsen, Ole and Sørensen, Mette and Hertel, Ole and Chawes, Bo L K. and Vissing, Nadja and Bønnelykke, Klaus and Bisgaard, Hans},
  title = {Predictors of indoor fine particulate matter in infants' bedrooms in Denmark.},
  journal = {Environ Res},
  school = {Institute of Cancer Epidemiology, Danish Cancer Society, Strandboulevarden 49, 2100 Copenhagen, Denmark. ole@cancer.dk},
  year = {2011},
  volume = {111},
  number = {1},
  pages = {87--93},
  url = {http://dx.doi.org/10.1016/j.envres.2010.10.007},
  doi = {https://doi.org/10.1016/j.envres.2010.10.007}
}
Paternoster, L. Weidinger, S. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis. 2011 Nat Genet 22197932 27,959 143
Authors: Paternoster, L., Standl, M., Chen, C.-M., Ramasamy, A., Bønnelykke, K., Duijts, L., Ferreira, M.A., Alves, A.C., Thyssen, J.P., Albrecht, E., Baurecht, H., Feenstra, B., Sleiman, P.M.A., Hysi, P., Warrington, N.M., Curjuric, I., Myhre, R., Curtin, J.A., Groen-Blokhuis, M.M., Kerkhof, M., Sääf, A., Franke, A., Ellinghaus, D., Fölster-Holst, R., Dermitzakis, E., Montgomery, S.B., Prokisch, H., Heim, K., Hartikainen, A.-L., Pouta, A., Pekkanen, J., Blakemore, A.I.F., Buxton, J.L., Kaakinen, M., Duffy, D.L., Madden, P.A., Heath, A.C., Montgomery, G.W., Thompson, P.J., Matheson, M.C., Le Souëf, P., , A.A.G.C.(A.A.G.C., St Pourcain, B., Smith, G.D., Henderson, J., Kemp, J.P., Timpson, N.J., Deloukas, P., Ring, S.M., Wichmann, H.-E., Müller-Nurasyid, M., Novak, N., Klopp, N., Rodr\iguez, E., McArdle, W., Linneberg, A., Menné, T., Nohr, E.A., Hofman, A., Uitterlinden, A.G., van Duijn, C.M., Rivadeneira, F., de Jongste, J.C., van der Valk, R.J.P., Wjst, M., Jogi, R., Geller, F., Boyd, H.A., Murray, J.C., Kim, C., Mentch, F., March, M., Mangino, M., Spector, T.D., Bataille, V., Pennell, C.E., Holt, P.G., Sly, P., Tiesler, C.M.T., Thiering, E., Illig, T., Imboden, M., Nystad, W., Simpson, A., Hottenga, J.-J., Postma, D., Koppelman, G.H., Smit, H.A., Söderhäll, C., Chawes, B., Kreiner-Møller, E., Bisgaard, H., Melén, E., Boomsma, D.I., Custovic, A., Jacobsson, B., Probst-Hensch, N.M., Palmer, L.J., Glass, D., Hakonarson, H., Melbye, M., Jarvis, D.L., Jaddoe, V.W.V., Gieger, C., , G.o.O.Y.A.(G.O.Y.A.C., Strachan, D.P., Martin, N.G., Jarvelin, M.-R., Heinrich, J., Evans, D.M., Weidinger, S. and , E.A.G.&.L.E.(E.A.G.L.E.C.
Abstract: Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10(-13)) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10(-9)), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10(-8)). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.
BibTeX:
@article{,
  author = {Paternoster, Lavinia and Standl, Marie and Chen, Chih-Mei and Ramasamy, Adaikalavan and Bønnelykke, Klaus and Duijts, Liesbeth and Ferreira, Manuel A. and Alves, Alexessander Couto and Thyssen, Jacob P. and Albrecht, Eva and Baurecht, Hansjörg and Feenstra, Bjarke and Sleiman, Patrick M A. and Hysi, Pirro and Warrington, Nicole M. and Curjuric, Ivan and Myhre, Ronny and Curtin, John A. and Groen-Blokhuis, Maria M. and Kerkhof, Marjan and Sääf, Annika and Franke, Andre and Ellinghaus, David and Fölster-Holst, Regina and Dermitzakis, Emmanouil and Montgomery, Stephen B. and Prokisch, Holger and Heim, Katharina and Hartikainen, Anna-Liisa and Pouta, Anneli and Pekkanen, Juha and Blakemore, Alexandra I F. and Buxton, Jessica L. and Kaakinen, Marika and Duffy, David L. and Madden, Pamela A. and Heath, Andrew C. and Montgomery, Grant W. and Thompson, Philip J. and Matheson, Melanie C. and Le Souëf, Peter and , Australian Asthma Genetics Consortium (A. A. G. C) and St Pourcain, Beate and Smith, George Davey and Henderson, John and Kemp, John P. and Timpson, Nicholas J. and Deloukas, Panos and Ring, Susan M. and Wichmann, H-Erich and Müller-Nurasyid, Martina and Novak, Natalija and Klopp, Norman and Rodr\iguez, Elke and McArdle, Wendy and Linneberg, Allan and Menné, Torkil and Nohr, Ellen A. and Hofman, Albert and Uitterlinden, André G. and van Duijn, Cornélia M. and Rivadeneira, Fernando and de Jongste, Johan C. and van der Valk, Ralf J P. and Wjst, Matthias and Jogi, Rain and Geller, Frank and Boyd, Heather A. and Murray, Jeffrey C. and Kim, Cecilia and Mentch, Frank and March, Michael and Mangino, Massimo and Spector, Tim D. and Bataille, Veronique and Pennell, Craig E. and Holt, Patrick G. and Sly, Peter and Tiesler, Carla M T. and Thiering, Elisabeth and Illig, Thomas and Imboden, Medea and Nystad, Wenche and Simpson, Angela and Hottenga, Jouke-Jan and Postma, Dirkje and Koppelman, Gerard H. and Smit, Henriette A. and Söderhäll, Cilla and Chawes, Bo and Kreiner-Møller, Eskil and Bisgaard, Hans and Melén, Erik and Boomsma, Dorret I. and Custovic, Adnan and Jacobsson, Bo and Probst-Hensch, Nicole M. and Palmer, Lyle J. and Glass, Daniel and Hakonarson, Hakon and Melbye, Mads and Jarvis, Deborah L. and Jaddoe, Vincent W V. and Gieger, Christian and , Genetics of Overweight Young Adults (G. O. Y. A) Consortium and Strachan, David P. and Martin, Nicholas G. and Jarvelin, Marjo-Riitta and Heinrich, Joachim and Evans, David M. and Weidinger, Stephan and , E. Arly Genetics & Lifecourse Epidemiology (E. A. G. L. E) Consortium},
  title = {Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis.},
  journal = {Nat Genet},
  school = {Medical Research Council Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, UK.},
  year = {2011},
  volume = {44},
  number = {2},
  pages = {187--192}
}
Hollegaard, M.V. Hougaard, D.M. Robustness of genome-wide scanning using archived dried blood spot samples as a DNA source. 2011 BMC Genet 21726430 2,266 29
Authors: Hollegaard, M.V., Grove, J., Grauholm, J., Kreiner-Møller, E., Bønnelykke, K., Nørgaard, M., Benfield, T.L., Nørgaard-Pedersen, B., Mortensen, P.B., Mors, O., Sørensen, H.T., Harboe, Z.B., Børglum, A.D., Demontis, D., Ørntoft, T.F., Bisgaard, H. and Hougaard, D.M.
Abstract: The search to identify disease-susceptible genes requires access to biological material from numerous well-characterized subjects. Archived residual dried blood spot (DBS) samples, also known as Guthrie cards, from national newborn screening programs may provide a DNA source for entire populations. Combined with clinical information from medical registries, DBS samples could provide a rich source for productive research. However, the amounts of DNA which can be extracted from these precious samples are minute and may be prohibitive for numerous genotypings. Previously, we demonstrated that DBS DNA can be whole-genome amplified and used for reliable genetic analysis on different platforms, including genome-wide scanning arrays. However, it remains unclear whether this approach is workable on a large sample scale. We examined the robustness of using DBS samples for whole-genome amplification following genome-wide scanning, using arrays from Illumina and Affymetrix.This study is based on 4,641 DBS samples from the Danish Newborn Screening Biobank, extracted for three separate genome-wide association studies. The amount of amplified DNA was significantly (P < 0.05) affected by the year of storage and storage conditions. Nine (0.2 DBS samples failed whole-genome amplification. A total of 4,586 (98.8 samples met our criterion of success of a genetic call-rate above 97%. The three studies used different arrays, with mean genotyping call-rates of 99.385% (Illumina Infinium Human610-Quad), 99.722% (Illumina Infinium HD HumanOmni1-Quad), and 99.206% (Affymetrix Axiom Genome-Wide CEU). We observed a concordance rate of 99.997% in the 38 methodological replications, and 99.999% in the 27 technical replications. Handling variables such as time of storage, storage conditions and type of filter paper were shown too significantly (P < 0.05) affect the genotype call-rates in some of the arrays, although the effect was minimal.Our study indicates that archived DBS samples from the Danish Newborn Screening Biobank represent a reliable resource of DNA for whole-genome amplification and subsequent genome-wide association studies. With call-rates equivalent to high quality DNA samples, our results point to new opportunities for using the neonatal biobanks available worldwide in the hunt for genetic components of disease.
BibTeX:
@article{,
  author = {Hollegaard, Mads V. and Grove, Jakob and Grauholm, Jonas and Kreiner-Møller, Eskil and Bønnelykke, Klaus and Nørgaard, Mette and Benfield, Thomas L. and Nørgaard-Pedersen, Bent and Mortensen, Preben B. and Mors, Ole and Sørensen, Henrik T. and Harboe, Zitta B. and Børglum, Anders D. and Demontis, Ditte and Ørntoft, Torben F. and Bisgaard, Hans and Hougaard, David M.},
  title = {Robustness of genome-wide scanning using archived dried blood spot samples as a DNA source.},
  journal = {BMC Genet},
  school = {Department of Clinical Biochemistry and Immunology, Statens Serum Institut, Ørestads Boulevard, Copenhagen, DK-2300, Denmark. mvh@ssi.dk},
  year = {2011},
  volume = {12},
  pages = {58},
  url = {http://dx.doi.org/10.1186/1471-2156-12-58},
  doi = {https://doi.org/10.1186/1471-2156-12-58}
}
Chawes, B.L.K. Bisgaard, H. Elevated eosinophil protein X in urine from healthy neonates precedes development of atopy in the first 6 years of life. 2011 Am J Respir Crit Care Med 21680952 13,204 8
Authors: Chawes, B.L.K., Bønnelykke, K. and Bisgaard, H.
Abstract: Biomarkers predicting development of atopic disease are needed for targeted preventive measures and to study if disease pathology may be active before onset of symptoms.To investigate whether eosinophil protein X, leukotriene-C4/D4/E4, and 11β-prostaglandin (PG) F2α (PGD2 metabolite) assessed in urine from healthy at-risk neonates precede development of atopic disease during the first 6 years of life.We measured eosinophil protein X (n = 369), leukotriene-C4/D4/E4 (n = 367), and 11β-PGF2α (n = 366) in urine from 1-month-old children participating in the Copenhagen Prospective Studies on Asthma in Childhood birth cohort. Clinical data on development of allergic sensitization, allergic rhinitis, nasal eosinophilia, blood eosinophilia, eczema, troublesome lung symptoms (significant cough or wheeze or dyspnea), and asthma were collected prospectively until age 6 years. Associations between urinary biomarkers and development of atopic traits were investigated using general estimating equations, logistic regression, and Cox regression.Eosinophil protein X in the urine of the asymptomatic 1-month-old neonates was significantly associated with development of allergic sensitization (odds ratio, 1.49; 95% confidence interval [CI], 1.08–1.89), nasal eosinophilia (odds ratio, 3.2; 95% CI, 1.2–8.8), and eczema (hazard ratio, 1.4; 95% CI, 1.0–2.0), but not with allergic rhinitis, asthma, or blood eosinophilia. Neither leukotriene-C4/D4/E4 nor 11β-PGF2α was associated with any of the atopic phenotypes.Eosinophil protein X in urine from asymptomatic neonates is a biomarker significantly associated with later development of allergic sensitization, nasal eosinophilia, and eczema during the first 6 years of life. These findings suggest activation of eosinophil granulocytes early in life before development of atopy-related symptoms.
BibTeX:
@article{,
  author = {Chawes, Bo Lund Krogsgaard and Bønnelykke, Klaus and Bisgaard, Hans},
  title = {Elevated eosinophil protein X in urine from healthy neonates precedes development of atopy in the first 6 years of life.},
  journal = {Am J Respir Crit Care Med},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen, Copenhagen, Denmark},
  year = {2011},
  volume = {184},
  number = {6},
  pages = {656--661},
  url = {http://dx.doi.org/10.1164/rccm.201101-0111OC},
  doi = {https://doi.org/10.1164/rccm.201101-0111OC}
}
Bisgaard, H. Krogfelt, K.A. Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age. 2011 J Allergy Clin Immunol 21782228 13,081 241
Authors: Bisgaard, H., Li, N., Bonnelykke, K., Chawes, B.L.K., Skov, T., Paludan-Müller, G., Stokholm, J., Smith, B. and Krogfelt, K.A.
Abstract: Changes in the human microbiome have been suggested as a risk factor for a number of lifestyle-related disorders, such as atopic diseases, possibly through a modifying influence on immune maturation in infancy.We aimed to explore the association between neonatal fecal flora and the development of atopic disorders until age 6 years, hypothesizing that the diversity of the intestinal microbiota influences disease development.We studied the intestinal microbiota in infants in the Copenhagen Prospective Study on Asthma in Childhood, a clinical study of a birth cohort of 411 high-risk children followed for 6 years by clinical assessments at 6-month intervals, as well as at acute symptom exacerbations. Bacterial flora was analyzed at 1 and 12 months of age by using molecular techniques based on 16S rRNA PCR combined with denaturing gradient gel electrophoresis, as well as conventional culturing. The main outcome measures were the development of allergic sensitization (skin test and specific serum IgE), allergic rhinitis, peripheral blood eosinophil counts, asthma, and atopic dermatitis during the first 6 years of life.We found that bacterial diversity in the early intestinal flora 1 and 12 months after birth was inversely associated with the risk of allergic sensitization (serum specific IgE P = .003; skin prick test P = .017), peripheral blood eosinophils (P = .034), and allergic rhinitis (P = .007). There was no association with the development of asthma or atopic dermatitis.Reduced bacterial diversity of the infant's intestinal flora was associated with increased risk of allergic sensitization, allergic rhinitis, and peripheral blood eosinophilia, but not asthma or atopic dermatitis, in the first 6 years of life. These results support the general hypothesis that an imbalance in the intestinal microbiome is influencing the development of lifestyle-related disorders, such as allergic disease.
BibTeX:
@article{,
  author = {Bisgaard, Hans and Li, Nan and Bonnelykke, Klaus and Chawes, Bo Lund Krogsgaard and Skov, Thomas and Paludan-Müller, Georg and Stokholm, Jakob and Smith, Birgitte and Krogfelt, Karen Angeliki},
  title = {Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age.},
  journal = {J Allergy Clin Immunol},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark. Bisgaard@copsac.com},
  year = {2011},
  volume = {128},
  number = {3},
  pages = {646--52.e1-5},
  url = {http://dx.doi.org/10.1016/j.jaci.2011.04.060},
  doi = {https://doi.org/10.1016/j.jaci.2011.04.060}
}
Bisgaard, H. Bønnelykke, K. Endotyping early childhood asthma by quantitative symptom assessment. 2011 J Allergy Clin Immunol 21439619 13,081 37
Authors: Bisgaard, H., Pipper, C.B. and Bønnelykke, K.
Abstract: Asthmatic symptoms in young children reflect a heterogeneous group of diseases. Symptoms remain the primary end-point in both research and clinical management, but there is a need for standardized symptom assessment.We sought to explore endotyping of early childhood asthma by prospective daily diary recordings of globally assessed symptoms during the first 6 years of life.Globally assessed troublesome lung symptoms were recorded in daily diaries during the first 6 years of life in the Copenhagen Prospective Studies on Asthma in Childhood birth cohort born of mothers with asthma. Symptom recordings adjusted for missing values were used to categorize children based on the temporal symptom pattern. We propose an alternative approach of quantitating symptom frequency and longitudinal assessment of age-at-onset to segment children. These different methods were compared by estimating the risk from the well-established genetic risk variants of ORMDL3.Six years of daily diary recordings were available in 307 children (75% of the birth cohort). We confirmed the archetypal temporal categories of transient early, persistent, and late-onset troublesome lung symptoms based on 3-year periods, finding no benefit from a finer temporal categorization of 2- or 1-year periods. Restricting categorization to symptoms during the summer improved specificity at the expense of sensitivity. Our alternative approach quantitating symptom frequency and age-at-onset exhibited a more powerful association with ORMDL3, whereas the study power was lost by restricting to doctor-verified wheeze.We propose a novel method for endotyping of early childhood asthma based on the frequency and age-of-onset of globally assessed troublesome lung symptoms analyzed longitudinally. This method showed the closest association with genetic variants, hence underlying molecular mechanisms and endotypes.
BibTeX:
@article{,
  author = {Bisgaard, Hans and Pipper, Christian Bressen and Bønnelykke, Klaus},
  title = {Endotyping early childhood asthma by quantitative symptom assessment.},
  journal = {J Allergy Clin Immunol},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen, Gentofte, Copenhagen, Denmark. Bisgaard@copsac.com},
  year = {2011},
  volume = {127},
  number = {5},
  pages = {1155--64.e2},
  url = {http://dx.doi.org/10.1016/j.jaci.2011.02.007},
  doi = {https://doi.org/10.1016/j.jaci.2011.02.007}
}
Bønnelykke, K. Bisgaard, H. Filaggrin gene variants and atopic diseases in early childhood assessed longitudinally from birth. 2010 Pediatr Allergy Immunol 20573035 3,775 36
Authors: Bønnelykke, K., Pipper, C.B., Tavendale, R., Palmer, C.N.A. and Bisgaard, H.
Abstract: Copenhagen Prospective Study on Asthma in Childhood (COPSAC) was one of the discovery cohorts of the association between eczema and variants in the filaggrin coding gene (FLG). Here, we study the FLG-associated risk of asthma symptoms in early life and describe the temporal relationship in the development of the different FLG-associated atopic outcomes: asthma, sensitization and eczema, assessed longitudinally from birth. A high-risk cohort of 411 children was assessed in a prospective clinical study from birth to school-age. Asthma, acute severe asthma exacerbations, sensitization and eczema were diagnosed prospectively by the investigators. FLG variants R501X and Del4 were determined in 382 Caucasians. Filaggrin variants increased risk of developing recurrent wheeze, asthma and asthma exacerbations (hazard ratio 1.82 [1.06-3.12], p = 0.03), which was expressed within the first 1.5 yr of life. Children with filaggrin variants had a marked and persistent increase in acute severe asthma exacerbations from 1 yr of age (incidence ratio 2.40 [1.19-4.81], p = 0.01) and increased risk of asthma by age 5 (odds ratio 2.62 [1.12-6.11], p = 0.03). FLG variants increased the risk of eczema, manifesting fully in the first year of life (point prevalence ratio for age 0-5 was 1.75 [1.29-2.37]; p-value = 0.0003) contrasting the increased risk of specific sensitization by age 4 (odds ratio 3.52 [1.72-7.25], p = 0.0007) but not age 1.5. This study describes a FLG-associated pattern of atopic diseases characterized by the early onset of asthma symptoms and eczema and later development of sensitization. The association of filaggrin variants with asthma suggests skin barrier dysfunction as a novel, and potentially modifiable, mechanism driving early childhood asthma.
BibTeX:
@article{,
  author = {Bønnelykke, Klaus and Pipper, Christian B. and Tavendale, Roger and Palmer, Colin N A. and Bisgaard, Hans},
  title = {Filaggrin gene variants and atopic diseases in early childhood assessed longitudinally from birth.},
  journal = {Pediatr Allergy Immunol},
  school = {Copenhagen Studies on Asthma in Childhood, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark. kb@copsac.dk},
  year = {2010},
  volume = {21},
  number = {6},
  pages = {954--961},
  url = {http://dx.doi.org/10.1111/j.1399-3038.2010.01073.x},
  doi = {https://doi.org/10.1111/j.1399-3038.2010.01073.x}
}
Smyth, A.R. Merkus, P.J. Respiratory medicines for children: current evidence, unlicensed use and research priorities. 2010 Eur Respir J 19840958 10,569 25
Authors: Smyth, A.R., Barbato, A., Beydon, N., Bisgaard, H., de Boeck, K., Brand, P., Bush, A., Fauroux, B., de Jongste, J., Korppi, M., O'Callaghan, C., Pijnenburg, M., Ratjen, F., Southern, K., Spencer, D., Thomson, A., Vyas, H., Warris, A. and Merkus, P.J.
Abstract: This European Respiratory Society task force has reviewed the evidence for paediatric medicines in respiratory disease occurring in adults and children. We describe off-licence use, research priorities and ongoing studies. Off-licence and off-label prescribing in children is widespread and potentially harmful. Research areas in asthma include novel formulations and regimens, and individualised prescribing. In cystic fibrosis, future studies will focus on screened infants and robust outcome measures are needed. Other areas include new enzyme and antibiotic formulations and the basic defect. Research into pneumonia should include evaluation of new antibacterials and regimens, rapid diagnostic tests and, in pleural infection, antibiotic penetration, fibrinolytics and surveillance. In uncommon conditions, such as primary ciliary dyskinesia, congenital pulmonary abnormalities or neuromuscular disorders, drugs indicated for other conditions (e.g. dornase alfa) are commonly used and trials are needed. In neuromuscular disorders, the beta-agonists may enhance muscle strength and are in need of evaluation. Studies of antibiotic prophylaxis, immunoglobulin and antifungal drugs are needed in immune deficiency. We hope that this summary of the evidence for respiratory medicines in children, highlighting gaps and research priorities, will be useful for the pharmaceutical industry, the paediatric committee of the European Medicines Agency, academic investigators and the lay public.
BibTeX:
@article{,
  author = {Smyth, A. R. and Barbato, A. and Beydon, N. and Bisgaard, H. and de Boeck, K. and Brand, P. and Bush, A. and Fauroux, B. and de Jongste, J. and Korppi, M. and O'Callaghan, C. and Pijnenburg, M. and Ratjen, F. and Southern, K. and Spencer, D. and Thomson, A. and Vyas, H. and Warris, A. and Merkus, P. J.},
  title = {Respiratory medicines for children: current evidence, unlicensed use and research priorities.},
  journal = {Eur Respir J},
  school = {University of Nottingham Division of Child Health, Queens Medical Centre, Nottingham, NG7 2UH, UK. alan.smyth@nottingham.ac.uk},
  year = {2010},
  volume = {35},
  number = {2},
  pages = {247--265},
  url = {http://dx.doi.org/10.1183/09031936.00139508},
  doi = {https://doi.org/10.1183/09031936.00139508}
}
Sleiman, P.M.A. Hakonarson, H. Variants of DENND1B associated with asthma in children. 2010 N Engl J Med 20032318 72,406 198
Authors: Sleiman, P.M.A., Flory, J., Imielinski, M., Bradfield, J.P., Annaiah, K., Willis-Owen, S.A.G., Wang, K., Rafaels, N.M., Michel, S., Bonnelykke, K., Zhang, H., Kim, C.E., Frackelton, E.C., Glessner, J.T., Hou, C., Otieno, F.G., Santa, E., Thomas, K., Smith, R.M., Glaberson, W.R., Garris, M., Chiavacci, R.M., Beaty, T.H., Ruczinski, I., Orange, J.S., Orange, J.M., Allen, J., Spergel, J.M., Grundmeier, R., Mathias, R.A., Christie, J.D., von Mutius, E., Cookson, W.O.C., Kabesch, M., Moffatt, M.F., Grunstein, M.M., Barnes, K.C., Devoto, M., Magnusson, M., Li, H., Grant, S.F.A., Bisgaard, H. and Hakonarson, H.
Abstract: Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown.We carried out a genomewide association study involving children with asthma. The sample included 793 North American children of European ancestry with persistent asthma who required daily inhaled glucocorticoid therapy and 1988 matched controls (the discovery set). We also tested for genomewide association in an independent cohort of 917 persons of European ancestry who had asthma and 1546 matched controls (the replication set). Finally, we tested for an association between 20 single-nucleotide polymorphisms (SNPs) at chromosome 1q31 and asthma in 1667 North American children of African ancestry who had asthma and 2045 ancestrally matched controls.In our meta-analysis of all samples from persons of European ancestry, we observed an association, with genomewide significance, between asthma and SNPs at the previously reported locus on 17q21 and an additional eight SNPs at a novel locus on 1q31. The SNP most strongly associated with asthma was rs2786098 (P=8.55x10(-9)). We observed replication of the association of asthma with SNP rs2786098 in the independent series of persons of European ancestry (combined P=9.3x10(-11)). The alternative allele of each of the eight SNPs on chromosome 1q31 was strongly associated with asthma in the children of African ancestry (P=1.6x10(-13) for the comparison across all samples). The 1q31 locus contains the 1q31 locus contains DENND1B, a gene expressed by natural killer cells and dendritic cells. DENND1B protein is predicted to interact with the tumor necrosis factor α receptor [corrected].We have identified a locus containing DENND1B on chromosome 1q31.3 that is associated with susceptibility to asthma.
BibTeX:
@article{,
  author = {Sleiman, Patrick M A. and Flory, James and Imielinski, Marcin and Bradfield, Jonathan P. and Annaiah, Kiran and Willis-Owen, Saffron A G. and Wang, Kai and Rafaels, Nicholas M. and Michel, Sven and Bonnelykke, Klaus and Zhang, Haitao and Kim, Cecilia E. and Frackelton, Edward C. and Glessner, Joseph T. and Hou, Cuiping and Otieno, F George and Santa, Erin and Thomas, Kelly and Smith, Ryan M. and Glaberson, Wendy R. and Garris, Maria and Chiavacci, Rosetta M. and Beaty, Terri H. and Ruczinski, Ingo and Orange, Jordan S. and Orange, Jordan M. and Allen, Julian and Spergel, Jonathan M. and Grundmeier, Robert and Mathias, Rasika A. and Christie, Jason D. and von Mutius, Erika and Cookson, William O C. and Kabesch, Michael and Moffatt, Miriam F. and Grunstein, Michael M. and Barnes, Kathleen C. and Devoto, Marcella and Magnusson, Mark and Li, Hongzhe and Grant, Struan F A. and Bisgaard, Hans and Hakonarson, Hakon},
  title = {Variants of DENND1B associated with asthma in children.},
  journal = {N Engl J Med},
  school = {Center for Applied Genomics, Philadelphia, PA 19104-4318, USA.},
  year = {2010},
  volume = {362},
  number = {1},
  pages = {36--44},
  url = {http://dx.doi.org/10.1056/NEJMoa0901867},
  doi = {https://doi.org/10.1056/NEJMoa0901867}
}
Raaschou-Nielsen, O. Bisgaard, H. Long-term exposure to indoor air pollution and wheezing symptoms in infants. 2010 Indoor Air 20028431 4,383 16
Authors: Raaschou-Nielsen, O., Hermansen, M.N., Loland, L., Buchvald, F., Pipper, C.B., Sørensen, M., Loft, S. and Bisgaard, H.
Abstract: Long-term exposure to air pollution is suspected to cause recurrent wheeze in infants. The few previous studies have had ambiguous results. The objective of this study was to estimate the impact of measured long-term exposure to indoor air pollution on wheezing symptoms in infants. We monitored wheezing symptoms in diaries for a birth cohort of 411 infants. We measured long-term exposure to nitrogen oxides (NO(x)), NO(2), formaldehyde, PM(2.5) and black smoke in the infants' bedrooms and analyzed risk associations during the first 18 months of life by logistic regression with the dichotomous end-point 'any symptom-day' (yes/no) and by standard linear regression with the end-point 'number of symptom-days'. The results showed no systematic association between risk for wheezing symptoms and the levels of these air pollutants with various indoor and outdoor sources. In conclusion, we found no evidence of an association between long-term exposure to indoor air pollution and wheezing symptoms in infants, suggesting that indoor air pollution is not causally related to the underlying disease. Practical Implications Nitrogen oxides, formaldehyde and fine particles were measured in the air in infants' bedrooms. The results showed no evidence of an association between long-term exposure and wheezing symptoms in the COPSAC birth cohort.
BibTeX:
@article{,
  author = {Raaschou-Nielsen, O. and Hermansen, M. N. and Loland, L. and Buchvald, F. and Pipper, C. B. and Sørensen, M. and Loft, S. and Bisgaard, H.},
  title = {Long-term exposure to indoor air pollution and wheezing symptoms in infants.},
  journal = {Indoor Air},
  school = {Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen Ø, Denmark.},
  year = {2010},
  volume = {20},
  number = {2},
  pages = {159--167},
  url = {http://dx.doi.org/10.1111/j.1600-0668.2009.00635.x},
  doi = {https://doi.org/10.1111/j.1600-0668.2009.00635.x}
}
Poorisrisak, P. Bisgaard, H. Causal direction between respiratory syncytial virus bronchiolitis and asthma studied in monozygotic twins. 2010 Chest 20435661 6,044 32
Authors: Poorisrisak, P., Halkjaer, L.B., Thomsen, S.F., Stensballe, L.G., Kyvik, K.O., Skytthe, A., Schioetz, P.O. and Bisgaard, H.
Abstract: Respiratory syncytial virus (RSV) bronchiolitis has been associated with later development of asthma, wheezing, abnormal pulmonary function, and sensitization. Our aim was to determine the differential effect within monozygotic (MZ) twin pairs discordant for severe RSV bronchiolitis in infancy on the subsequent development of asthma, pulmonary function, and allergy.Thirty-seven MZ twin pairs discordant for RSV hospitalization in infancy (mean age 10.6 months) were compared at the mean age of 7.6 years for lung function, bronchial responsiveness, fractional exhaled nitric oxide (Feno), asthma diagnosis, use of asthma medication, and skin prick test to common inhalant allergens.There were no differences within MZ twin pairs discordant for RSV hospitalization in infancy with respect to pulmonary function, Feno, asthma prevalence, asthma medication use, or sensitization (P > .1 for all comparisons).We found no differential effect from severity of RSV infection on the development of asthma and allergy in MZ twin pairs discordant for RSV hospitalization in infancy. This argues against a specific effect of severe RSV infection in the development of asthma and allergy. Because of the small sample size, this study must be considered as a hypothesis-generating study.
BibTeX:
@article{,
  author = {Poorisrisak, Porntiva and Halkjaer, Liselotte Brydensholt and Thomsen, Simon Francis and Stensballe, Lone Graff and Kyvik, Kirsten Ohm and Skytthe, Axel and Schioetz, Peter Oluf and Bisgaard, Hans},
  title = {Causal direction between respiratory syncytial virus bronchiolitis and asthma studied in monozygotic twins.},
  journal = {Chest},
  school = {Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, L213 Ledreborg alle 34, DK-2820 Copenhagen, Denmark.},
  year = {2010},
  volume = {138},
  number = {2},
  pages = {338--344},
  url = {http://dx.doi.org/10.1378/chest.10-0365},
  doi = {https://doi.org/10.1378/chest.10-0365}
}
Kindlund, K. Bisgaard, H. Birth weight and risk of asthma in 3-9-year-old twins: exploring the fetal origins hypothesis. 2010 Thorax 19996338 8,272 46
Authors: Kindlund, K., Thomsen, S.F., Stensballe, L.G., Skytthe, A., Kyvik, K.O., Backer, V. and Bisgaard, H.
Abstract: To examine the relationship between birth weight and risk of asthma in a population of twins.Birth weight of all live twins (8280 pairs) born in Denmark between 1994 and 2000 was linked to information on asthma obtained from parent-completed questionnaires at age 3-9 years. Conditional logistic regression was used to calculate the risk of asthma.Subjects with a history of asthma at age 3-9 years weighed on average 122 g (95% CI 85 to 160) less at birth than subjects who had not developed asthma, p<0.001. There was a linear increase in asthma risk with decreasing birth weight, OR (per 100 g) 1.04 (95% CI 1.03 to 1.05), p<0.001. Within twin pairs, the lower birthweight twin had a significantly increased risk of asthma compared with the heavier co-twin (11.3% vs 9.9, OR 1.30 (95% CI 1.10 to 1.54), p=0.002. The result remained significant after adjusting for sex, birth length and Apgar score, OR 1.31 (95% CI 1.03 to 1.65), p=0.027. The risk tended to be higher in monozygotic co-twins compared with dizygotic co-twins, especially for high birth weight differences.Low birth weight is a risk factor for asthma independently of gestational age, sex, birth length and Apgar score, but this may be due, in part, to residual non-genetic confounding factors. This finding lends support to the "fetal origins hypothesis" suggesting undisclosed prenatal determinants for the risk of asthma.
BibTeX:
@article{,
  author = {Kindlund, Karin and Thomsen, Simon Francis and Stensballe, Lone Graff and Skytthe, Axel and Kyvik, Kirsten Ohm and Backer, Vibeke and Bisgaard, Hans},
  title = {Birth weight and risk of asthma in 3-9-year-old twins: exploring the fetal origins hypothesis.},
  journal = {Thorax},
  school = {Department of Respiratory Medicine, Bispebjerg Hospital, DK-2400 Copenhagen NV, Denmark.},
  year = {2010},
  volume = {65},
  number = {2},
  pages = {146--149},
  url = {http://dx.doi.org/10.1136/thx.2009.117101},
  doi = {https://doi.org/10.1136/thx.2009.117101}
}
Giwercman, C. Bisgaard, H. Increased risk of eczema but reduced risk of early wheezy disorder from exclusive breast-feeding in high-risk infants. 2010 J Allergy Clin Immunol 20236698 13,081 52
Authors: Giwercman, C., Halkjaer, L.B., Jensen, S.M., Bønnelykke, K., Lauritzen, L. and Bisgaard, H.
Abstract: Breast-feeding is recommended for the prevention of eczema, asthma, and allergy, particularly in high-risk families, but recent studies have raised concern that this may not protect children and may even increase the risk. However, disease risk, disease manifestation, lifestyle, and the choice to breast-feed are interrelated, and therefore, analyzing true causal effects presents a number of methodologic challenges.First, to assess the effect from duration of exclusive breast-feeding on the development of eczema and wheezy disorders during the first 2 years of life in a high-risk clinical birth cohort. Second, to assess any influence from the fatty acid composition of mother's milk on the risk from breast-feeding.We studied disease development during the first two years of life of the 411 infants from the Copenhagen Study on Asthma in Childhood (COPSAC) birth cohort, born to mothers with a history of asthma. We analyzed the effect from duration of breast-feeding before disease onset on the disease risk, avoiding the effect from disease-related modification of exposure (inverse causation). Polyunsaturated fatty acids were measured in breast milk.Breast-feeding significantly increased the risk of eczema adjusted for demographics, filaggrin variants, parents' eczema, and pets at home (N = 306; relative risk, 2.09; 95% CI 1.15-3.80; P = .016) but reduced the risk of wheezy episodes (relative risk, 0.67; 95% CI 0.48-0.96; P = .021) and of severe wheezy exacerbation (relative risk, 0.16; 95% CI 0.03-1.01; P = .051). There was no association between the fatty acid composition of mother's milk and the risk of eczema or wheeze.The risk of eczema was increased in infants with increasing duration of breast-feeding. In contrast, the risk of wheezy disorder and severe wheezy exacerbations was reduced. There were no significant effects from the fatty acid composition of the breast milk on risk of eczema or wheezy disorders.
BibTeX:
@article{,
  author = {Giwercman, Charlotte and Halkjaer, Liselotte B. and Jensen, Signe Marie and Bønnelykke, Klaus and Lauritzen, Lotte and Bisgaard, Hans},
  title = {Increased risk of eczema but reduced risk of early wheezy disorder from exclusive breast-feeding in high-risk infants.},
  journal = {J Allergy Clin Immunol},
  school = {Copenhagen Prospective Study on Asthma in Childhood, Health Sciences, University of Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark.},
  year = {2010},
  volume = {125},
  number = {4},
  pages = {866--871},
  url = {http://dx.doi.org/10.1016/j.jaci.2010.01.026},
  doi = {https://doi.org/10.1016/j.jaci.2010.01.026}
}
Chawes, B.L.K. Bisgaard, H. Upper and lower airway patency are associated in young children. 2010 Chest 20118204 6,044 18
Authors: Chawes, B.L.K., Kreiner-Møller, E. and Bisgaard, H.
Abstract: Although allergic rhinitis and asthma frequently coexist, the nature of this association is poorly understood. Therefore, we examined whether upper and lower airway patency are associated.We investigated 221 6-year-old children from the Copenhagen Prospective Study on Asthma in Childhood birth cohort, assessing upper airway patency by acoustic rhinometry before and after alpha-agonist, and lower airway patency by spirometry before and after beta2-agonist. Furthermore, we measured blood eosinophil count, nasal eosinophilia, total IgE, and fraction of exhaled nitric oxide. Associations were investigated by generalized linear models.Decongested nasal airway patency and post-beta2 FEV(1) were significantly associated (P = .007). The association remained significant after adjustments for sex, body size, FVC, and atopic diseases (beta-coefficient 2.85 cm(3); 95% CI, 0.42 to 5.29; P = .02). Baseline values of upper and lower airway patency were also significantly associated (beta-coefficient 0.89 cm(3); 95% CI, 0.26-1.51; P = .01). In addition, blood eosinophil count and nasal eosinophilia were inversely associated with decongested nasal airway patency, beta-coefficient -0.42 cm(3) (95% CI, -0.77 to -0.07; P = .02) and beta-coefficient -0.47 cm(3) (95% CI, -0.89 to -0.05; P = .03), respectively.We found a strong and consistent association between upper and lower airway patency. This may be due to a common pathology, as suggested by the inverse association between decongested nasal airway patency, blood eosinophil count, and nasal eosinophilia. Alternatively, the association between upper and lower airway patency might reflect a physiologic background for the common comorbidity.
BibTeX:
@article{,
  author = {Chawes, Bo Lund Krogsgaard and Kreiner-Møller, Eskil and Bisgaard, Hans},
  title = {Upper and lower airway patency are associated in young children.},
  journal = {Chest},
  school = {Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Denmark.},
  year = {2010},
  volume = {137},
  number = {6},
  pages = {1332--1337},
  url = {http://dx.doi.org/10.1378/chest.09-2601},
  doi = {https://doi.org/10.1378/chest.09-2601}
}
Chawes, B.L.K. Hansel, T.T. A novel method for assessing unchallenged levels of mediators in nasal epithelial lining fluid. 2010 J Allergy Clin Immunol 20304470 13,081 38
Authors: Chawes, B.L.K., Edwards, M.J., Shamji, B., Walker, C., Nicholson, G.C., Tan, A.J., Følsgaard, N.V., Bønnelykke, K., Bisgaard, H. and Hansel, T.T.
BibTeX:
@article{,
  author = {Chawes, Bo L K. and Edwards, Matthew J. and Shamji, Betty and Walker, Christoph and Nicholson, Grant C. and Tan, Andrew J. and Følsgaard, Nilofar V. and Bønnelykke, Klaus and Bisgaard, Hans and Hansel, Trevor T.},
  title = {A novel method for assessing unchallenged levels of mediators in nasal epithelial lining fluid.},
  journal = {J Allergy Clin Immunol},
  year = {2010},
  volume = {125},
  number = {6},
  pages = {1387--1389.e3},
  url = {http://dx.doi.org/10.1016/j.jaci.2010.01.039},
  doi = {https://doi.org/10.1016/j.jaci.2010.01.039}
}
Chawes, B.L.K. Bisgaard, H. Elevated exhaled nitric oxide in high-risk neonates precedes transient early but not persistent wheeze. 2010 Am J Respir Crit Care Med 20299533 13,204 36
Authors: Chawes, B.L.K., Buchvald, F., Bischoff, A.L., Loland, L., Hermansen, M., Halkjaer, L.B., Bønnelykke, K. and Bisgaard, H.
Abstract: Elevated fractional exhaled nitric oxide (Fe(NO)) concentration has been suggested to predict early childhood wheeze and sensitization.To investigate the association between Fe(NO) in asymptomatic neonates and the development of wheeze patterns and atopic intermediary phenotypes in the first 6 years of life.We measured Fe(NO) in 253 healthy 1-month-old neonates from the Copenhagen Prospective Study on Asthma in Childhood birth cohort and monitored prospectively wheezy episodes by daily diary cards during the first 6 years of life. Total IgE, specific IgE, and blood eosinophil count were assessed at age 6 months, 4 years, and 6 years. Associations were studied by Cox regression, logistic regression, and generalized linear models.Increased neonatal Fe(NO) level was significantly associated with the development of recurrent wheeze in the first year of life (hazard ratio, 2.63; 95% confidence interval, 1.1 to 6.2; P = 0.026) but not thereafter. The association was unaffected by environmental tobacco smoke exposure. Fe(NO) was not associated with elevated levels of total IgE, specific IgE, or blood eosinophil count at any age point and was unrelated to neonatal lung function.An elevated Fe(NO) level in asymptomatic neonates born to mothers with asthma preceded the development of transient early wheezing, but not persistent wheezing during preschool age, and was unrelated to atopy. This suggests an early disease process other than small airway caliber contributing to the transient wheezing phenotype.
BibTeX:
@article{,
  author = {Chawes, Bo L K. and Buchvald, Frederik and Bischoff, Anne Louise and Loland, Lotte and Hermansen, Mette and Halkjaer, Liselotte B. and Bønnelykke, Klaus and Bisgaard, Hans},
  title = {Elevated exhaled nitric oxide in high-risk neonates precedes transient early but not persistent wheeze.},
  journal = {Am J Respir Crit Care Med},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Danish Pediatric Asthma Center, Health Sciences, University of Copenhagen, Copenhagen University Hospital, Gentofte, Ledreborg Allé 34, 2820 Gentofte, Denmark.},
  year = {2010},
  volume = {182},
  number = {2},
  pages = {138--142},
  url = {http://dx.doi.org/10.1164/rccm.200909-1377OC},
  doi = {https://doi.org/10.1164/rccm.200909-1377OC}
}
Chawes, B.L.K. Bisgaard, H. Children with allergic and nonallergic rhinitis have a similar risk of asthma. 2010 J Allergy Clin Immunol 20816191 13,081 56
Authors: Chawes, B.L.K., Bønnelykke, K., Kreiner-Møller, E. and Bisgaard, H.
Abstract: Both allergic and nonallergic rhinitis have been associated with increased prevalence of asthma.To characterize asthma and intermediary asthma endpoints in young children with allergic and nonallergic rhinitis.Thirty-eight 7-year-old children with allergic rhinitis, 67 with nonallergic rhinitis, and 185 without rhinitis from the Copenhagen Prospective Study on Asthma in Childhood birth cohort were compared for prevalence of asthma, eczema, food sensitization, filaggrin null-mutations, total IgE, blood eosinophil count, fractional exhaled nitric oxide (FeNO), lung function, and bronchial responsiveness.Children with allergic rhinitis compared with asymptomatic controls had increased prevalence of asthma (21% vs 5 P = .002), food sensitization (47% vs 13 P < .001), and eczema (66% vs 43 P = .01) and increased total IgE (155 kU/L vs 41 kU/L; P < .001), blood eosinophil count (0.46 x 10(9)/L vs 0.30 x 10(9)/L; P = .01), FeNO (15.9 ppb vs 6.6 ppb; P < .001), and bronchial hyperresponsiveness (23% vs 9 P = .008). Filaggrin null-mutations were associated with allergic rhinitis (odds ratio, 3.3; 95% CI, 1.3-8.3) but did not modify these associations. Children with nonallergic rhinitis also had increased asthma prevalence (20% vs 5 P = .001) but showed no association with filaggrin null-mutations, eczema, food sensitization, total IgE, blood eosinophil count, FeNO, or bronchial responsiveness.Asthma is similarly associated with allergic and nonallergic rhinitis, suggesting a link between upper and lower airways beyond allergy associated inflammation. Only children with allergic rhinitis had increased bronchial responsiveness and elevated FeNO, suggesting different endotypes of asthma symptoms in young children with allergic and nonallergic rhinitis.
BibTeX:
@article{,
  author = {Chawes, Bo Lund Krogsgaard and Bønnelykke, Klaus and Kreiner-Møller, Eskil and Bisgaard, Hans},
  title = {Children with allergic and nonallergic rhinitis have a similar risk of asthma.},
  journal = {J Allergy Clin Immunol},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen, and the Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark.},
  year = {2010},
  volume = {126},
  number = {3},
  pages = {567--73.e1-8},
  url = {http://dx.doi.org/10.1016/j.jaci.2010.06.026},
  doi = {https://doi.org/10.1016/j.jaci.2010.06.026}
}
Brasholt, M. Bisgaard, H. Physical activity in young children is reduced with increasing bronchial responsiveness. 2010 J Allergy Clin Immunol 20392480 13,081 22
Authors: Brasholt, M., Baty, F. and Bisgaard, H.
Abstract: Physical activity is essential for young children to develop adequately and for quality of life. It can be lower in children with subclinical asthma, and therefore methods to reveal subclinical reduction in physical activity in young children are warranted.We sought to study an association between physical activity in preschool children and objectively assessed intermediary asthma phenotypes.We studied 253 five-year-old children (127 girls) participating in the Copenhagen Prospective Studies on Asthma in Childhood. The main outcome measure was level of physical activity assessed objectively with accelerometers worn on an ankle for 4 weeks. Objective assessment of asthma intermediary phenotypes included prebronchodilator and postbronchodilator specific airway resistance, bronchial responsiveness to cold dry-air hyperventilation, and exhaled nitric oxide levels. Analyses were performed with generalized linear model and principal component analysis.Physical activity was inversely associated with bronchial responsiveness (relative rate, 0.89; 95% CI, 0.83-0.95; P = .007) and significantly increased in the months of spring and summer (P < .001) and in boys (relative rate, 1.16; 95% CI, 1.09-1.25; P < .001). Physical activity was independent of asthma diagnosis, age, body mass index, baseline specific airway resistance, reversibility to beta(2)-agonist, sensitization, and exhaled nitric oxide level.Physical activity in preschool children was reduced with increasing bronchial responsiveness. The reduced physical activity was subclinical and not realized by parents or doctors despite daily diary cards and close clinical follow-up since birth. This observation warrants awareness of even very mild asthma symptoms in clinical practice.
BibTeX:
@article{,
  author = {Brasholt, Martin and Baty, Florent and Bisgaard, Hans},
  title = {Physical activity in young children is reduced with increasing bronchial responsiveness.},
  journal = {J Allergy Clin Immunol},
  school = {Copenhagen Prospective Studies on Asthma in Childhood; the Danish Pediatric Asthma Center, Health Sciences, University of Copenhagen; and Copenhagen University Hospital, Gentofte, Copenhagen, Denmark.},
  year = {2010},
  volume = {125},
  number = {5},
  pages = {1007--1012},
  url = {http://dx.doi.org/10.1016/j.jaci.2010.02.002},
  doi = {https://doi.org/10.1016/j.jaci.2010.02.002}
}
Bisgaard, H. Johnston, S.L. Association of bacteria and viruses with wheezy episodes in young children: prospective birth cohort study. 2010 BMJ 20921080 20,785 135
Authors: Bisgaard, H., Hermansen, M.N., Bønnelykke, K., Stokholm, J., Baty, F., Skytt, N.L., Aniscenko, J., Kebadze, T. and Johnston, S.L.
Abstract: To study the association between wheezy symptoms in young children and the presence of bacteria in the airways.Birth cohort study.Clinical research unit in Copenhagen.Children of asthmatic mothers, from age 4 weeks to 3 years, with planned visits and acute admissions to the research clinic.Frequency of bacteria and virus carriage in airway aspirates during wheezy episodes and at planned visits without respiratory symptoms.984 samples (361 children) were analysed for bacteria, 844 (299 children) for viruses, and 696 (277 children) for both viruses and bacteria. Wheezy episodes were associated with both bacterial infection (odds ratio 2.9, 95% confidence interval 1.9 to 4.3; P<0.001) and virus infection (2.8, 1.7 to 4.4; P<0.001). The associations of bacteria and viruses were independent of each other.Acute wheezy episodes in young children were significantly associated with bacterial infections similar to but independent of the association with virus infections.
BibTeX:
@article{,
  author = {Bisgaard, Hans and Hermansen, Mette Northman and Bønnelykke, Klaus and Stokholm, Jakob and Baty, Florent and Skytt, Nanna Lassen and Aniscenko, Julia and Kebadze, Tatiana and Johnston, Sebastian L.},
  title = {Association of bacteria and viruses with wheezy episodes in young children: prospective birth cohort study.},
  journal = {BMJ},
  school = {The Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen, and The Danish Pediatric Asthma Centre, Copenhagen University Hospital, Gentofte, Ledreborg Allé 34, DK-2820 Gentofte, Copenhagen, Denmark. Bisgaard@copsac.com},
  year = {2010},
  volume = {341},
  pages = {c4978}
}
Bisgaard, H. Bønnelykke, K. Long-term studies of the natural history of asthma in childhood. 2010 J Allergy Clin Immunol 20688204 13,081 81
Authors: Bisgaard, H. and Bønnelykke, K.
Abstract: Segmentation of children with asthma and other wheezy disorders remains the main research challenge today, as it was when described 2 centuries ago. Early childhood wheezy disorders follow different temporal trajectories, probably representing different underlying mechanisms (endophenotypes). Prospective identification of endophenotypes allowing accurate prediction of the clinical course is currently not possible. The variability of the clinical course remains an enigma and difficult to predict. Three of 4 school-aged children with asthma have outgrown disease by midadulthood. The risk of persistence increases with severity, sensitization, smoking, and female sex. Genetic risk variants might help disentangle the heterogeneity of asthma and other wheezy disorders. At early school age, children with asthma have reduced lung function. It is an important and unresolved question whether the airflow limitation associated with asthma already existed at birth or developed along with symptoms. Likewise, the association between the infant's bronchial responsiveness and development of asthma and other wheezy disorders is unclear. Neither primary prevention through manipulation of environmental factors nor secondary prevention through the use of inhaled corticosteroids can effectively halt the long-term disease progression in childhood. In conclusion, the natural history of asthma and the associated airway changes is still poorly understood, and we have not managed to translate findings from long-term studies into a deeper understanding of the underlying endophenotypes or improved disease management. We propose the need for a translational research approach based on long-term clinical studies of birth cohorts with comprehensive and objective assessments of intermediate phenotypes and environmental exposures combined with interdisciplinary basic research and a systems biology approach.
BibTeX:
@article{,
  author = {Bisgaard, Hans and Bønnelykke, Klaus},
  title = {Long-term studies of the natural history of asthma in childhood.},
  journal = {J Allergy Clin Immunol},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Health Sciences, University of Copenhagen, Copenhagen, Denmark. Bisgaard@copsac.com},
  year = {2010},
  volume = {126},
  number = {2},
  pages = {187--97; quiz 198-9},
  url = {http://dx.doi.org/10.1016/j.jaci.2010.07.011},
  doi = {https://doi.org/10.1016/j.jaci.2010.07.011}
}
Bønnelykke, K. Bisgaard, H. Transfer of maternal IgE can be a common cause of increased IgE levels in cord blood. 2010 J Allergy Clin Immunol 20816197 13,081 32
Authors: Bønnelykke, K., Pipper, C.B. and Bisgaard, H.
Abstract: IgE in cord blood is thought to be a product of the fetus. A high level of total IgE is therefore used as a measure of atopic propensity in the newborn. We recently found strong evidence that allergen-specific IgE in cord blood was the result of transfer of maternal IgE to fetal blood or cord blood (maternofetal transfer) rather than fetal production. This also suggests that total IgE in cord blood might primarily be a maternal product.We sought to determine to what extent increased levels of total IgE in cord blood is the result of maternofetal transfer of IgE.Total IgE in cord blood was analyzed in a prospective birth cohort study. Maternofetal transfer of IgE was detected by means of high-sensitivity analyses of cord blood IgA and allergen-specific IgE and comparison with parental IgE levels and levels at 6 months of age.Forty-six percent of cord blood samples with increased IgE levels (>or=0.5 IU/mL) showed indication of maternofetal transfer of IgE. Maternal origin of IgE in these samples was validated by showing reduced levels of IgE at 6 months of age compared with samples with no indication of maternofetal transfer (geometric mean, 9.4 vs 5.4 IU/mL; P = .01). Maternofetal transfer was not appropriately accounted for by the conventional method of cord blood IgA measurement.Maternofetal transfer might be a common cause of increased cord blood IgE levels. Future studies should take potential maternofetal transfer into account or use other markers of atopy.
BibTeX:
@article{,
  author = {Bønnelykke, Klaus and Pipper, Christian Bressen and Bisgaard, Hans},
  title = {Transfer of maternal IgE can be a common cause of increased IgE levels in cord blood.},
  journal = {J Allergy Clin Immunol},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Danish Pediatric Asthma Center, Health Sciences, University of Copenhagen, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark.},
  year = {2010},
  volume = {126},
  number = {3},
  pages = {657--663},
  url = {http://dx.doi.org/10.1016/j.jaci.2010.06.027},
  doi = {https://doi.org/10.1016/j.jaci.2010.06.027}
}
Stensballe, L.G. Bisgaard, H. The causal direction in the association between respiratory syncytial virus hospitalization and asthma. 2009 J Allergy Clin Immunol 19130934 13,081 74
Authors: Stensballe, L.G., Simonsen, J.B., Thomsen, S.F., Larsen, A.-M.H., Lysdal, S.H., Aaby, P., Kyvik, K.O., Skytthe, A., Backer, V. and Bisgaard, H.
Abstract: Earlier studies have reported an increased risk of asthma after respiratory syncytial virus (RSV) hospitalization. Other studies found that asthmatic disposition and propensity to wheeze increase the risk of RSV hospitalization.The current study examined the causal direction of the associations between RSV hospitalization and asthma in a population-based cohort of twins.We conducted a prospective cohort study examining the associations between RSV hospitalization and asthma by using registry information on RSV hospitalization and asthma among 18,614 Danish twins born 1994 to 2003. The associations between RSV and asthma were examined in both directions: we examined the risk of asthma after RSV hospitalization, and the risk of RSV hospitalization in children with asthma in the same population-based cohort.Asthma hospitalization after RSV hospitalization was increased as much as 6-fold to 8-fold during the first 2 months after RSV hospitalization but was no longer increased 1 year later. Asthma increased the risk of RSV hospitalization by 3-fold, and the risk was not time-dependent. Analyzing these associations on the basis of asthma defined from use of inhaled corticosteroid did not materially change the risk estimates.There is a bidirectional association between severe RSV infection and asthma. Severe RSV infection is associated with a short-term increase in the risk of subsequent asthma, suggesting that RSV induce bronchial hyperresponsiveness; and asthma is associated with a long-term increased susceptibility for severe RSV disease, suggesting a host factor being responsible for the severe response to RSV infection. This suggests that severe RSV infection and asthma may share a common genetic predisposition and/or environmental exposure.
BibTeX:
@article{,
  author = {Stensballe, Lone Graff and Simonsen, Jacob Brunbjerg and Thomsen, Simon Francis and Larsen, Anne-Marie Hellesøe and Lysdal, Susan Hovmand and Aaby, Peter and Kyvik, Kirsten Ohm and Skytthe, Axel and Backer, Vibeke and Bisgaard, Hans},
  title = {The causal direction in the association between respiratory syncytial virus hospitalization and asthma.},
  journal = {J Allergy Clin Immunol},
  school = {Bandim Health Project, Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. LGN@ssi.dk},
  year = {2009},
  volume = {123},
  number = {1},
  pages = {131--137.e1},
  url = {http://dx.doi.org/10.1016/j.jaci.2008.10.042},
  doi = {https://doi.org/10.1016/j.jaci.2008.10.042}
}
Skov, L. Bisgaard, H. Neonatal colonization with Staphylococcus aureus is not associated with development of atopic dermatitis. 2009 Br J Dermatol 19239467 4,706 14
Authors: Skov, L., Halkjaer, L.B., Agner, T., Frimodt-Møller, N., Jarløv, J.O. and Bisgaard, H.
Abstract: Staphylococcus aureus in atopic skin has been associated with exacerbation of eczema. Objectives To investigate a possible association between neonatal colonization with S. aureus and the risk of atopic dermatitis (AD) during the first 3 years of life.The study participants were 356 children born of mothers with asthma from the Copenhagen Prospective Study on Asthma in Childhood. Swabs from the vestibulum nasi and the perineum were cultured at 1 month and 1 year, from acute eczema, and from parents (vestibulum nasi and pharynx). AD development and severity were monitored prospectively.Of the neonates, 5.3% had positive swabs for S. aureus cultured from the vestibulum nasi (51.3 and/or the perineum (11.3. Forty-two per cent developed AD, but without association between colonization with S. aureus at 1 month of age and risk of developing AD at 3 years of age. There was a 70% concordance for S. aureus carriage between neonates and parents. At 1 year of age 11.3% children had swabs positive for S. aureus. Fourteen per cent of children tested at the 1-year visit developed AD after the visit but before 3 years of age, but again, there was no association between colonization with S. aureus and the risk of AD. In children seen at acute visits the severity of AD measured by scoring of atopic dermatitis (SCORAD) was significantly higher in children with a positive culture for S. aureus in lesions.Colonization with S. aureus at 1 month of age is not associated with an increased risk of developing AD during the first 3 years of life.
BibTeX:
@article{,
  author = {Skov, L. and Halkjaer, L. B. and Agner, T. and Frimodt-Møller, N. and Jarløv, J. O. and Bisgaard, H.},
  title = {Neonatal colonization with Staphylococcus aureus is not associated with development of atopic dermatitis.},
  journal = {Br J Dermatol},
  school = {Department of Dermato-Allergology, Copenhagen University Hospital Gentofte, Denmark.},
  year = {2009},
  volume = {160},
  number = {6},
  pages = {1286--1291},
  url = {http://dx.doi.org/10.1111/j.1365-2133.2009.09051.x},
  doi = {https://doi.org/10.1111/j.1365-2133.2009.09051.x}
}
Thomsen, S.F. Bisgaard, H. Exploring the association between severe respiratory syncytial virus infection and asthma: a registry-based twin study. 2009 Am J Respir Crit Care Med 19286626 13,204 107
Authors: Thomsen, S.F., van der Sluis, S., Stensballe, L.G., Posthuma, D., Skytthe, A., Kyvik, K.O., Duffy, D.L., Backer, V. and Bisgaard, H.
Abstract: Severe respiratory syncytial virus (RSV) infection is associated with asthma but the nature of this association is imperfectly understood.To examine the nature of the association between severe RSV infection and asthma in a population-based sample of twins.Data on hospitalization due to RSV infection was gathered for all twins born in Denmark between 1994 and 2000 (8,280 pairs) and linked to information on asthma obtained from hospital discharge registries and parent-completed questionnaires. Genetic variance components models and direction of causation models were fitted to the observed data.RSV hospitalization and asthma were positively associated (r = 0.43), and genetic determinants for the two disorders overlapped completely. Modeling the direction of causation between RSV hospitalization and asthma showed that a model in which asthma "causes" RSV hospitalization fitted the data significantly better (P = 0.39 for deterioration in model fit) than a model in which RSV hospitalization "causes" asthma (P < 0.001 for deterioration in model fit), even when sex, birth weight, and maternal smoking during pregnancy were accounted for.RSV infection that is severe enough to warrant hospitalization does not cause asthma but is an indicator of the genetic predisposition to asthma.
BibTeX:
@article{,
  author = {Thomsen, Simon Francis and van der Sluis, Sophie and Stensballe, Lone G. and Posthuma, Danielle and Skytthe, Axel and Kyvik, Kirsten O. and Duffy, David L. and Backer, Vibeke and Bisgaard, Hans},
  title = {Exploring the association between severe respiratory syncytial virus infection and asthma: a registry-based twin study.},
  journal = {Am J Respir Crit Care Med},
  school = {Department of Respiratory Medicine, Bispebjerg Hospital, Copenhagen NV, Denmark. sft@city.dk},
  year = {2009},
  volume = {179},
  number = {12},
  pages = {1091--1097},
  url = {http://dx.doi.org/10.1164/rccm.200809-1471OC},
  doi = {https://doi.org/10.1164/rccm.200809-1471OC}
}
Poorisrisak, P. Bisgaard, H. Accuracy of whole-body plethysmography requires biological calibration. 2009 Chest 19497894 6,044 11
Authors: Poorisrisak, P., Vrang, C., Henriksen, J.M., Klug, B., Hanel, B. and Bisgaard, H.
Abstract: Specific airway resistance (sRaw) measured by whole-body plethysmography in young children is increasingly used in research and clinical practice. The method is precise and feasible. However, there is no available method for calibration of the resistance measure, which raises concern of accuracy. Our aim was to determine the agreement of sRaw measurements in six centers and expand normative sRaw values for nonasthmatic children including these centers.Identical hardware with different software versions was used at the six centers. Measurements followed a standard operating procedure: (1) seven healthy young children were brought to each of the six centers for sRaw measurements; and (2) 105 healthy preschool children (52 boys; mean age, 5.1 years; interquartile range, 4.3 to 6.0) were recruited locally for sRaw measurements.(1) The sRaw of the seven-children study group was significantly lower at two centers compared with the other four centers, and one center had significantly higher sRaw than all the other centers (p < 0.05). Error in the factory settings of the software was subsequently discovered in one of the deviating centers. (2) Normative data (105 preschool children) were generated and were without significant difference between centers and independent of height, weight, age, and gender. We subsequently pooled these normative data (105 children) with our previous data from 121 healthy young children (overall mean sRaw, 1.27; SD, 0.25).Control using biological standards revealed errors in the factory setting and highlights the need for developing methods for verification of resistance measures to assure accuracy. Normative data were subsequently generated. Importantly, other centers using such normative data should first consider proper calibration before applying reference values.
BibTeX:
@article{,
  author = {Poorisrisak, Porntiva and Vrang, Carsten and Henriksen, Jorn Molgaard and Klug, Bent and Hanel, Birgitte and Bisgaard, Hans},
  title = {Accuracy of whole-body plethysmography requires biological calibration.},
  journal = {Chest},
  school = {Copenhagen Prospective Study on Asthma in Children, Danish Pediatric Asthma Center, Health Sciences, University of Copenhagen, Copenhagen University Hospital, Gentofte, Denmark. Electronic address: Bisgaard@copsac.dk.},
  year = {2009},
  volume = {135},
  number = {6},
  pages = {1476--1480},
  url = {http://dx.doi.org/10.1378/chest.08-1555},
  doi = {https://doi.org/10.1378/chest.08-1555}
}
Flory, J.H. Hakonarson, H. 17q12-21 variants interact with smoke exposure as a risk factor for pediatric asthma but are equally associated with early-onset versus late-onset asthma in North Americans of European ancestry. 2009 J Allergy Clin Immunol 19660801 13,081 54
Authors: Flory, J.H., Sleiman, P.M., Christie, J.D., Annaiah, K., Bradfield, J., Kim, C.E., Glessner, J., Imielinski, M., Li, H., Frackelton, E.C., Cuiping, H., Otieno, G., Thomas, K., Smith, R., Glaberson, W., Garris, M., Chiavacci, R., Allen, J., Spergel, J., Grundmeier, R., Grunstein, M., Magnusson, M., Grant, S.F.A., Bønnelykke, K., Bisgaard, H. and Hakonarson, H.
BibTeX:
@article{,
  author = {Flory, James H. and Sleiman, Patrick M. and Christie, Jason D. and Annaiah, Kiran and Bradfield, Jonathan and Kim, Cecilia E. and Glessner, Joseph and Imielinski, Marcin and Li, Hongzhe and Frackelton, Edward C. and Cuiping, Hou and Otieno, George and Thomas, Kelly and Smith, Ryan and Glaberson, Wendy and Garris, Maria and Chiavacci, Rosetta and Allen, Julian and Spergel, Jonathan and Grundmeier, Robert and Grunstein, Michael and Magnusson, Michael and Grant, Struan F A. and Bønnelykke, Klaus and Bisgaard, Hans and Hakonarson, Hakon},
  title = {17q12-21 variants interact with smoke exposure as a risk factor for pediatric asthma but are equally associated with early-onset versus late-onset asthma in North Americans of European ancestry.},
  journal = {J Allergy Clin Immunol},
  year = {2009},
  volume = {124},
  number = {3},
  pages = {605--607},
  url = {http://dx.doi.org/10.1016/j.jaci.2009.05.047},
  doi = {https://doi.org/10.1016/j.jaci.2009.05.047}
}
Chawes, B.L.K. Bisgaard, H. Objective assessments of allergic and nonallergic rhinitis in young children. 2009 Allergy 19663868 7,361 37
Authors: Chawes, B.L.K., Kreiner-Møller, E. and Bisgaard, H.
Abstract: Allergic and nonallergic rhinitis are common childhood disorders.To study nasal eosinophilia and nasal airway patency in young children with allergic and nonallergic rhinitis to assess the pathology behind such diagnoses.We investigated 255 children at six years of age from the Copenhagen Prospective Study on Asthma in Childhood birth cohort assessing rhinitis history, specific immunoglobulin E relevant to rhinitis symptoms, nasal eosinophilia and nasal airway patency by acoustic rhinometry before and after decongestion. Associations were studied in a multivariate graphical model corrected for gender, height and nasal steroid usage.Allergic rhinitis was significantly and directly associated with irreversible nasal airway obstruction (reduced decongested nasal airway patency) (P = 0.004), whereas nonallergic rhinitis was not. Both allergic rhinitis (P = 0.000) and nonallergic rhinitis (P = 0.014) were directly and significantly associated with nasal eosinophilia, but this association was stronger for allergic rhinitis.Allergic rhinitis and nonallergic rhinitis are of different pathologies as suggested from their different associations not only to allergy but importantly also to irreversible nasal airway obstruction and eosinophilic inflammation. Allergic rhinitis was significantly associated with nasal eosinophilia and irreversible nasal airway obstruction suggesting chronic inflammation and structural remodeling of the nasal mucosa in children at the age of 6 years. Nonallergic rhinitis exhibited no change in the nasal airway patency, but some nasal mucosal eosinophilia albeit less than children with allergic rhinitis.
BibTeX:
@article{,
  author = {Chawes, B L K. and Kreiner-Møller, E. and Bisgaard, H.},
  title = {Objective assessments of allergic and nonallergic rhinitis in young children.},
  journal = {Allergy},
  school = {Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte Copenhagen, Denmark.},
  year = {2009},
  volume = {64},
  number = {10},
  pages = {1547--1553},
  url = {http://dx.doi.org/10.1111/j.1398-9995.2009.02085.x},
  doi = {https://doi.org/10.1111/j.1398-9995.2009.02085.x}
}
Bisgaard, H. Pipper, C.B. Prenatal determinants of neonatal lung function in high-risk newborns. 2009 J Allergy Clin Immunol 19152964 13,081 43
Authors: Bisgaard, H., Loland, L., Holst, K.K. and Pipper, C.B.
Abstract: Neonatal lung function is suspected to be associated with wheezy disorders, but little is known about risk factors for the early lung function.To study prenatal determinants of neonatal lung function.This is a clinical, prospective birth cohort study of 411 newborns, the Copenhagen Prospective Study on Asthma in Childhood, in a single-center research clinic dedicated solely to this longitudinal birth cohort study. Lung function was determined at 1 month of age by infant spirometry (the raised volume rapid thoraco-abdominal compression technique) and bronchial responsiveness to methacholine by transcutaneous oxygen measurements. Risk factor analyses included anthropometrics; demographics; socioeconomic factors; parental atopic history; previous deliveries; exposures during the third trimester to the mother's smoking, alcohol, and medicines; third trimester pregnancy complications including mother's asthma status; and mode of delivery.Lung function was determined in 404 neonates, age 6 weeks. Neonates with body mass index in the upper quartile had 14% lower baseline forced expiratory volume at 0.5 second, and neonates of mothers smoking during the third trimester had 7% lower baseline forced expiratory volume at 0.5 second. Sex or parental atopic disease did not affect the neonatal lung function and bronchial responsiveness. Maternal intake of paracetamol during the third trimester was associated with doubling of the bronchial responsiveness in the neonates, but the statistical significance may have been driven by outliers. Bronchial responsiveness exhibited a parabola development with tripling of bronchial responsiveness reaching the nadir at 3 months of age, but this needs replication in a study with repetitive measurements within individuals.High body mass index in newborns and mothers smoking is associated with reduced neonatal lung function. This suggests that the association between body proportion and wheezing disorders may be a result of shared genes or prenatal nutrition.
BibTeX:
@article{,
  author = {Bisgaard, Hans and Loland, Lotte and Holst, Klaus K. and Pipper, Christian B.},
  title = {Prenatal determinants of neonatal lung function in high-risk newborns.},
  journal = {J Allergy Clin Immunol},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Danish Pediatric Asthma Center, Health Sciences, University of Copenhagen, Copenhagen University Hospital, Hellerup, Denmark. Bisgaard@copsac.com},
  year = {2009},
  volume = {123},
  number = {3},
  pages = {651--7, 657.e1-4},
  url = {http://dx.doi.org/10.1016/j.jaci.2008.11.036},
  doi = {https://doi.org/10.1016/j.jaci.2008.11.036}
}
Bisgaard, H. Noonan, G. Safety and tolerability of montelukast in placebo-controlled pediatric studies and their open-label extensions. 2009 Pediatr Pulmonol 19449366 2,758 49
Authors: Bisgaard, H., Skoner, D., Boza, M.L., Tozzi, C.A., Newcomb, K., Reiss, T.F., Knorr, B. and Noonan, G.
Abstract: Montelukast is a potent leukotriene-receptor antagonist administered once daily that provides clinical benefit in the treatment of asthma and allergic rhinitis in children and adults. Because of its wide use as a pediatric controller, there is a need for a further review of the safety and tolerability of montelukast in children.To summarize safety and tolerability data for montelukast from previously reported as well as from unpublished placebo-controlled, double-blind, pediatric studies and their active-controlled open-label extension/extended studies.These studies evaluated 2,751 pediatric patients 6 months to 14 years of age with persistent asthma, intermittent asthma associated with upper respiratory infection, or allergic rhinitis. These patients were enrolled in seven randomized, placebo-controlled, double-blind registration and post-registration studies and three active-controlled open-label extension/extended studies conducted by Merck Research Laboratories between 1995 and 2004.Montelukast was well tolerated in all studies. Clinical and laboratory adverse experiences for patients treated with montelukast were generally mild and transient. The most frequent clinical adverse events for all treatments (placebo, montelukast, active control/usual care) in virtually all studies were upper respiratory infection, worsening asthma, pharyngitis, and fever.The clinical and laboratory safety profile for montelukast was similar to that observed for placebo or active control/usual care therapies. The safety profile of montelukast did not change with long-term use.
BibTeX:
@article{,
  author = {Bisgaard, Hans and Skoner, David and Boza, Maria L. and Tozzi, Carol A. and Newcomb, Kathleen and Reiss, Theodore F. and Knorr, Barbara and Noonan, Gertrude},
  title = {Safety and tolerability of montelukast in placebo-controlled pediatric studies and their open-label extensions.},
  journal = {Pediatr Pulmonol},
  school = {Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark. bisgaard@copsac.dk},
  year = {2009},
  volume = {44},
  number = {6},
  pages = {568--579},
  url = {http://dx.doi.org/10.1002/ppul.21018},
  doi = {https://doi.org/10.1002/ppul.21018}
}
Bisgaard, H. Strand, M. Risk analysis of early childhood eczema. 2009 J Allergy Clin Immunol 19501236 13,081 51
Authors: Bisgaard, H., Halkjaer, L.B., Hinge, R., Giwercman, C., Palmer, C., Silveira, L. and Strand, M.
Abstract: The increasing prevalence of eczema suggests the role of environmental factors triggering a genetic predisposition.To analyze the effect of environmental exposures in early life and genetic predisposition on the development of eczema before age 3 years.The Copenhagen Study on Asthma in Childhood is a prospective clinical study of a birth cohort of 411 children born of mothers with asthma. Eczema was diagnosed, treated, and monitored at the clinical research unit, and complete follow-up for the first 3 years of life was available for 356 children. Risk assessments included filaggrin loss-of-function mutation; parent's atopic disease; sex; social status; previous deliveries; third trimester complications and exposures; anthropometrics at birth; month of birth; duration solely breast-fed; introduction of egg, cow's milk, and fish; time spent in day care; cat and dog at home; feather pillow; nicotine in infant's hair; and temperature and humidity in bedroom.Eczema developed in 43.5% of the infants. Filaggrin mutation (odds ratio [OR], 3.20; 95% CI, 1.46-7.02; P = .004), mother's eczema (OR, 2.80; 95% CI, 1.70-4.63; P < .0001), and father's allergic rhinitis (OR, 1.91; 95% CI, 1.09-3.33; P = .02) were directly associated with risk of eczema. Risk of eczema was significantly reduced by birth length (OR per cm increase, 0.87; 95% CI, 0.78-0.97; P = .02), increased bedroom temperature (probably inverse causality; OR, 0.80; 95% CI, 0.66-0.97; P = .02), and dog living in the home (OR, 0.44; 95% CI, 0.23-0.87; P = .02).Dog exposure reduced the risk of eczema, whereas short length at birth, filaggrin mutation, and parental atopy increased the risk of eczema by age 3 years.
BibTeX:
@article{,
  author = {Bisgaard, Hans and Halkjaer, Liselotte B. and Hinge, Rikke and Giwercman, Charlotte and Palmer, Colin and Silveira, Lori and Strand, Matthew},
  title = {Risk analysis of early childhood eczema.},
  journal = {J Allergy Clin Immunol},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Danish Pediatric Asthma Center, Health Sciences, University of Copenhagen, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark. bisgaard@copsac.com},
  year = {2009},
  volume = {123},
  number = {6},
  pages = {1355--60.e5},
  url = {http://dx.doi.org/10.1016/j.jaci.2009.03.046},
  doi = {https://doi.org/10.1016/j.jaci.2009.03.046}
}
Bisgaard, H. Hakonarsson, H. Chromosome 17q21 gene variants are associated with asthma and exacerbations but not atopy in early childhood. 2009 Am J Respir Crit Care Med 19029000 13,204 128
Authors: Bisgaard, H., Bønnelykke, K., Sleiman, P.M.A., Brasholt, M., Chawes, B., Kreiner-Møller, E., Stage, M., Kim, C., Tavendale, R., Baty, F., Pipper, C.B., Palmer, C.N.A. and Hakonarsson, H.
Abstract: An asthma predisposition locus on chromosome 17q12-q21 has recently been replicated in different ethnic groups.To characterize the asthma and atopy phenotypes in early childhood that associate with the 17q12-21 locus.The single nucleotide polymorphism (SNP), rs7216389, was genotyped in 376 of 411 children from the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohort born to mothers with asthma together with 305 mothers and 224 fathers. Nineteen additional SNPs in the region were genotyped in the children. Investigator-diagnosed clinical endpoints were based on diary cards and clinic visits every 6 months and at acute symptoms from birth. Lung function, bronchial responsiveness, and sensitization were tested longitudinally from early infancy.rs7216389 was significantly associated with the development of wheeze (hazard ratio 1.64 [1.05-2.59], P value = 0.03), asthma (hazard ratio, 1.88 [1.15-3.07], P = 0.01), and acute severe exacerbations (hazard ratio 2.66 [1.58-4.48], P value = 0.0002). The effect on wheeze and asthma was observed for early onset but not late onset of disease. The increased risk of exacerbations persisted from 1 to 6 years of age (incidence ratio 2.48 [1.42-4.32], P value = 0.001), and increased bronchial responsiveness was present in infancy and at 4 years of age, but not at 6 years. In contrast, rs7216389 conferred no risk of eczema, rhinitis, or allergic sensitization.Variation at the chromosome 17q12-q21 locus was associated with approximately twofold increased risk of recurrent wheeze, asthma, asthma exacerbations, and bronchial hyperresponsiveness from early infancy to school age but without conferring risk of eczema, rhinitis, or allergic sensitization. These longitudinal clinical data show this locus to be an important genetic determinant of nonatopic asthma in children.
BibTeX:
@article{,
  author = {Bisgaard, Hans and Bønnelykke, Klaus and Sleiman, Patrick M A. and Brasholt, Martin and Chawes, Bo and Kreiner-Møller, Eskil and Stage, Malene and Kim, Cecilia and Tavendale, Roger and Baty, Florent and Pipper, Christian Bressen and Palmer, Colin N A. and Hakonarsson, Hakon},
  title = {Chromosome 17q21 gene variants are associated with asthma and exacerbations but not atopy in early childhood.},
  journal = {Am J Respir Crit Care Med},
  school = {Copenhagen Studies on Asthma in Childhood, The Danish Paediatrics Asthma Centre, Faculty of Health Sciences, University of Copenhagen, Gentofte Hospital, Ledreborg Alle 34, DK-2900 Gentofte, Copenhagen, Denmark. Bisgaard@copsac.dk},
  year = {2009},
  volume = {179},
  number = {3},
  pages = {179--185},
  url = {http://dx.doi.org/10.1164/rccm.200809-1436OC},
  doi = {https://doi.org/10.1164/rccm.200809-1436OC}
}
Andersen, Z.J. Bisgaard, H. Ambient air pollution triggers wheezing symptoms in infants. 2008 Thorax 18267985 8,272 57
Authors: Andersen, Z.J., Loft, S., Ketzel, M., Stage, M., Scheike, T., Hermansen, M.N. and Bisgaard, H.
Abstract: There is limited evidence for the role of air pollution in the development and triggering of wheezing symptoms in young children. A study was undertaken to examine the effect of exposure to air pollution on wheezing symptoms in children under the age of 3 years with genetic susceptibility to asthma.Daily recordings of symptoms were obtained for 205 children participating in the birth cohort study Copenhagen Prospective Study on Asthma in Children and living in Copenhagen for the first 3 years of life. Daily air pollution levels for particulate matter <10 microm in diameter (PM(10)) and the concentrations of ultrafine particles, nitrogen dioxide (NO(2)), nitrogen oxide (NO(x)) and carbon monoxide (CO) were available from a central background monitoring station in Copenhagen. The association between incident wheezing symptoms and air pollution on the concurrent and previous 4 days was estimated by a logistic regression model (generalised estimating equation) controlling for temperature, season, gender, age, exposure to smoking and paternal history of asthma.Significant positive associations were found between concentrations of PM(10), NO(2), NO(x), CO and wheezing symptoms in infants (aged 0-1 year) with a delay of 3-4 days. Only the traffic-related gases (NO(2), NO(x)) showed significant effects throughout the 3 years of life, albeit attenuating after the age of 1 year.Air pollution related to traffic is significantly associated with triggering of wheezing symptoms in the first 3 years of life.
BibTeX:
@article{,
  author = {Andersen, Z. J. and Loft, S. and Ketzel, M. and Stage, M. and Scheike, T. and Hermansen, M. N. and Bisgaard, H.},
  title = {Ambient air pollution triggers wheezing symptoms in infants.},
  journal = {Thorax},
  school = {Department of Biostatistics, Institute of Public Health, Copenhagen University, Øster Farimagsgade 5 Entr. B, P O Box 2099, 1014 Copenhagen K, Denmark. zorana@cancer.dk},
  year = {2008},
  volume = {63},
  number = {8},
  pages = {710--716},
  url = {http://dx.doi.org/10.1136/thx.2007.085480},
  doi = {https://doi.org/10.1136/thx.2007.085480}
}
Bønnelykke, K. Bisgaard, H. Sensitization does not develop in utero. 2008 J Allergy Clin Immunol 18328892 13,081 52
Authors: Bønnelykke, K., Pipper, C.B. and Bisgaard, H.
Abstract: Intrauterine sensitization has been suggested to play a role in the development of atopic disease in children, and this has led to current guidelines recommending allergen avoidance during pregnancy.To investigate the relevance of allergen-specific IgE in cord blood to sensitization in early infancy and the origin of such IgE.Inhalant and food allergen-specific IgE in cord blood was analyzed and compared with specific IgE in infant blood at 6 months of age and in parental blood. Cord blood IgA was measured to detect maternal blood contamination of cord blood.Allergen-specific IgE, primarily against inhalant allergens, was detected in 14% of cord blood samples. However, corresponding specific IgE was not found in infant blood at 6 months of age. Specific IgE in cord blood completely matched specific IgE in maternal blood with respect to allergen specificity, level of specific IgE, and ratio of total IgE/specific IgE. Finally, there was a correlation between specific IgE and IgA in cord blood.Allergen-specific IgE in cord blood does not reflect intrauterine sensitization but seems to be the result of transfer of maternal IgE to the fetus.
BibTeX:
@article{,
  author = {Bønnelykke, Klaus and Pipper, Christian Bressen and Bisgaard, Hans},
  title = {Sensitization does not develop in utero.},
  journal = {J Allergy Clin Immunol},
  school = {Danish Pediatric Asthma Center, Department of Pediatrics, Copenhagen University Hospital, Copenhagen, Denmark. kb@copsac.dk},
  year = {2008},
  volume = {121},
  number = {3},
  pages = {646--651},
  url = {http://dx.doi.org/10.1016/j.jaci.2007.12.1149},
  doi = {https://doi.org/10.1016/j.jaci.2007.12.1149}
}
Sleiman, P.M.A. Hakonarson, H. ORMDL3 variants associated with asthma susceptibility in North Americans of European ancestry. 2008 J Allergy Clin Immunol 18760456 13,081 71
Authors: Sleiman, P.M.A., Annaiah, K., Imielinski, M., Bradfield, J.P., Kim, C.E., Frackelton, E.C., Glessner, J.T., Eckert, A.W., Otieno, F.G., Santa, E., Thomas, K., Smith, R.M., Glaberson, W., Garris, M., Gunnlaugsson, S., Chiavacci, R.M., Allen, J., Spergel, J., Grundmeier, R., Grunstein, M.M., Magnusson, M., Bisgaard, H., Grant, S.F.A. and Hakonarson, H.
BibTeX:
@article{,
  author = {Sleiman, Patrick M A. and Annaiah, Kiran and Imielinski, Marcin and Bradfield, Jonathan P. and Kim, Cecilia E. and Frackelton, Edward C. and Glessner, Joseph T. and Eckert, Andrew W. and Otieno, F George and Santa, Erin and Thomas, Kelly and Smith, Ryan M. and Glaberson, Wendy and Garris, Maria and Gunnlaugsson, Sigfus and Chiavacci, Rosetta M. and Allen, Julian and Spergel, Jonathan and Grundmeier, Robert and Grunstein, Michael M. and Magnusson, Mark and Bisgaard, Hans and Grant, Struan F A. and Hakonarson, Hakon},
  title = {ORMDL3 variants associated with asthma susceptibility in North Americans of European ancestry.},
  journal = {J Allergy Clin Immunol},
  year = {2008},
  volume = {122},
  number = {6},
  pages = {1225--1227},
  url = {http://dx.doi.org/10.1016/j.jaci.2008.06.041},
  doi = {https://doi.org/10.1016/j.jaci.2008.06.041}
}
Thomsen, S.F. Bisgaard, H. Increased concordance of severe respiratory syncytial virus infection in identical twins. 2008 Pediatrics 18310197 5,705 48
Authors: Thomsen, S.F., Stensballe, L.G., Skytthe, A., Kyvik, K.O., Backer, V. and Bisgaard, H.
Abstract: We estimated differences in the severity of respiratory syncytial virus infection attributable to genetic and environmental factors.Record linkage data on hospitalizations attributable to respiratory syncytial virus infection were gathered on all twins (12,346 pairs) born in Denmark between 1994 and 2003. Latent-factor models of genetic and environmental effects were fitted to the observed data by using maximal likelihood methods.Identical twins resembled each other significantly more than did fraternal twins for respiratory syncytial virus hospitalization (concordance rate: 0.66 vs 0.53), which suggests genetic influences on disease severity. Genetic factors accounted for 16 family environment for 73 and nonshared environment for 11% of the individual susceptibility to develop severe respiratory syncytial virus infection.The severity of respiratory syncytial virus infection is determined partly by genetic factors. This result should stimulate the search for genetic markers of disease severity.
BibTeX:
@article{,
  author = {Thomsen, Simon Francis and Stensballe, Lone Graff and Skytthe, Axel and Kyvik, Kirsten Ohm and Backer, Vibeke and Bisgaard, Hans},
  title = {Increased concordance of severe respiratory syncytial virus infection in identical twins.},
  journal = {Pediatrics},
  school = {Department of Respiratory Medicine, Bispebjerg Hospital, Bispebjerg Bakke 23, Building 60 DK-2400 Copenhagen NV, Denmark. sft@city.dk},
  year = {2008},
  volume = {121},
  number = {3},
  pages = {493--496},
  url = {http://dx.doi.org/10.1542/peds.2007-1889},
  doi = {https://doi.org/10.1542/peds.2007-1889}
}
Swern, A.S. Bisgaard, H. Predicting an asthma exacerbation in children 2 to 5 years of age. 2008 Ann Allergy Asthma Immunol 19119707 3,728 16
Authors: Swern, A.S., Tozzi, C.A., Knorr, B. and Bisgaard, H.
Abstract: Asthma exacerbations in young children are prevalent. Identification of symptoms or other factors that are precursors of asthma exacerbations would be useful for early treatment and prevention.To determine whether diary symptoms and beta2-agonist use before an exacerbation could predict an asthma exacerbation in children 2 to 5 years of age.Post hoc analyses were conducted on data collected in a study of 689 patients 2 to 5 years of age with asthma symptoms, randomly assigned to montelukast, 4 mg, or placebo daily for 12 weeks. During the study, 196 patients had an exacerbation. Caregiver-reported information (daytime cough, breathing difficulties, limitation of activity, nighttime cough or awakening, daytime and nighttime beta2-agonist use) were analyzed using general estimating equations with an exchangeable within-subject log odds ratio regression structure to identify predictors of an exacerbation.Average symptom scores and beta2-agonist use increased significantly before exacerbation but at different rates. A combination of daytime cough and wheeze and nighttime beta2-agonist use 1 day before the exacerbation was identified as strongly predictive of an exacerbation. These methods predicted 149 (66.8 of the exacerbations with a very low false-positive rate of 14.2%.No individual symptom was predictive of an imminent asthma exacerbation, but a combination of increased daytime cough, daytime wheeze, and nighttime beta2-agonist use 1 day before an asthma exacerbation was a strong predictor of an exacerbation in children.
BibTeX:
@article{,
  author = {Swern, Arlene S. and Tozzi, Carol A. and Knorr, Barbara and Bisgaard, Hans},
  title = {Predicting an asthma exacerbation in children 2 to 5 years of age.},
  journal = {Ann Allergy Asthma Immunol},
  school = {Merck Research Laboratories, Rahway, New Jersey 07065, USA. swern_arlene@verizon.net},
  year = {2008},
  volume = {101},
  number = {6},
  pages = {626--630},
  url = {http://dx.doi.org/10.1016/S1081-1206(10)60226-8},
  doi = {https://doi.org/10.1016/S1081-1206(10)60226-8}
}
Kjaer, B.B. Bisgaard, H. Lung function and bronchial responsiveness after Mycoplasma pneumoniae infection in early childhood. 2008 Pediatr Pulmonol 18435477 2,758 15
Authors: Kjaer, B.B., Jensen, J.S., Nielsen, K.G., Fomsgaard, A., Böttiger, B., Dohn, B. and Bisgaard, H.
Abstract: Mycoplasma (M.) pneumoniae has been associated with exacerbation of symptoms in asthmatic school children and adults; and an etiological role in asthma has been suggested. The purpose of this study was to investigate whether infection with M. pneumoniae in early childhood has a long-term influence on lung function and bronchial responsiveness. In a retrospective, clinical cohort-study children younger than 5 years-of-age when PCR-tested for M. pneumoniae were enrolled. Sixty-five children with clinical symptoms suggesting infection with M. pneumoniae during an epidemic season completed a clinical follow-up examination including lung function testing (28 PCR-positive and 37 PCR-negative). In addition to the PCR-test for M. pneumoniae all respiratory tract specimens were additionally tested for other atypical bacteria and for viruses by PCR. Lung function was measured as specific airway resistance by whole-body plethysmography and bronchial hyperresponsiveness was assessed by cold, dry air hyperventilation. Neither baseline lung function nor bronchial response to cold dry air hyperventilation differed between M. pneumoniae-positive and -negative children: mean baseline lung function were 1.17 versus 1.21 (kPa sec), P = 0.45; and mean change in specific resistance was 13% versus 9 P = 0.42. In conclusion, M. pneumoniae infection in early childhood was not associated with long-term effects on lung function and bronchial hyperresponsiveness 2 years after infection.
BibTeX:
@article{,
  author = {Kjaer, Birgitte B. and Jensen, Jørgen S. and Nielsen, Kim G. and Fomsgaard, Anders and Böttiger, Blenda and Dohn, Birthe and Bisgaard, Hans},
  title = {Lung function and bronchial responsiveness after Mycoplasma pneumoniae infection in early childhood.},
  journal = {Pediatr Pulmonol},
  school = {Department of Paediatrics, Copenhagen University Hospital, Glostrup, Denmark. bbk@dadlnet.dk},
  year = {2008},
  volume = {43},
  number = {6},
  pages = {567--575},
  url = {http://dx.doi.org/10.1002/ppul.20813},
  doi = {https://doi.org/10.1002/ppul.20813}
}
Loland, L. Bisgaard, H. Feasibility of repetitive lung function measurements by raised volume rapid thoracoabdominal compression during methacholine challenge in young infants. 2008 Chest 17951623 6,044 17
Authors: Loland, L. and Bisgaard, H.
Abstract: The aim of the study was to evaluate the feasibility of lung function measurements by the raised volume rapid thoracoabdominal compression (RVRTC) technique during bronchial methacholine challenge in young infants.Four hundred two healthy infants were tested at 1 month of age with RVRTC during repeated methacholine challenges with quadrupling doses from 0.037 to 16.674 mumol.Measurement of baseline lung function was successful in 99% and the provocative dose (PD) was achieved in 79% of infants by forced expiratory volume in 0.5 s (FEV(0.5)). Additionally, the PD was successfully measured in 87% by transcutaneous oxygen pressure. No serious adverse events were observed during testing or after discharge from the clinic. The methacholine dose range was appropriate as PD could be determined in the majority of infants. FEV(0.5) values in 21% of infants dropped > 40% during the test. Short-lasting, self-limiting episodes of hypoxemia of < 80% occurred in 1% of infants and bradycardia < 90 beats/min in 19% of infants. The most common observations by parents were changes in the patterns of sleeping (95, eating (57, and behavior (58 of the infant after hospital discharge. The mean acceptability rating among parents was 8 on a scale from 1 to 10, with 13% rating < or = 5. It took one operator 3 h to complete the test, with the actual lung function testing accounting for half the time.This very comprehensive experience with standardized measurements of lung function by RVRTC during methacholine challenge in young infants in a single center leads us to conclude that the test is feasible and safe to perform in asymptomatic young infants.
BibTeX:
@article{,
  author = {Loland, Lotte and Bisgaard, Hans},
  title = {Feasibility of repetitive lung function measurements by raised volume rapid thoracoabdominal compression during methacholine challenge in young infants.},
  journal = {Chest},
  school = {Danish Pediatric Asthma Center, Department of Pediatrics, Copenhagen University Hospital, Gentofte, Niels Andersens Vej 65, DK-2900 Hellerup, Denmark.},
  year = {2008},
  volume = {133},
  number = {1},
  pages = {115--122},
  url = {http://dx.doi.org/10.1378/chest.07-1328},
  doi = {https://doi.org/10.1378/chest.07-1328}
}
Holgate, S. Wahn, U. The Brussels Declaration: the need for change in asthma management. 2008 Eur Respir J 19043008 10,569 76
Authors: Holgate, S., Bisgaard, H., Bjermer, L., Haahtela, T., Haughney, J., Horne, R., McIvor, A., Palkonen, S., Price, D.B., Thomas, M., Valovirta, E. and Wahn, U.
Abstract: Asthma is a highly prevalent condition across Europe and numerous guidelines have been developed to optimise management. However, asthma can be neither cured nor prevented, treatment choices are limited and many patients have poorly controlled or uncontrolled asthma. The Brussels Declaration on Asthma, sponsored by The Asthma, Allergy and Inflammation Research Charity, was developed to call attention to the shortfalls in asthma management and to urge European policy makers to recognise that asthma is a public health problem that should be a political priority. The Declaration urges recognition and action on the following points: the systemic inflammatory component of asthma should be better understood and considered in assessments of treatment efficacy; current research must be communicated and responded to quickly; the European Medicines Agency guidance note on asthma should be updated; "real world" studies should be funded and results used to inform guidelines; variations in care across Europe should be addressed; people with asthma should participate in their own care; the impact of environmental factors should be understood; and targets should be set for improvement. The present paper reviews the evidence supporting the need for change in asthma management and summarises the ten key points contained in the Brussels Declaration.
BibTeX:
@article{,
  author = {Holgate, S. and Bisgaard, H. and Bjermer, L. and Haahtela, T. and Haughney, J. and Horne, R. and McIvor, A. and Palkonen, S. and Price, D. B. and Thomas, M. and Valovirta, E. and Wahn, U.},
  title = {The Brussels Declaration: the need for change in asthma management.},
  journal = {Eur Respir J},
  school = {Infection, Inflammation and Repair AIR Division, Level F, South Block, MP810, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK. s.holgate@soton.ac.uk},
  year = {2008},
  volume = {32},
  number = {6},
  pages = {1433--1442},
  url = {http://dx.doi.org/10.1183/09031936.00053108},
  doi = {https://doi.org/10.1183/09031936.00053108}
}
Giwercman, C. Menné, T. Classification of atopic hand eczema and the filaggrin mutations. 2008 Contact Dermatitis 18976374 4,335 10
Authors: Giwercman, C., Lerbaek, A., Bisgaard, H. and Menné, T.
Abstract: Hand eczema is a common disease with various risk factors of which atopic dermatitis is known to be one of the most important. Recently, two mutations in the gene coding for filaggrin, a protein important for the skin barrier, have repeatedly been shown to be associated with atopic dermatitis. Moreover, one study point towards an association between the filaggrin null alleles and the subgroup of patients having both hand eczema and atopic dermatitis. For the remainder of hand eczema patients, still unknown genetic risk factors exist. We propose that in future, classification of atopic hand eczema should distinguish between patients with and without the filaggrin null alleles and to further differentiate between associations with type I allergy, type IV allergy and exposure to irritants, respectively. Furthermore, we suggest future studies of atopic hand eczema to analyse for the filaggrin mutations. We believe this will increase the possibility of subgrouping this otherwise heterogenic disease and thereby enable a better phenotype-genotype characterization of hand eczema. This could improve the preventive initiatives, secure better information of patients about the prognosis for their disease, and possibly enable targeted treatment.
BibTeX:
@article{,
  author = {Giwercman, Charlotte and Lerbaek, Anne and Bisgaard, Hans and Menné, Torkil},
  title = {Classification of atopic hand eczema and the filaggrin mutations.},
  journal = {Contact Dermatitis},
  school = {Department of Dermatology, Copenhagen University Hospital Gentofte, DK-2900 Hellerup, Denmark. c_giwercman@hotmail.com},
  year = {2008},
  volume = {59},
  number = {5},
  pages = {257--260},
  url = {http://dx.doi.org/10.1111/j.1600-0536.2008.01426.x},
  doi = {https://doi.org/10.1111/j.1600-0536.2008.01426.x}
}
Brand, P.L.P. Bush, A. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. 2008 Eur Respir J 18827155 10,569 460
Authors: Brand, P.L.P., Baraldi, E., Bisgaard, H., Boner, A.L., Castro-Rodriguez, J.A., Custovic, A., de Blic, J., de Jongste, J.C., Eber, E., Everard, M.L., Frey, U., Gappa, M., Garcia-Marcos, L., Grigg, J., Lenney, W., Le Souëf, P., McKenzie, S., Merkus, P.J.F.M., Midulla, F., Paton, J.Y., Piacentini, G., Pohunek, P., Rossi, G.A., Seddon, P., Silverman, M., Sly, P.D., Stick, S., Valiulis, A., van Aalderen, W.M.C., Wildhaber, J.H., Wennergren, G., Wilson, N., Zivkovic, Z. and Bush, A.
Abstract: There is poor agreement on definitions of different phenotypes of preschool wheezing disorders. The present Task Force proposes to use the terms episodic (viral) wheeze to describe children who wheeze intermittently and are well between episodes, and multiple-trigger wheeze for children who wheeze both during and outside discrete episodes. Investigations are only needed when in doubt about the diagnosis. Based on the limited evidence available, inhaled short-acting beta(2)-agonists by metered-dose inhaler/spacer combination are recommended for symptomatic relief. Educating parents regarding causative factors and treatment is useful. Exposure to tobacco smoke should be avoided; allergen avoidance may be considered when sensitisation has been established. Maintenance treatment with inhaled corticosteroids is recommended for multiple-trigger wheeze; benefits are often small. Montelukast is recommended for the treatment of episodic (viral) wheeze and can be started when symptoms of a viral cold develop. Given the large overlap in phenotypes, and the fact that patients can move from one phenotype to another, inhaled corticosteroids and montelukast may be considered on a trial basis in almost any preschool child with recurrent wheeze, but should be discontinued if there is no clear clinical benefit. Large well-designed randomised controlled trials with clear descriptions of patients are needed to improve the present recommendations on the treatment of these common syndromes.
BibTeX:
@article{,
  author = {Brand, P L P. and Baraldi, E. and Bisgaard, H. and Boner, A. L. and Castro-Rodriguez, J. A. and Custovic, A. and de Blic, J. and de Jongste, J. C. and Eber, E. and Everard, M. L. and Frey, U. and Gappa, M. and Garcia-Marcos, L. and Grigg, J. and Lenney, W. and Le Souëf, P. and McKenzie, S. and Merkus, P J F M. and Midulla, F. and Paton, J. Y. and Piacentini, G. and Pohunek, P. and Rossi, G. A. and Seddon, P. and Silverman, M. and Sly, P. D. and Stick, S. and Valiulis, A. and van Aalderen, W M C. and Wildhaber, J. H. and Wennergren, G. and Wilson, N. and Zivkovic, Z. and Bush, A.},
  title = {Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach.},
  journal = {Eur Respir J},
  school = {Princess Amalia Children's Clinic, Isala klinieken, Zwolle, The Netherlands. p.l.p.brand@isala.nl},
  year = {2008},
  volume = {32},
  number = {4},
  pages = {1096--1110},
  url = {http://dx.doi.org/10.1183/09031936.00002108},
  doi = {https://doi.org/10.1183/09031936.00002108}
}
Bisgaard, H. Custovic, A. Gene-environment interaction in the onset of eczema in infancy: filaggrin loss-of-function mutations enhanced by neonatal cat exposure. 2008 PLoS Med 18578563 11,862 139
Authors: Bisgaard, H., Simpson, A., Palmer, C.N.A., Bønnelykke, K., McLean, I., Mukhopadhyay, S., Pipper, C.B., Halkjaer, L.B., Lipworth, B., Hankinson, J., Woodcock, A. and Custovic, A.
Abstract: Loss-of-function variants in the gene encoding filaggrin (FLG) are major determinants of eczema. We hypothesized that weakening of the physical barrier in FLG-deficient individuals may potentiate the effect of environmental exposures. Therefore, we investigated whether there is an interaction between FLG loss-of-function mutations with environmental exposures (pets and dust mites) in relation to the development of eczema.We used data obtained in early life in a high-risk birth cohort in Denmark and replicated the findings in an unselected birth cohort in the United Kingdom. Primary outcome was age of onset of eczema; environmental exposures included pet ownership and mite and pet allergen levels. In Copenhagen (n = 379), FLG mutation increased the risk of eczema during the first year of life (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.27-4.00, p = 0.005), with a further increase in risk related to cat exposure at birth amongst children with FLG mutation (HR 11.11, 95% CI 3.79-32.60, p < 0.0001); dog exposure was moderately protective (HR 0.49, 95% CI 0.24-1.01, p = 0.05), but not related to FLG genotype. In Manchester (n = 503) an independent and significant association of the development of eczema by age 12 mo with FLG genotype was confirmed (HR 1.95, 95% CI 1.13-3.36, p = 0.02). In addition, the risk increased because of the interaction of cat ownership at birth and FLG genotype (HR 3.82, 95% CI 1.35-10.81, p = 0.01), with no significant effect of the interaction with dog ownership (HR 0.59, 95% CI 0.16-2.20, p = 0.43). Mite-allergen had no effects in either cohort. The observed effects were independent of sensitisation.We have demonstrated a significant interaction between FLG loss-of-function main mutations (501x and 2282del4) and cat ownership at birth on the development of early-life eczema in two independent birth cohorts. Our data suggest that cat but not dog ownership substantially increases the risk of eczema within the first year of life in children with FLG loss-of-function variants, but not amongst those without. FLG-deficient individuals may need to avoid cats but not dogs in early life.
BibTeX:
@article{,
  author = {Bisgaard, Hans and Simpson, Angela and Palmer, Colin N A. and Bønnelykke, Klaus and McLean, Irwin and Mukhopadhyay, Somnath and Pipper, Christian B. and Halkjaer, Liselotte B. and Lipworth, Brian and Hankinson, Jenny and Woodcock, Ashley and Custovic, Adnan},
  title = {Gene-environment interaction in the onset of eczema in infancy: filaggrin loss-of-function mutations enhanced by neonatal cat exposure.},
  journal = {PLoS Med},
  school = {Copenhagen Prospective Studies on Asthma in Childhood, Danish Paediatric Asthma Centre, Copenhagen, University Hospital Gentofte, Copenhagen, Denmark. bisgaard@copsac.com},
  year = {2008},
  volume = {5},
  number = {6},
  pages = {e131},
  url = {http://dx.doi.org/10.1371/journal.pmed.0050131},
  doi = {https://doi.org/10.1371/journal.pmed.0050131}
}
Bisgaard, H. Knorr, B.A. Study of montelukast for the treatment of respiratory symptoms of post-respiratory syncytial virus bronchiolitis in children. 2008 Am J Respir Crit Care Med 18583576 13,204 80
Authors: Bisgaard, H., Flores-Nunez, A., Goh, A., Azimi, P., Halkas, A., Malice, M.-P., Marchal, J.-L., Dass, S.B., Reiss, T.F. and Knorr, B.A.
Abstract: A pilot study (Bisgaard H; Study Group on Montelukast and Respiratory Syncytial Virus. A randomized trial of montelukast in respiratory syncytial virus postbronchiolitis. Am J Respir Crit Care Med 2003;167:379-383) reported the efficacy of montelukast in post-respiratory syncytial virus (RSV) bronchiolitic respiratory symptoms.To evaluate the efficacy and safety of montelukast, 4 and 8 mg, in treating recurrent respiratory symptoms of post-RSV bronchiolitis in children in a large, multicenter study.This was a double-blind study of 3- to 24-month-old children who had been hospitalized for a first or second episode of physician-diagnosed RSV bronchiolitis and who tested positive for RSV. Patients (n = 979) were randomized to placebo or to montelukast at 4 or 8 mg/day for 4 weeks (period I) and 20 weeks (period II). The primary end point was percentage symptom-free days ( day with no daytime cough, wheeze, and shortness of breath, and no nighttime cough).No significant differences were seen between montelukast and placebo in %SFD over period I: mean +/- SD for placebo and for montelukast at 4 and 8 mg were 37.0 +/- 30.7, 38.6 +/- 30.4, and 38.5 +/- 29.9, respectively. Least-squares mean differences (95% confidence interval) between montelukast (4 mg) and placebo and between montelukast (8 mg) and placebo were 1.9% (-2.9, 6.7) and 1.6% (-3.2, 6.5), respectively. Secondary end points were similar across treatments. Both doses were generally well tolerated. During the first two treatment weeks, average %SFD was approximately 29%. In post hoc analyses of patients (n = 523) with persistent symptoms (%SFD < or = 30% over Weeks 1-2), differences in %SFD were seen between montelukast and placebo over Weeks 3-24: difference were 5.7 (0.0, 11.3) for montelukast (4 mg) minus placebo and 5.9 (0.1, 11.7) for montelukast (8 mg) minus placebo.In this study, montelukast did not improve respiratory symptoms of post-RSV bronchiolitis in children.
BibTeX:
@article{,
  author = {Bisgaard, Hans and Flores-Nunez, Alejandro and Goh, Anne and Azimi, Parvin and Halkas, Andrew and Malice, Marie-Pierre and Marchal, Jean-Louis and Dass, S Balachandra and Reiss, Theodore F. and Knorr, Barbara A.},
  title = {Study of montelukast for the treatment of respiratory symptoms of post-respiratory syncytial virus bronchiolitis in children.},
  journal = {Am J Respir Crit Care Med},
  school = {Danish Pediatric Asthma Center, Department of Pediatrics, Copenhagen University Hospital, Gentofte, DK-2900 Copenhagen, Denmark. bisgaard@copsac.dk},
  year = {2008},
  volume = {178},
  number = {8},
  pages = {854--860},
  url = {http://dx.doi.org/10.1164/rccm.200706-910OC},
  doi = {https://doi.org/10.1164/rccm.200706-910OC}
}
Bønnelykke, K. Bisgaard, H. Early bioavailability of inhaled salbutamol reflects lung dose in children. 2008 Br J Clin Pharmacol 18637892 3,493 1
Authors: Bønnelykke, K., Jespersen, J.J. and Bisgaard, H.
BibTeX:
@article{,
  author = {Bønnelykke, Klaus and Jespersen, Jacob J. and Bisgaard, Hans},
  title = {Early bioavailability of inhaled salbutamol reflects lung dose in children.},
  journal = {Br J Clin Pharmacol},
  year = {2008},
  volume = {66},
  number = {4},
  pages = {562--563},
  url = {http://dx.doi.org/10.1111/j.1365-2125.2008.03195.x},
  doi = {https://doi.org/10.1111/j.1365-2125.2008.03195.x}
}
Sørensen, M. Loft, S. Biomarkers of exposure to environmental tobacco smoke in infants. 2007 Biomarkers 17438652 2,006 23
Authors: Sørensen, M., Bisgaard, H., Stage, M. and Loft, S.
BibTeX:
@article{,
  author = {Sørensen, M. and Bisgaard, H. and Stage, M. and Loft, S.},
  title = {Biomarkers of exposure to environmental tobacco smoke in infants.},
  journal = {Biomarkers},
  school = {Institute of Public Health, University of Copenhagen, Copenhagen, Denmark.},
  volume = {12},
  number = {1},
  pages = {38--46},
  url = {http://dx.doi.org/10.1080/13547500600943148},
  doi = {https://doi.org/10.1080/13547500600943148}
}
Bisgaard, H. What drives prescription patterns in pediatric asthma management? 2007 J Allergy Clin Immunol 17637472 13,081 9
Authors: Bisgaard, H.
BibTeX:
@article{,
  author = {Bisgaard, Hans},
  title = {What drives prescription patterns in pediatric asthma management?},
  journal = {J Allergy Clin Immunol},
  year = {2007},
  volume = {120},
  number = {4},
  pages = {969--972},
  url = {http://dx.doi.org/10.1016/j.jaci.2007.06.011},
  doi = {https://doi.org/10.1016/j.jaci.2007.06.011}
}
Beydon, N. Wilson, N.M. An official American Thoracic Society/European Respiratory Society statement: pulmonary function testing in preschool children. 2007 Am J Respir Crit Care Med 17545458 13,204 539
Authors: Beydon, N., Davis, S.D., Lombardi, E., Allen, J.L., Arets, H.G.M., Aurora, P., Bisgaard, H., Davis, G.M., Ducharme, F.M., Eigen, H., Gappa, M., Gaultier, C., Gustafsson, P.M., Hall, G.L., Hantos, Z., Healy, M.J.R., Jones, M.H., Klug, B., Lødrup Carlsen, K.C., McKenzie, S.A., Marchal, F., Mayer, O.H., Merkus, P.J.F.M., Morris, M.G., Oostveen, E., Pillow, J.J., Seddon, P.C., Silverman, M., Sly, P.D., Stocks, J., Tepper, R.S., Vilozni, D., Wilson, N.M., , A.T.S.R.S.W.G.o.I. and Testing, Y.C.P.F.
BibTeX:
@article{,
  author = {Beydon, Nicole and Davis, Stephanie D. and Lombardi, Enrico and Allen, Julian L. and Arets, Hubertus G M. and Aurora, Paul and Bisgaard, Hans and Davis, G Michael and Ducharme, Francine M. and Eigen, Howard and Gappa, Monika and Gaultier, Claude and Gustafsson, Per M. and Hall, Graham L. and Hantos, Zoltán and Healy, Michael J R. and Jones, Marcus H. and Klug, Bent and Lødrup Carlsen, Karin C. and McKenzie, Sheila A. and Marchal, Francçois and Mayer, Oscar H. and Merkus, Peter J F M. and Morris, Mohy G. and Oostveen, Ellie and Pillow, J Jane and Seddon, Paul C. and Silverman, Michael and Sly, Peter D. and Stocks, Janet and Tepper, Robert S. and Vilozni, Daphna and Wilson, Nicola M. and , American Thoracic Society/European Respiratory Society Working Group on Infant and Young Children Pulmonary Function Testing},
  title = {An official American Thoracic Society/European Respiratory Society statement: pulmonary function testing in preschool children.},
  journal = {Am J Respir Crit Care Med},
  year = {2007},
  volume = {175},
  number = {12},
  pages = {1304--1345}
}
Lerbaek, A. Menné, T. Filaggrin null alleles are not associated with hand eczema or contact allergy. 2007 Br J Dermatol 17970802 4,706 42
Authors: Lerbaek, A., Bisgaard, H., Agner, T., Ohm Kyvik, K., Palmer, C.N.A. and Menné, T.
Abstract: The filaggrin protein is a key component of stratum corneum and homo- or heterozygotes for the filaggrin variant alleles R501X and 2282del4 have varying degrees of impaired skin barrier. The variant alleles have repeatedly been shown to be associated with atopic dermatitis. Any possible association with hand eczema or contact allergy are unexplored.To explore associations between the variant alleles, hand eczema, contact allergy and atopic dermatitis.In total, 183 adult individuals participated in a clinical examination of the hands, patch testing and filaggrin genotyping. Children without any evidence of atopic dermatitis from the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) study were used as controls. The chi(2) test was used for comparison of allele frequencies.The majority (73 had hand eczema, 25% had contact allergy and 14% had a diagnosis of atopic dermatitis. The association between atopic dermatitis and the filaggrin variant alleles was confirmed (odds ratio 3.5, P = 0.015). Allele frequencies in individuals with hand eczema or contact allergy were not statistically significantly increased.There is no association between the variant alleles and hand eczema or contact allergy.
BibTeX:
@article{,
  author = {Lerbaek, A. and Bisgaard, H. and Agner, T. and Ohm Kyvik, K. and Palmer, C N A. and Menné, T.},
  title = {Filaggrin null alleles are not associated with hand eczema or contact allergy.},
  journal = {Br J Dermatol},
  school = {National Allergy Research Centre, Gentofte Hospital, University of Copenhagen, Ledreborg Allé 40, 1, 2820 Gentofte, Denmark. anne.lerbaek@dadlnet.dk},
  year = {2007},
  volume = {157},
  number = {6},
  pages = {1199--1204},
  url = {http://dx.doi.org/10.1111/j.1365-2133.2007.08252.x},
  doi = {https://doi.org/10.1111/j.1365-2133.2007.08252.x}
}
Bisgaard, H. Weiss, S.T. Determinants of lung function and airway hyperresponsiveness in asthmatic children. 2007 Respir Med 17336509 3,217 10
Authors: Bisgaard, H., Pedersen, S., Anhøj, J., Agertoft, L., Hedlin, G., Gulsvik, A., Bjermer, L., Carlsen, K.H., Nordvall, L., Lundbäck, B., Wennergren, G., Werner, S., Bønnelykke, K. and Weiss, S.T.
Abstract: Asthma patients exhibit an increased rate of loss of lung function. Determinants to such decline are largely unknown and the modifying effect of steroid therapy is disputed. This cross-sectional study aimed to elucidate factors contributing to such decline and the possible modifying effect of steroid treatment.We analyzed determinants of lung function and airway hyperresponsiveness (AHR) in a Scandinavian study of 2390 subjects from 550 families. Families were selected for the presence of two or more asthmatic children as part of a genetic study, Scandinavian Asthma Genetic Study (SAGA).The primary analysis studied the association between the lung function and delay of inhaled corticosteroids (ICS) after asthma diagnosis among asthmatic children and young adults with a history of regular ICS treatment (N=919). FEV(1) percent predicted (FEV(1)% pred) was 0.25% lower per year of delay from diagnosis until treatment (p=0.039). This association was significantly greater in allergy skin prick test negative children. There was no significant influence of gender, age at asthma onset, or smoking. In the secondary analysis of the whole population of 2390 asthmatics and non-asthmatics, FEV(1)% pred was inversely related to having asthmatic siblings (-7.9 p<0.0001), asthma diagnosis (-2.7 p=0.0007), smoking (-3.5 p=0.0027), and positive allergy skin prick test (-0.47% per test; p=0.012), while positively related to being of female gender (1.8 p=0.0029). Risk of AHR was higher by having asthmatic siblings (OR 2.7; p<0.0001), being of female gender (OR 2.0; p<0.0001), and having asthma (OR 2.0; p<0.0001).These data suggest that lung function is lower in asthmatics with delayed introduction of ICS therapy, smoking, and positive allergy skin prick test. Lung function is lower and AHR higher in female asthmatics and subjects with asthmatic siblings or established asthma.
BibTeX:
@article{,
  author = {Bisgaard, H. and Pedersen, S. and Anhøj, J. and Agertoft, L. and Hedlin, G. and Gulsvik, A. and Bjermer, L. and Carlsen, K. H. and Nordvall, L. and Lundbäck, B. and Wennergren, G. and Werner, S. and Bønnelykke, K. and Weiss, S. T.},
  title = {Determinants of lung function and airway hyperresponsiveness in asthmatic children.},
  journal = {Respir Med},
  school = {Danish Paediatric Asthma Center, Copenhagen University Hospital, Gentofte, DK-2900 Copenhagen, Denmark. Bisgaard@copsac.dk},
  year = {2007},
  volume = {101},
  number = {7},
  pages = {1477--1482},
  url = {http://dx.doi.org/10.1016/j.rmed.2007.01.013},
  doi = {https://doi.org/10.1016/j.rmed.2007.01.013}
}
Bisgaard, H. Szefler, S. Prevalence of asthma-like symptoms in young children. 2007 Pediatr Pulmonol 17598172 2,758 1
Authors: Bisgaard, H. and Szefler, S.
Abstract: To determine the prevalence, impact, and treatment of asthma-like symptoms in preschool children in USA and Europe.7251 households in USA and Europe with at least one child aged 1-5 years were interviewed by telephone for recurrent days troubled by cough, wheeze or breathlessness during the recent 6 winter months.9490 young children were identified, 32% of whom were reported to suffer from recurrent days with troublesome cough, wheeze or breathlessness. Detailed interview with the 2700 mothers of the symptomatic children showed that 24% of this interview population suffered weekly symptoms despite current treatment with considerable impact on lifestyle and healthcare resource use. Antibiotics, cough- and herbal-medications were the most commonly used treatments. Anti-asthmatic and anti-allergy agents were prescribed in the order: inhaled beta2-agonists > inhaled corticosteroid > oral anti-histamines > oral corticosteroids. The reported symptom burden was higher in Southern Europe and there were pronounced regional differences in treatment and diagnostic terms.Recurrent days with cough, wheeze or breathlessness in preschool children represents a major cause of morbidity in preschool children despite current treatment. There is a striking lack of international consensus on diagnosis and treatment. This uncontrolled morbidity highlights a significant unmet clinical need in preschool children.
BibTeX:
@article{,
  author = {Bisgaard, Hans and Szefler, Stanley},
  title = {Prevalence of asthma-like symptoms in young children.},
  journal = {Pediatr Pulmonol},
  school = {Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark. bisgaard@copsac.dk},
  year = {2007},
  volume = {42},
  number = {8},
  pages = {723--728},
  url = {http://dx.doi.org/10.1002/ppul.20644},
  doi = {https://doi.org/10.1002/ppul.20644}
}
Bisgaard, H. Pipper, C.B. Childhood asthma after bacterial colonization of the airway in neonates. 2007 N Engl J Med 17928596 72,406 461
Authors: Bisgaard, H., Hermansen, M.N., Buchvald, F., Loland, L., Halkjaer, L.B., Bønnelykke, K., Brasholt, M., Heltberg, A., Vissing, N.H., Thorsen, S.V., Stage, M. and Pipper, C.B.
Abstract: Pathological features of the airway in young children with severe recurrent wheeze suggest an association between bacterial colonization and the initiating events of early asthma. We conducted a study to investigate a possible association between bacterial colonization of the hypopharynx in asymptomatic neonates and later development of recurrent wheeze, asthma, and allergy during the first 5 years of life.The subjects were children from the Copenhagen Prospective Study on Asthma in Childhood birth cohort who were born to mothers with asthma. Aspirates from the hypopharyngeal region of asymptomatic 1-month-old infants were cultured for Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus. Wheeze was monitored prospectively on diary cards during the first 5 years of life. Blood eosinophil count and total IgE and specific IgE were measured at 4 years of age. Lung function was measured and asthma was diagnosed at 5 years of age.Hypopharyngeal samples were cultured from 321 neonates at 1 month of age. Twenty-one percent of the infants were colonized with S. pneumoniae, M. catarrhalis, H. influenzae, or a combination of these organisms; colonization with one or more of these organisms, but not colonization with S. aureus, was significantly associated with persistent wheeze (hazard ratio, 2.40; 95% confidence interval [CI], 1.45 to 3.99), acute severe exacerbation of wheeze (hazard ratio, 2.99; 95% CI, 1.66 to 5.39), and hospitalization for wheeze (hazard ratio, 3.85; 95% CI, 1.90 to 7.79). Blood eosinophil counts and total IgE at 4 years of age were significantly increased in children colonized neonatally with S. pneumoniae, M. catarrhalis, H. influenzae, or a combination of these organisms, but specific IgE was not significantly affected. The prevalence of asthma and the reversibility of airway resistance after beta2-agonist administration at 5 years of age were significantly increased in the children colonized neonatally with these organisms as compared with the children without such colonization (33% vs. 10% and 23% vs. 18 respectively).Neonates colonized in the hypopharyngeal region with S. pneumoniae, H. influenzae, or M. catarrhalis, or with a combination of these organisms, are at increased risk for recurrent wheeze and asthma early in life.
BibTeX:
@article{,
  author = {Bisgaard, Hans and Hermansen, Mette Northman and Buchvald, Frederik and Loland, Lotte and Halkjaer, Liselotte Brydensholt and Bønnelykke, Klaus and Brasholt, Martin and Heltberg, Andreas and Vissing, Nadja Hawwa and Thorsen, Sannie Vester and Stage, Malene and Pipper, Christian Bressen},
  title = {Childhood asthma after bacterial colonization of the airway in neonates.},
  journal = {N Engl J Med},
  school = {Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Copenhagen. bisgaard@copsac.dk},
  year = {2007},
  volume = {357},
  number = {15},
  pages = {1487--1495},
  url = {http://dx.doi.org/10.1056/NEJMoa052632},
  doi = {https://doi.org/10.1056/NEJMoa052632}
}
Bønnelykke, K. Bisgaard, H. Age dependent systemic exposure to inhaled salbutamol. 2007 Br J Clin Pharmacol 17335545 3,493 9
Authors: Bønnelykke, K., Jespersen, J.J. and Bisgaard, H.
Abstract: To determine the effect of age on systemic exposure to inhaled salbutamol in children.Fifty-eight asthmatic children, aged 3-16 years, inhaled 400 microg of salbutamol from a pressurized metered dose inhaler with spacer. The 20 min serum profile was analyzed.Prescribing a dose on a microg kg(-1) basis caused reduced systemic exposure in young children (Y) compared with older children (O) (C(max-microg kg(-1)-adjusted) Y : O ratio (95 = 0.55 (0.47, 0.65)) whereas a fixed nominal dose irrespective of age caused increased exposure in young children (C(max) Y : O ratio (95 = 1.7 (1.3, 2.2)).For similar systemic exposure, dosing should be adjusted to age or size but not on a fixed microg kg(-1) basis, which may lead to unnecessary suboptimal dosing.
BibTeX:
@article{,
  author = {Bønnelykke, Klaus and Jespersen, Jakob Jessing and Bisgaard, Hans},
  title = {Age dependent systemic exposure to inhaled salbutamol.},
  journal = {Br J Clin Pharmacol},
  school = {Danish Pediatric Asthma Center; Copenhagen University Hospital, Gentofte, Copenhagen, Denmark. kb@copsac.dk},
  year = {2007},
  volume = {64},
  number = {2},
  pages = {241--244},
  url = {http://dx.doi.org/10.1111/j.1365-2125.2007.02868.x},
  doi = {https://doi.org/10.1111/j.1365-2125.2007.02868.x}
}
Vahlkvist, S. Bisgaard, H. Daily home measurements of exhaled nitric oxide in asthmatic children during natural birch pollen exposure. 2006 J Allergy Clin Immunol 16750986 13,081 62
Authors: Vahlkvist, S., Sinding, M., Skamstrup, K. and Bisgaard, H.
Abstract: Fractional exhaled nitric oxide (FENO) is a sensitive marker of eosinophilic airway inflammation in asthma. Available methods have restricted measurements to the clinic, giving only a snapshot of the disease, which by nature is highly variable.We sought to investigate the feasibility, repeatability, accuracy, sensitivity, and biologic plausibility of new handheld equipment for FENO measurements. We studied day-to-day home measurements of FENO during the birch pollen season in children with allergy to birch pollen and a history of mild asthma and rhinoconjunctivitis during this season, as well as in nonatopic children.Eleven children with mild asthma and allergy to birch pollen, performed daily home measurements of FENO for 6 weeks before and during the birch pollen season by using a handheld FENO monitor (NIOX MINO). Additionally, FENO (chemiluminescence equipment [NIOX]) and spirometry were measured at the inclusion and completion visit in the clinic. Peak expiratory flow rate (PEFR) and symptoms were recorded daily.Daily FENO (NIOX MINO) increased significantly (P < .001) with increasing pollen count. FENO (NIOX MINO) and FENO (NIOX) exhibited a correlation coefficient of 0.98, but FENO (NIOX MINO) was significantly higher than FE(NO) (NIOX) (P < .01). PEFR and FEV1 remained unchanged, and few symptoms were recorded.Exhaled nitric oxide levels increased significantly during the pollen season, even though the patients reported only few asthmatic symptoms and no change in PEFR or spirometry. Daily measurements of FENO (NIOX MINO) might allow early detection of disease deterioration, and future studies could address such a measure for dynamic treatment strategies.This simple handheld device expands the potential use of FENO to a wider group of asthma clinics and even home measurements.
BibTeX:
@article{,
  author = {Vahlkvist, Signe and Sinding, Marianne and Skamstrup, Kirsten and Bisgaard, Hans},
  title = {Daily home measurements of exhaled nitric oxide in asthmatic children during natural birch pollen exposure.},
  journal = {J Allergy Clin Immunol},
  school = {Danish Pediatric Asthma Centre, Copenhagen University Hospital.},
  year = {2006},
  volume = {117},
  number = {6},
  pages = {1272--1276},
  url = {http://dx.doi.org/10.1016/j.jaci.2006.03.018},
  doi = {https://doi.org/10.1016/j.jaci.2006.03.018}
}
Palmer, C.N.A. McLean, W.H.I. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. 2006 Nat Genet 16550169 27,959 1462
Authors: Palmer, C.N.A., Irvine, A.D., Terron-Kwiatkowski, A., Zhao, Y., Liao, H., Lee, S.P., Goudie, D.R., Sandilands, A., Campbell, L.E., Smith, F.J.D., O'Regan, G.M., Watson, R.M., Cecil, J.E., Bale, S.J., Compton, J.G., DiGiovanna, J.J., Fleckman, P., Lewis-Jones, S., Arseculeratne, G., Sergeant, A., Munro, C.S., El Houate, B., McElreavey, K., Halkjaer, L.B., Bisgaard, H., Mukhopadhyay, S. and McLean, W.H.I.
Abstract: Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.
BibTeX:
@article{,
  author = {Palmer, Colin N A. and Irvine, Alan D. and Terron-Kwiatkowski, Ana and Zhao, Yiwei and Liao, Haihui and Lee, Simon P. and Goudie, David R. and Sandilands, Aileen and Campbell, Linda E. and Smith, Frances J D. and O'Regan, Gráinne M. and Watson, Rosemarie M. and Cecil, Jo E. and Bale, Sherri J. and Compton, John G. and DiGiovanna, John J. and Fleckman, Philip and Lewis-Jones, Sue and Arseculeratne, Gehan and Sergeant, Ann and Munro, Colin S. and El Houate, Brahim and McElreavey, Ken and Halkjaer, Liselotte B. and Bisgaard, Hans and Mukhopadhyay, Somnath and McLean, W H Irwin},
  title = {Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.},
  journal = {Nat Genet},
  school = {Population Pharmacogenetics Group, Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.},
  year = {2006},
  volume = {38},
  number = {4},
  pages = {441--446},
  url = {http://dx.doi.org/10.1038/ng1767},
  doi = {https://doi.org/10.1038/ng1767}
}
Loland, L. Bisgaard, H. Sensitivity of bronchial responsiveness measurements in young infants. 2006 Chest 16537866 6,044 22
Authors: Loland, L., Buchvald, F.F., Halkjaer, L.B., Anhøj, J., Hall, G.L., Persson, T., Krause, T.G. and Bisgaard, H.
Abstract: There is limited evidence on the preferred methods for evaluating lung function in infancy. The objective of this study was to compare sensitivity and repeatability of indexes of lung function in young infants during induced airway obstruction.The study population consisted of 402 infants (median age, 6 weeks). Forced flow-volume measurements were obtained by the raised volume rapid thoracoabdominal compression technique and were compared with indexes of tidal breathing, measurements of transcutaneous oxygen (Ptco(2)), and auscultation during methacholine challenge testing.Ptco(2) was the most sensitive parameter to detect increasing airway obstruction during methacholine challenge, followed by forced expiratory volume at 0.5 s (FEV(0.5)). Both were superior to other indexes of forced spirometry as well as tidal breathing indexes and auscultation. Coefficients of variations for Ptco(2) and FEV(0.5) were 4% and 7 respectively.Ptco(2) and FEV(0.5) are the most sensitive parameters for measurement of bronchial responsiveness in young infants. Measurements of baseline lung function should preferably be made using FEV(0.5.) Measurements of bronchial responsiveness are best assessed using Ptco(2), which may be performed in nonsedated infants and improve feasibility of future studies on lung function in infancy.
BibTeX:
@article{,
  author = {Loland, Lotte and Buchvald, Frederik F. and Halkjaer, Liselotte Brydensholt and Anhøj, Jacob and Hall, Graham L. and Persson, Tore and Krause, Tyra Grove and Bisgaard, Hans},
  title = {Sensitivity of bronchial responsiveness measurements in young infants.},
  journal = {Chest},
  school = {Danish Pediatric Asthma Center, Department of Pediatrics, Copenhagen University Hospital, Gentofte, Niels Andersens Vej 65, DK-2900 Hellerup, Denmark.},
  year = {2006},
  volume = {129},
  number = {3},
  pages = {669--675},
  url = {http://dx.doi.org/10.1378/chest.129.3.669},
  doi = {https://doi.org/10.1378/chest.129.3.669}
}
Hermansen, M.N. Bisgaard, H. Acute relief of exercise-induced bronchoconstriction by inhaled formoterol in children with persistent asthma. 2006 Chest 16685010 6,044 17
Authors: Hermansen, M.N., Nielsen, K.G., Buchvald, F., Jespersen, J.J., Bengtsson, T. and Bisgaard, H.
Abstract: To compare the acute bronchodilatory effect of the long-acting beta2-agonist formoterol against the short-acting beta2-agonist (SABA) terbutaline during exercise-induced bronchoconstriction (EIB) in children with asthma.A randomized, double-blind, placebo-controlled, crossover study of the immediate effect of formoterol, 9 microg, vs terbutaline, 0.5 mg, and placebo administered as dry powder at different study days. Exercise challenge test was used as a model of acute bronchoconstriction.Twenty-four 7- to 15-year-old children with persistent asthma.The children performed standardized treadmill exercise tests, breathing dry air, with a submaximal workload. Study medication was administered 5 min after exercise if FEV1 dropped > or = 15% within 5 min after exercise. FEV1 and forced expiratory flows were measured repeatedly until 60 min after dose.Formoterol and terbutaline offered a significant acute bronchodilatory effect from 3 min after dose compared with placebo (p < 0.001). There was no difference between formoterol and terbutaline in FEV1 5 min after dose (p = 0.15), with a mean increase from each predrug baseline of 62% of the maximum increase for both. Median times to recovery within 5% of baseline FEV1 were 5.0 min and 7.4 min for formoterol and terbutaline, respectively (p = 0.33).Single-dose formoterol, 9 microg, via dry powder inhaler provided an acute bronchodilatory effect similar to terbutaline during EIB in schoolchildren with persistent asthma. Formoterol is at least as effective as SABA and may be considered an alternative in the treatment of acute bronchoconstriction in school children.
BibTeX:
@article{,
  author = {Hermansen, Mette Northman and Nielsen, Kim Gjerum and Buchvald, Frederik and Jespersen, Jakob Jessing and Bengtsson, Thomas and Bisgaard, Hans},
  title = {Acute relief of exercise-induced bronchoconstriction by inhaled formoterol in children with persistent asthma.},
  journal = {Chest},
  school = {Department of Pediatrics, Copenhagen University Hospital, Gentofte, Niels Andersens Vej 65, DK-2900 Hellerup, Denmark.},
  year = {2006},
  volume = {129},
  number = {5},
  pages = {1203--1209},
  url = {http://dx.doi.org/10.1378/chest.129.5.1203},
  doi = {https://doi.org/10.1378/chest.129.5.1203}
}
Lauritzen, L. Bisgaard, H. Fatty acid composition of human milk in atopic Danish mothers. 2006 Am J Clin Nutr 16825695 6,926 23
Authors: Lauritzen, L., Halkjaer, L.B., Mikkelsen, T.B., Olsen, S.F., Michaelsen, K.F., Loland, L. and Bisgaard, H.
Abstract: Atopic dermatitis has been related to a disturbed metabolism of polyunsaturated fatty acids (PUFAs).We tested whether the PUFA composition of breast milk differs significantly between mothers with atopic dermatitis, mothers with other types of atopy, and nonatopic mothers. We also investigated whether differences in diet can explain possible observed differences.Mothers with current or previous asthma (n = 396) were divided into 3 groups according to history of atopic dermatitis and allergic rhinitis. Breast-milk samples were collected from 314 women approximately 3 wk after delivery. The habitual diet of the women was assessed with food-frequency questionnaires in the 25th week of gestation (n = 207). Breast-milk samples and simultaneous dietary data from 14 nonatopic mothers were used for comparison.Compared with the milk of nonatopic mothers, that of atopic mothers had significantly higher concentrations of 22:5n-6 and lower concentrations of 20:5n-3; moreover, 20:4n-6/20:5n-3, 22:5n-6/22:6n-3, and long-chain n-3 PUFA/18:3n-3 were shifted toward n-6 PUFA and 18:3n-3 in nonatopic and atopic mothers, respectively. No differences in breast-milk PUFA composition were evident between the subject groups. The diets of the groups differed only slightly with respect to protein intake. However, the PUFA composition of the breast milk was associated with diet and time of milk sampling, and the above difference in milk PUFAs disappeared when those factors were taken into account.Our data do not support the possibility that the fatty acid composition of breast milk is affected by atopic dermatitis or atopy in general, because most differences in breast-milk PUFA composition appear to be explained by the diet.
BibTeX:
@article{,
  author = {Lauritzen, Lotte and Halkjaer, Liselotte Brydensholt and Mikkelsen, Tina B. and Olsen, Sjurdur F. and Michaelsen, Kim F. and Loland, Lotte and Bisgaard, Hans},
  title = {Fatty acid composition of human milk in atopic Danish mothers.},
  journal = {Am J Clin Nutr},
  school = {Department of Human Nutrition, Center for Advanced Food Studies, The Royal Veterinary and Agricultural University, Frederiksberg, Denmark. ll@kvl.dk},
  year = {2006},
  volume = {84},
  number = {1},
  pages = {190--196}
}
Halkjaer, L.B. Bisgaard, H. Development of atopic dermatitis during the first 3 years of life: the Copenhagen prospective study on asthma in childhood cohort study in high-risk children. 2006 Arch Dermatol 16702493 5,817 65
Authors: Halkjaer, L.B., Loland, L., Buchvald, F.F., Agner, T., Skov, L., Strand, M. and Bisgaard, H.
Abstract: To describe the development of atopic dermatitis (AD) during the first 3 years of life and identify the localization of the early skin lesions that predicts the development of AD.Prospective, longitudinal, birth cohort study of children born to mothers with a history of asthma, followed up for 3 years with scheduled visits every 6 months as well as visits for onset or acute exacerbations of skin symptoms.The cohort was recruited from greater Copenhagen, Denmark, and followed up at a clinical research unit, which controlled all diagnoses and treatment of skin diseases.A total of 411 infants were enrolled in the cohort; 55 had incomplete follow-up and were excluded from certain analyses.Atopic dermatitis was defined based on the criteria of Hanifin and Rajka, and severity was assessed by the SCORAD (Scoring Atopic Dermatitis) index. Predictive odds ratios of early skin lesions for those who developed AD vs those who did not were calculated.The cumulative incidence of AD by age 3 years was 44% (155/356). The prevalence rate peaked at age 2 years for boys and at age 2.5 years for girls, but there were no other sex differences in the proportion of children developing AD. Skin involvement in infants with AD was found to begin at the scalp, forehead, ear, and neck in a balaclava-like pattern and continue to the extensor sides and trunk, finally affecting the flexor sides of the extremities. Early skin lesions of arms and joints best predicted AD at age 3 years.Atopic dermatitis begins at the scalp, forehead, ear, and neck in a balaclava-like pattern. Eczema at the arms and joints provides the highest predictive value for the development of AD at age 3 years. This may be used for early prediction and intervention of AD.
BibTeX:
@article{,
  author = {Halkjaer, Liselotte Brydensholt and Loland, Lotte and Buchvald, Frederik F. and Agner, Tove and Skov, Lone and Strand, Matthew and Bisgaard, Hans},
  title = {Development of atopic dermatitis during the first 3 years of life: the Copenhagen prospective study on asthma in childhood cohort study in high-risk children.},
  journal = {Arch Dermatol},
  school = {Danish Pediatric Asthma Centre, Department of Pediatrics, Copenhagen University Hospital, Gentofte, Denmark.},
  year = {2006},
  volume = {142},
  number = {5},
  pages = {561--566},
  url = {http://dx.doi.org/10.1001/archderm.142.5.561},
  doi = {https://doi.org/10.1001/archderm.142.5.561}
}
Gammelgaard, A. Bisgaard, H. Perceptions of parents on the participation of their infants in clinical research. 2006 Arch Dis Child 16820387 3,265 16
Authors: Gammelgaard, A., Knudsen, L.E. and Bisgaard, H.
Abstract: To analyse the motivations and perceptions of parents on the participation of their infants and young children in a comprehensive and invasive clinical research study.Semistructured qualitative interviews were conducted with 23 mothers with asthma whose infants and young children were participating in the Copenhagen Prospective Study on Asthma in Childhood. The interviews were audiotaped, transcribed and analysed using the template analysis method.Parents were motivated by altruism and by the opportunity to get their child checked regularly by medical experts to prevent the possible development of asthma. Parents found it very important that their children enjoyed their visits to the research clinic, and that they could withdraw from the study if their child started responding negatively to those visits. No apparent difference was seen in the attitude between the parents of children with lung or skin symptoms and those of healthy children.It is possible to design and accomplish invasive clinical research on infants and young children in a manner that parents find ethically sound.
BibTeX:
@article{,
  author = {Gammelgaard, A. and Knudsen, L. E. and Bisgaard, H.},
  title = {Perceptions of parents on the participation of their infants in clinical research.},
  journal = {Arch Dis Child},
  school = {Department of Medical Philosophy and Clinical Theory, Institute of Public Health, University of Copenhagen, Copenhagen N, Denmark. a.gammelgaard@medphil.ku.dk},
  year = {2006},
  volume = {91},
  number = {12},
  pages = {977--980},
  url = {http://dx.doi.org/10.1136/adc.2006.096073},
  doi = {https://doi.org/10.1136/adc.2006.096073}
}
Bisgaard, H. Hultquist, C. Budesonide/formoterol maintenance plus reliever therapy: a new strategy in pediatric asthma. 2006 Chest 17166990 6,044 112
Authors: Bisgaard, H., Le Roux, P., Bjåmer, D., Dymek, A., Vermeulen, J.H. and Hultquist, C.
Abstract: A fixed combination of long-acting beta(2)-agonists (LABA) plus inhaled corticosteroids (ICS) has never been proven to reduce asthma exacerbations vs ICS alone in children. This 12-month, double-blind, randomized study in 341 children (age range, 4 to 11 years) with asthma uncontrolled on ICS investigated whether a novel regimen using budesonide/formoterol for maintenance and reliever therapy (Symbicort maintenance and relief therapy [SMART]) [Symbicort; AstraZeneca R&D, Lund, Sweden] could reduce exacerbations.Patients received SMART (budesonide/formoterol 80/4.5 microg qd maintenance plus additional inhalations for symptom relief), budesonide/formoterol 80/4.5 microg qd for maintenance (fixed combination), or higher-dose budesonide 320 microg qd (fixed-dose budesonide). Blinded as-needed medication (terbutaline 0.4 microg) was provided in both fixed-dose groups.SMART prolonged the time to first exacerbation vs fixed-dose budesonide (p = 0.02) and fixed-dose combination (p < 0.001). Rates of exacerbation requiring medical intervention were reduced by 70 to 79% with SMART vs fixed-dose budesonide and fixed-dose combination (0.08/patient vs 0.28/patient and 0.40/patient, respectively; both p < 0.001). Mild exacerbation days and awakenings were significantly lower with SMART; yearly growth improved by 1.0 cm vs fixed-dose budesonide (p < 0.01).The SMART regimen using budesonide/formoterol for both maintenance and as-needed symptom relief reduces the exacerbation rate compared with both fixed-dose combination and higher fixed-dose ICS alone in children with asthma.
BibTeX:
@article{,
  author = {Bisgaard, Hans and Le Roux, Pascal and Bjåmer, Ditlef and Dymek, Andrzej and Vermeulen, Jan H. and Hultquist, Christer},
  title = {Budesonide/formoterol maintenance plus reliever therapy: a new strategy in pediatric asthma.},
  journal = {Chest},
  school = {Danish Pediatric Asthma Center, Department of Pediatrics, Copenhagen University Hospital, Gentofte, DK-2900 Copenhagen, Denmark. bisgaard@copsac.dk},
  year = {2006},
  volume = {130},
  number = {6},
  pages = {1733--1743},
  url = {http://dx.doi.org/10.1378/chest.130.6.1733},
  doi = {https://doi.org/10.1378/chest.130.6.1733}
}
Bisgaard, H. Szefler, S. Long-acting beta2 agonists and paediatric asthma. 2006 Lancet 16443026 47,831 44
Authors: Bisgaard, H. and Szefler, S.
BibTeX:
@article{,
  author = {Bisgaard, Hans and Szefler, Stan},
  title = {Long-acting beta2 agonists and paediatric asthma.},
  journal = {Lancet},
  school = {Danish Paediatric Asthma Centre, Copenhagen, University Hospital, DK-2900 Gentofte, Copenhagen, Denmark. Bisgaard@copsac.dk},
  year = {2006},
  volume = {367},
  number = {9507},
  pages = {286--288},
  url = {http://dx.doi.org/10.1016/S0140-6736(06)68051-3},
  doi = {https://doi.org/10.1016/S0140-6736(06)68051-3}
}
Bisgaard, H. Buchvald, F. Intermittent inhaled corticosteroids in infants with episodic wheezing. 2006 N Engl J Med 16687712 72,406 343
Authors: Bisgaard, H., Hermansen, M.N., Loland, L., Halkjaer, L.B. and Buchvald, F.
Abstract: We hypothesized that asthma is preceded by a stage of recurrent episodes of wheezing during the first years of life and that inhaled corticosteroid therapy during symptomatic episodes in this early phase may delay progression to persistent wheezing.We assigned one-month-old infants to treatment with two-week courses of inhaled budesonide (400 mug per day) or placebo, initiated after a three-day episode of wheezing, in this single-center, randomized, double-blind, prospective study of three years' duration. The primary outcome was the number of symptom-free days; key secondary outcomes were the time to discontinuation due to persistent wheezing and safety, as evaluated by height and bone mineral density at the end of the study.We enrolled 411 infants and randomly assigned 294 to receive budesonide at a first episode of wheezing. The proportion of symptom-free days was 83 percent in the budesonide group and 82 percent in the placebo group (absolute difference, 1 percent; 95 percent confidence interval, -4.8 to 6.9 percent). Twenty-four percent of children in the budesonide group had persistent wheezing, as compared with 21 percent in the placebo group (hazard ratio, 1.22; 95 percent confidence interval, 0.71 to 2.13)--a finding that was unaffected by the presence or absence of atopic dermatitis. The mean duration of the acute episodes was 10 days in both groups and was independent of respiratory viral status. Height and bone mineral density were not affected by treatment.Intermittent inhaled corticosteroid therapy had no effect on the progression from episodic to persistent wheezing and no short-term benefit during episodes of wheezing in the first three years of life. (ClinicalTrials.gov number, NCT00234390.).
BibTeX:
@article{,
  author = {Bisgaard, Hans and Hermansen, Mette Northman and Loland, Lotte and Halkjaer, Liselotte Brydensholt and Buchvald, Frederik},
  title = {Intermittent inhaled corticosteroids in infants with episodic wheezing.},
  journal = {N Engl J Med},
  school = {Danish Pediatric Asthma Center, Copenhagen University Hospital, Gentofte, Copenhagen.},
  year = {2006},
  volume = {354},
  number = {19},
  pages = {1998--2005},
  url = {http://dx.doi.org/10.1056/NEJMoa054692},
  doi = {https://doi.org/10.1056/NEJMoa054692}
}
Sazonov Kocevar, V. Bisgaard, H. Association between allergic rhinitis and hospital resource use among asthmatic children in Norway. 2005 Allergy 15679719 7,361 27
Authors: Sazonov Kocevar, V., Thomas 3rd, J., Jonsson, L., Valovirta, E., Kristensen, F., Yin, D.D. and Bisgaard, H.
Abstract: Preliminary evidence suggests that inadequately controlled allergic rhinitis in asthmatic patients can contribute towards increased asthma exacerbations and poorer symptom control, which may increase medical resource use. The objective of this study was therefore to assess the effect of concomitant allergic rhinitis on asthma-related hospital resource utilization among children below 15 years of age with asthma in Norway.A population-based retrospective cohort study of children (aged 0-14 years) with asthma was conducted using data from a patient-specific public national database of hospital admissions during a 2-year period, 1998-1999. Multivariate linear regression, adjusting for risk factors including age, gender, year of admission, urban/rural residence and severity of asthma episode, estimated the association between allergic rhinitis and total hospital days. A multivariate Cox proportional-hazards model estimated relative hazard of readmission according to concomitant allergic rhinitis status.Among 2961 asthmatic children under 15 years of age with at least one asthma-related hospital admission over a 2-year period, 795 (26.8 had a recorded history of allergic rhinitis. Asthmatic children with allergic rhinitis had a 1.72-times greater hazard of asthma-related readmissions than asthmatic children without allergic rhinitis. Multivariate analysis revealed that history of concomitant allergic rhinitis was a significant predictor of increased number of hospital days per year (least-squares mean difference 0.23 days, P < 0.05).Concomitant allergic rhinitis in asthmatic children was associated with increased likelihood of asthma-related hospital readmissions and greater total hospital days.
BibTeX:
@article{,
  author = {Sazonov Kocevar, V. and Thomas, 3rd, J and Jonsson, L. and Valovirta, E. and Kristensen, F. and Yin, D. D. and Bisgaard, H.},
  title = {Association between allergic rhinitis and hospital resource use among asthmatic children in Norway.},
  journal = {Allergy},
  school = {Merck and Co., Whitehouse Station, NJ 08889, USA.},
  year = {2005},
  volume = {60},
  number = {3},
  pages = {338--342},
  url = {http://dx.doi.org/10.1111/j.1398-9995.2005.00712.x},
  doi = {https://doi.org/10.1111/j.1398-9995.2005.00712.x}
}
Santanello, N.C. Bisgaard, H. Validation of a pediatric caregiver diary to measure symptoms of postacute respiratory syncytial virus bronchiolitis. 2005 Pediatr Pulmonol 15858804 2,758 9
Authors: Santanello, N.C., Norquist, J.M., Nelsen, L.M., Williams, V.S.L., Hill, C.D. and Bisgaard, H.
Abstract: Acute respiratory syncytial virus (RSV)-induced bronchiolitis is often associated with continuing respiratory symptoms following hospitalization. To date, there is no validated objective measure to evaluate symptoms of RSV-induced bronchiolitis. We report on the reliability, validity, and responsiveness of the bronchiolitis caregiver diary (BCD) of symptoms and healthcare utilization associated with postacute RSV. The BCD measures four symptoms (daytime cough, wheeze, trouble breathing, and nighttime cough), healthcare utilization, and rescue medication for worsening of lung symptoms. Data from the 4-week treatment period of the reported prospective, placebo-controlled trial of montelukast for treatment of postacute RSV were used to assess reliability (internal consistency and test-retest), construct validity (cross-sectional and longitudinal correlations), discriminant validity (known-groups analyses), and responsiveness. The primary outcome of this study was the percentage of symptom-free days (SFD). The secondary outcome was a composite symptom score (CSS; average of daytime cough, wheezing, and trouble breathing). Cronbach's alpha of 0.85 indicated that the four symptoms were internally consistent, supporting a unidimensional scale structure. Test-retest reliabilities for the percentage of SFD and CSS were above the recommended cut point of 0.70. Cross-sectional and longitudinal correlations were sizeable and statistically significant, demonstrating construct validity. Hypothesized known-group differences were statistically significant in the appropriate direction. Responsiveness analyses indicated moderate effect sizes for percentage of SFD. In conclusion, the BCD provides a valid, reliable, and responsive tool for the assessment of symptoms of postacute RSV-induced bronchiolitis, capable of measuring moderate effect sizes, and demonstrating responsiveness to therapy.
BibTeX:
@article{,
  author = {Santanello, Nancy C. and Norquist, Josephine M. and Nelsen, Linda M. and Williams, Valerie S L. and Hill, Cheryl D. and Bisgaard, Hans},
  title = {Validation of a pediatric caregiver diary to measure symptoms of postacute respiratory syncytial virus bronchiolitis.},
  journal = {Pediatr Pulmonol},
  school = {Merck Research Laboratories, West Point, Pennsylvania 19486, USA. nancy_santanello@merck.com},
  year = {2005},
  volume = {40},
  number = {1},
  pages = {31--38},
  url = {http://dx.doi.org/10.1002/ppul.20232},
  doi = {https://doi.org/10.1002/ppul.20232}
}
Pedersen, S.E. Schiøtz, P.O. [No risk of development of osteoporosis or inhibition of growth in children with asthma treated with inhaled corticosteroids]. 2005 Ugeskr Laeger 16008003 0 1
Authors: Pedersen, S.E., Bisgaard, H. and Schiøtz, P.O.
BibTeX:
@article{,
  author = {Pedersen, Søren Erik and Bisgaard, Hans and Schiøtz, Peter Oluf},
  title = {[No risk of development of osteoporosis or inhibition of growth in children with asthma treated with inhaled corticosteroids].},
  journal = {Ugeskr Laeger},
  school = {Dansk Børneastmacenter, Gentofte. spconsult@post1.tele.dk},
  year = {2005},
  volume = {167},
  number = {23},
  pages = {2502--2503}
}
O'Byrne, P.M. Bateman, E.D. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. 2005 Am J Respir Crit Care Med 15502112 13,204 0
Authors: O'Byrne, P.M., Bisgaard, H., Godard, P.P., Pistolesi, M., Palmqvist, M., Zhu, Y., Ekström, T. and Bateman, E.D.
Abstract: Asthma control is improved by combining inhaled corticosteroids with long-acting beta2-agonists. However, fluctuating asthma control still occurs. We hypothesized that in patients receiving low maintenance dose budesonide/formoterol (bud/form), replacing short-acting beta2-agonist (SABA) reliever with as-needed bud/form would provide rapid symptom relief and simultaneous adjustment in antiinflammatory therapy, thereby reducing exacerbations. In this double-blind, randomized, parallel-group study, 2,760 patients with asthma aged 4-80 years (FEV1 60-100% predicted) received either terbutaline 0.4 mg as SABA with bud/form 80/4.5 microg twice a day (bud/form + SABA) or bud 320 microg twice a day (bud + SABA) or bud/form 80/4.5 microg twice a day with 80/4.5 microg as-needed (bud/form maintenance + relief). Children used a once-nocte maintenance dose. Bud/form maintenance + relief prolonged time to first severe exacerbation (p < 0.001; primary endpoint), resulting in a 45-47% lower exacerbation risk versus bud/form + SABA (hazard ratio, 0.55; 95% confidence interval, 0.44, 0.67) or bud + SABA (hazard ratio, 0.53; 95% confidence interval 0.43, 0.65). Bud/form maintenance + relief also prolonged the time to the first, second, and third exacerbation requiring medical intervention (p < 0.001), reduced severe exacerbation rate, and improved symptoms, awakenings, and lung function compared with both fixed dosing regimens.
BibTeX:
@article{,
  author = {O'Byrne, Paul M. and Bisgaard, Hans and Godard, Philippe P. and Pistolesi, Massimo and Palmqvist, Mona and Zhu, Yuanjue and Ekström, Tommy and Bateman, Eric D.},
  title = {Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma.},
  journal = {Am J Respir Crit Care Med},
  school = {Firestone Institute for Respiratory Health, St. Joseph's Hospital, Hamilton, Ontario, Canada. obyrnep@mcmaster.ca},
  year = {2005},
  volume = {171},
  number = {2},
  pages = {129--136},
  url = {http://dx.doi.org/10.1164/rccm.200407-884OC},
  doi = {https://doi.org/10.1164/rccm.200407-884OC}
}
Nielsen, K.G. Bisgaard, H. Cold air challenge and specific airway resistance in preschool children. 2005 Paediatr Respir Rev 16298308 2,214 17
Authors: Nielsen, K.G. and Bisgaard, H.
Abstract: Important asthma outcomes such as lung function and bronchial hyperresponsiveness are probably determined in early childhood. Early and longitudinal objective assessment of lung function and bronchial hyperresponsiveness is necessary to enable early diagnosis, monitor intervention and improve prognosis in preschool children. Cold air challenge and plethysmographic measurement of specific airway resistance (sRaw) are feasible candidate methods for diagnosis, clinical monitoring and research during this critical period of lung growth and development. Methodology and practical aspects of cold air challenge and assessment of sRaw in preschool children are reviewed. Reference values are provided for sRaw and have allowed discrimination between health and respiratory disease, both in cross-sectional and longitudinal studies. Bronchial hyperresponsiveness can be determined with acceptable repeatability and provides good discrimination between asthmatics and healthy. The effects of classic anti-asthmatic therapies have also been documented with these techniques. The need for further standardisation and improvement of these methods and future perspectives are outlined.
BibTeX:
@article{,
  author = {Nielsen, Kim Gjerum and Bisgaard, Hans},
  title = {Cold air challenge and specific airway resistance in preschool children.},
  journal = {Paediatr Respir Rev},
  school = {Pediatric Pulmonary Service, Pediatric Clinic I, Juliane Marie Centre, Rigshospitalet, Copenhagen University Hospital, Denmark. kgn@dadlnet.dk},
  year = {2005},
  volume = {6},
  number = {4},
  pages = {255--266},
  url = {http://dx.doi.org/10.1016/j.prrv.2005.09.013},
  doi = {https://doi.org/10.1016/j.prrv.2005.09.013}
}
Nielsen, K.G. Bisgaard, H. Hyperventilation with cold versus dry air in 2- to 5-year-old children with asthma. 2005 Am J Respir Crit Care Med 15542794 13,204 16
Authors: Nielsen, K.G. and Bisgaard, H.
Abstract: Cold air challenge (CACh) has been shown to discriminate between children with asthma and healthy young children. Hyperventilation with dry room-temperature air is a simplified alternative. We compared responsiveness in young children with asthma between two standardized, single-step protocols: dry air challenge (DACh) performed as 6 minutes of eucapnic hyperventilation with dry room-temperature air and CACh as 4 minutes of hyperventilation. Response was measured as specific airway resistance by whole-body plethysmography and expressed as change from baseline in numbers of within-subject SDs (SDw). The challenge sequence was randomly assigned. A comparator challenge was performed 1 hour later if the first challenge gave a change of 3 SDw or more. Forty 2- to 5-year-old children with asthma were included. Responsiveness to cold versus dry air showed significant, but weak, correlation (r(2) = 0.34, p < 0.0001), but responsiveness to CACh exceeded DACh (7.6 vs. 5.4 SDw, p < 0.02). CACh seemed to induce reduction in response to the following DACh (p < 0.01), whereas no such reduction was seen after DACh.Responsiveness to CACh exceeded responsiveness to DACh, and CACh seemed to induce refractoriness in contrast to DACh, probably because of the additional stimulus from airway cooling. This finding suggests CACh as the preferred method of challenge.
BibTeX:
@article{,
  author = {Nielsen, Kim G. and Bisgaard, Hans},
  title = {Hyperventilation with cold versus dry air in 2- to 5-year-old children with asthma.},
  journal = {Am J Respir Crit Care Med},
  school = {Department of Pediatrics, Pulmonary Service, Copenhagen University Hospital, Rigshospitalet DK-2100, Copenhagen, Denmark. kgn@dadlnet.dk},
  year = {2005},
  volume = {171},
  number = {3},
  pages = {238--241},
  url = {http://dx.doi.org/10.1164/rccm.200404-528OC},
  doi = {https://doi.org/10.1164/rccm.200404-528OC}
}
Buchvald, F. Bisgaard, H. Exhaled nitric oxide predicts exercise-induced bronchoconstriction in asthmatic school children. 2005 Chest 16236842 6,044 38
Authors: Buchvald, F., Hermansen, M.N., Nielsen, K.G. and Bisgaard, H.
Abstract: Exercise-induced bronchoconstriction (EIB) is of particular importance in children with asthma. It is an important measure of asthma control and should be monitored by exercise testing. However, exercise testing puts a large demand on health-care resources and is therefore not widely used in routine monitoring of pediatric asthma control. The fractional concentration of exhaled nitric oxide (FeNO) also reflects uncontrolled asthma. We hypothesized that FeNO may be used for prescreening of asthmatic children to exclude those with good asthma control unlikely to have EIB, thereby reducing the need for exercise testing.The aim of this study was to estimate the value of FeNO as a predictor of EIB in asthmatic children.Stable outpatient asthmatic school children performed standard exercise challenge tests and measurement of FeNO.FeNO and response to a standardized submaximal exercise test on the treadmill were measured in 111 school children with asthma. EIB could be excluded with a probability of 90% in asthmatic children with FeNO levels < 20 parts per billion (ppb) without current inhaled corticosteroid treatment, and < 12 ppb in children with current inhaled corticosteroid treatment.Measurement of FeNO is a simple, and time- and resource-efficient tool that may be used to screen for EIB testing and therefore optimizes the resources for exercise testing in pediatric asthma monitoring.
BibTeX:
@article{,
  author = {Buchvald, Frederik and Hermansen, Mette N. and Nielsen, Kim G. and Bisgaard, Hans},
  title = {Exhaled nitric oxide predicts exercise-induced bronchoconstriction in asthmatic school children.},
  journal = {Chest},
  school = {Danish Pediatric Asthma Centre, Department of Pediatrics, Copenhagen University Hospital, DK-2900 Gentofte, Niels Andersensvej 79, 2900 Hellerup, Denmark.},
  year = {2005},
  volume = {128},
  number = {4},
  pages = {1964--1967},
  url = {http://dx.doi.org/10.1378/chest.128.4.1964},
  doi = {https://doi.org/10.1378/chest.128.4.1964}
}
Buchvald, F. Bisgaard, H. Measurements of exhaled nitric oxide in healthy subjects age 4 to 17 years. 2005 J Allergy Clin Immunol 15940124 13,081 258
Authors: Buchvald, F., Baraldi, E., Carraro, S., Gaston, B., De Jongste, J., Pijnenburg, M.W.H., Silkoff, P.E. and Bisgaard, H.
Abstract: Fractional exhaled nitric oxide (FE NO ) is used in monitoring of asthma.The aim of this multicenter study was to establish normal values of FE NO and assess feasibility in children with a standardized method and equipment approved for clinical use.FE NO was measured in healthy subjects of 4 to 17 years according to American Thoracic Society guidelines (single breath online, exhalation flow 50 mL/s) with a chemiluminescence analyzer (NIOX Exhaled Nitric Oxide Monitoring System, Aerocrine, Sweden) in 3 European and 2 US centers. Each child performed 3 acceptable nitric oxide measurements within 6 attempts and completed an extended International Study of Asthma and Allergy in Children questionnaire.Measurement of FE NO was attempted in 522 children. Four hundred five children completed the study according to the protocol. Geometric mean FE NO in 405 children was 9.7 ppb, and the upper 95% confidence limit was 25.2 ppb. FE NO increased significantly with age, and higher FE NO was seen in children with self-reported rhinitis/conjunctivitis or hay fever. The success rate was age-dependent and improved from 40% in the children 4 years old to almost 100% from the age of 10 years. The repeatability of 3 approved measurements was 1.6 ppb (95% CI, 1.49-1.64 ppb).FE NO in healthy children is below 15 to 25 ppb depending on age and self-reported atopy. Measurement of FE NO by NIOX is simple and safe and has a good repeatability. Feasibility depends on age and may be difficult in the preschool child.
BibTeX:
@article{,
  author = {Buchvald, Frederik and Baraldi, Eugenio and Carraro, Silvia and Gaston, Benjamin and De Jongste, Johan and Pijnenburg, Mariëlle W H. and Silkoff, Philip E. and Bisgaard, Hans},
  title = {Measurements of exhaled nitric oxide in healthy subjects age 4 to 17 years.},
  journal = {J Allergy Clin Immunol},
  school = {The Copenhagen Studies of Asthma in Childhood Research Clinic, Copenhagen University Hospital, Gentofte, Denmark.},
  year = {2005},
  volume = {115},
  number = {6},
  pages = {1130--1136},
  url = {http://dx.doi.org/10.1016/j.jaci.2005.03.020},
  doi = {https://doi.org/10.1016/j.jaci.2005.03.020}
}
Bisgaard, H. Nielsen, K.G. Plethysmographic measurements of specific airway resistance in young children. 2005 Chest 16002957 6,044 62
Authors: Bisgaard, H. and Nielsen, K.G.
Abstract: Validated methods for lung function measurements in young children are lacking. Plethysmographic measurement of specific airway resistance (sRaw) provides such a method applicable from 2 years of age. sRaw gauges airway resistance from the measurements of the pressure changes driving the airflow during tidal breathing. These measurements require no active cooperation and are therefore feasible in children from 2 years of age. The within-observer and between-observer variability of sRaw in young children compare favorably with alternative methods. Reference values are available for sRaw and have allowed discrimination of young children with respiratory disease. Bronchial hyperresponsiveness can be determined with acceptable short-term and long-term repeatability and provides good discrimination between asthmatics and healthy young children. The effects of the major antiasthmatic therapies have also been documented by this technique, and sRaw has recently been used in longitudinal studies of young children with chronic pulmonary diseases. Future developments should provide improved algorithms for thermal correction of the respired volumes and adapt the equipment to the special needs of young children. This article reviews the method, and proposes a protocol and criteria for quality assurance for assessment of sRaw in preschool children from 2 years of age. sRaw measurements offers a method for clinical monitoring and research during this critical period of growth and development early in life.
BibTeX:
@article{,
  author = {Bisgaard, Hans and Nielsen, Kim G.},
  title = {Plethysmographic measurements of specific airway resistance in young children.},
  journal = {Chest},
  school = {Copenhagen University Hospital, Gentofte, DK-2900 Copenhagen, Denmark. Bisgaard@copsac.dk},
  year = {2005},
  volume = {128},
  number = {1},
  pages = {355--362},
  url = {http://dx.doi.org/10.1378/chest.128.1.355},
  doi = {https://doi.org/10.1378/chest.128.1.355}
}
Bisgaard, H. Polos, P. Montelukast reduces asthma exacerbations in 2- to 5-year-old children with intermittent asthma. 2005 Am J Respir Crit Care Med 15542792 13,204 234
Authors: Bisgaard, H., Zielen, S., Garcia-Garcia, M.L., Johnston, S.L., Gilles, L., Menten, J., Tozzi, C.A. and Polos, P.
Abstract: The PREVIA study was designed to investigate the role of montelukast, a leukotriene receptor antagonist, in the prevention of viral-induced asthma exacerbations in children aged 2 to 5 years with a history of intermittent asthma symptoms. The study was a 12-month multicenter, double-blind, parallel-group study of patients with asthma exacerbations associated with respiratory infections and minimal symptoms between episodes. Patients were randomized to receive oral montelukast 4 or 5 mg (depending on age) (n = 278) or placebo (n = 271) once per day for 12 months. Caregivers recorded children's symptoms, beta-agonist use, and health care resource use in a diary card. Over 12 months of therapy, montelukast significantly reduced the rate of asthma exacerbations by 31.9% compared with placebo. The average rate of exacerbation episodes per patient was 1.60 episodes per year on montelukast compared with 2.34 episodes on placebo. Montelukast also delayed the median time to first exacerbation by approximately 2 months (p = 0.024), and the rate of inhaled corticosteroid courses (p = 0.027) compared with placebo. Montelukast effectively reduced asthma exacerbations in 2- to 5-year-old patients with intermittent asthma over 12 months of treatment and was generally well tolerated.
BibTeX:
@article{,
  author = {Bisgaard, Hans and Zielen, Stefen and Garcia-Garcia, Mar\ia Luz and Johnston, Sebastian L. and Gilles, Leen and Menten, Joris and Tozzi, Carol A. and Polos, Peter},
  title = {Montelukast reduces asthma exacerbations in 2- to 5-year-old children with intermittent asthma.},
  journal = {Am J Respir Crit Care Med},
  school = {Department of Pediatrics, Copenhagen University Hospital, DK-2920 Gentofte, Copenhagen, Denmark. Bisgaard@copsac.dk},
  year = {2005},
  volume = {171},
  number = {4},
  pages = {315--322},
  url = {http://dx.doi.org/10.1164/rccm.200407-894OC},
  doi = {https://doi.org/10.1164/rccm.200407-894OC}
}
Bisgaard, H. Szefler, S.J. Understanding mild persistent asthma in children: the next frontier. 2005 J Allergy Clin Immunol 15805988 13,081 23
Authors: Bisgaard, H. and Szefler, S.J.
Abstract: Limitations in asthma prevalence studies and difficulties in diagnosing pediatric asthma lead to uncertainty over the full extent of mild persistent asthma in children and adolescents. Although recent surveys have reported that the majority of pediatric patients with asthma in the United States and Europe have symptoms consistent with mild disease, these surveys have limitations in design. Thus, the true prevalence of mild asthma remains unknown. It is unclear whether children with mild persistent asthma progress to more severe asthma, but the risk of severe asthma exacerbations seems to be unrelated to the symptom severity. Clinical studies restricted to pediatric patients with mild asthma are limited, but available data do suggest substantial morbidity of mild persistent asthma in this population and support inhaled corticosteroid intervention. There is a need for further investigation into the true prevalence of mild persistent asthma in children and adolescents, and optimal treatment.
BibTeX:
@article{,
  author = {Bisgaard, Hans and Szefler, Stanley J.},
  title = {Understanding mild persistent asthma in children: the next frontier.},
  journal = {J Allergy Clin Immunol},
  school = {Danish Paediatric Asthma Center, Department of Paediatrics, University Hospital of Copenhagen, DK-2900 Gentofte, Copenhagen, Denmark. Bisgaard@copsac.dk},
  year = {2005},
  volume = {115},
  number = {4},
  pages = {708--713},
  url = {http://dx.doi.org/10.1016/j.jaci.2004.11.018},
  doi = {https://doi.org/10.1016/j.jaci.2004.11.018}
}
Bisgaard, H. The Copenhagen Prospective Study on Asthma in Childhood (COPSAC): design, rationale, and baseline data from a longitudinal birth cohort study. 2004 Ann Allergy Asthma Immunol 15521375 3,728 99
Authors: Bisgaard, H.
Abstract: The atopic diseases asthma, atopic dermatitis, and allergic rhinitis are the most common chronic diseases in children, and their prevalence has increased recently in industrialized nations. Little is known about the genetic-environmental interaction factors driving such proliferation.To investigate the relationships among genetic, environmental, and lifestyle factors in the development of atopic diseases in high-risk children with the aim of developing evidence-based prevention strategies.The Copenhagen Prospective Study on Asthma in Childhood is a single-center, birth cohort study of children of asthmatic mothers. Objective assessments begin at birth, with scheduled visits every 6 months and when acute symptoms manifest. Clinical outcomes comprise preasthma, asthma, atopic dermatitis, allergic rhinitis, allergy, lung function, and bronchial responsiveness. Exposure assessments comprise respiratory, intestinal, and skin microbiology; the child's diet; indoor and outdoor air quality; allergens; and indicators of lifestyle. Genetic characteristics of probands and parents are evaluated. Quality assurance follows Good Clinical Practice guidelines.Four hundred eleven infants of asthmatic mothers were enrolled at the age of 1 month. The children were born between August 2, 1998, and December 28, 2001. Compared with the Copenhagen population, mothers of the cohort population were less likely to have given natural childbirth. The households were slightly less affluent, with fewer children and fewer pets. Whites may be overrepresented. At age 2 years, 93% of the infants were still actively participating in the cohort.This longitudinal birth cohort study of high-risk Danish infants consists of objective phenotyping, detailed information on exposure, high data quality, and a high participant retention rate.
BibTeX:
@article{,
  author = {Bisgaard, Hans},
  title = {The Copenhagen Prospective Study on Asthma in Childhood (COPSAC): design, rationale, and baseline data from a longitudinal birth cohort study.},
  journal = {Ann Allergy Asthma Immunol},
  school = {Department of Pediatrics, Copenhagen University Hospital, Copenhagen, Denmark. Bisgaarad@copsac.dk},
  year = {2004},
  volume = {93},
  number = {4},
  pages = {381--389},
  url = {http://dx.doi.org/10.1016/S1081-1206(10)61398-1},
  doi = {https://doi.org/10.1016/S1081-1206(10)61398-1}
}
Nielsen, K.G. Bisgaard, H. Serial lung function and responsiveness in cystic fibrosis during early childhood. 2004 Am J Respir Crit Care Med 15028557 13,204 0
Authors: Nielsen, K.G., Pressler, T., Klug, B., Koch, C. and Bisgaard, H.
Abstract: In a 4-year prospective study, we evaluated specific airway resistance (sRaw) by whole-body plethysmography, respiratory resistance by the interrupter technique, and respiratory resistance and reactance at 5 Hz by the impulse oscillation technique combined with measurement of responsiveness to bronchodilators and cold air in 30 children (mean [range] age 5.7 [2 to 8] years) with cystic fibrosis (CF). Spirometry was done at school age. Mean sRaw was consistently abnormal: the mean z score (SD) was 2.52 (2.02) (p < 0.001) at the start and was unchanged 36 months later at 2.74 (2.02). Mean z score (SD) for FEV(1) at first satisfactory measurement, at a mean age (range) of 6.1 (4.9-7.5) years was -1.2 (1.2) and was further reduced to -1.85 (1.2) 4 years from inclusion at a mean age (range) of 9.9 (6.8-12) years. Neither respiratory resistance by the interrupter technique nor the impulse oscillation technique demonstrated consistent abnormal levels. Patients with CF as a group did not differ from healthy subjects in responsiveness to bronchodilators and cold air. sRaw may be a useful tool in CF during early childhood. Reduced lung function was documented from consistently abnormal levels of sRaw and FEV1 during the study. Bronchodilator responsiveness and response to cold air challenge were normal.
BibTeX:
@article{,
  author = {Nielsen, Kim G. and Pressler, Tacjana and Klug, Bent and Koch, Christian and Bisgaard, Hans},
  title = {Serial lung function and responsiveness in cystic fibrosis during early childhood.},
  journal = {Am J Respir Crit Care Med},
  school = {Department of Pediatrics, Pulmonary Service, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. kgn@dadlnet.dk},
  year = {2004},
  volume = {169},
  number = {11},
  pages = {1209--1216},
  url = {http://dx.doi.org/10.1164/rccm.200303-347OC},
  doi = {https://doi.org/10.1164/rccm.200303-347OC}
}
Jeganathan, D. Mitchison, H.M. Loci for primary ciliary dyskinesia map to chromosome 16p12.1-12.2 and 15q13.1-15.1 in Faroe Islands and Israeli Druze genetic isolates. 2004 J Med Genet 14985390 5,451 32
Authors: Jeganathan, D., Chodhari, R., Meeks, M., Faeroe, O., Smyth, D., Nielsen, K., Amirav, I., Luder, A.S., Bisgaard, H., Gardiner, R.M., Chung, E.M.K. and Mitchison, H.M.
BibTeX:
@article{,
  author = {Jeganathan, D. and Chodhari, R. and Meeks, M. and Faeroe, O. and Smyth, D. and Nielsen, K. and Amirav, I. and Luder, A. S. and Bisgaard, H. and Gardiner, R. M. and Chung, E M K. and Mitchison, H. M.},
  title = {Loci for primary ciliary dyskinesia map to chromosome 16p12.1-12.2 and 15q13.1-15.1 in Faroe Islands and Israeli Druze genetic isolates.},
  journal = {J Med Genet},
  year = {2004},
  volume = {41},
  number = {3},
  pages = {233--240}
}
Holgate, S.T. Reginster, J.Y. Summary of recommendations for the design of clinical trials and the registration of drugs used in the treatment of asthma. 2004 Respir Med 15191031 3,217 13
Authors: Holgate, S.T., Bousquet, J., Chung, K.F., Bisgaard, H., Pauwels, R., Fabbri, L., Rabe, K., Doherty, M., Snell, N.J.C., Cuss, F., D'Amato, M., Reginster, J.Y., , G.f.t.R.o.E. and in Science: Asthma section, E.
Abstract: With new drugs being introduced to treat asthma it is timely to review criteria that can be used to assess efficacy in clinical trials. Anti-asthma drugs are classified into symptoms-modifying, symptom preventers and disease modifying agents. Attention is drawn to the types of experimental evidence required in preclinical studies to support further clinical development of a new therapy. Clinical trials demand careful selection of patients to maximise the strength of the efficacy signal according to the type of trial being designed. While provocation tests are useful in suggesting efficacy, negative tests do not necessarily indicate lack of anti-asthma activity. Therapeutic trial designs need to take account of duration of treatment, dose-response relationships and confirmatory trials. Outcome measures include symptoms, lung function, reduction in concomitant medication, exacerbations, quality of life and measures of inflammation. Interpretation of results need to include the clinical relevance of any changes as well as statistical significance. Special consideration needs to be given to the evaluation of drugs for acute severe asthma, asthma in children and older people, co-morbidity such as rhinitis, and inhaler devices. As with all drugs introduced into practice, careful attention needs to be paid to both short- and long-term safety.
BibTeX:
@article{,
  author = {Holgate, S. T. and Bousquet, J. and Chung, K. F. and Bisgaard, H. and Pauwels, R. and Fabbri, L. and Rabe, K. and Doherty, M. and Snell, N J C. and Cuss, F. and D'Amato, M. and Reginster, J. Y. and , Group for the Respect of Ethics and Excellence in Science: Asthma section},
  title = {Summary of recommendations for the design of clinical trials and the registration of drugs used in the treatment of asthma.},
  journal = {Respir Med},
  school = {RCMB Division, School of Medicine, University of Southampton, UK. s.holgate@soton.ac.uk},
  year = {2004},
  volume = {98},
  number = {6},
  pages = {479--487}
}
Heitmann, B.L. Bisgaard, H. Changes in body water distribution during treatment with inhaled steroid in pre-school children. 2004 Ann Hum Biol 15204348 1,240 5
Authors: Heitmann, B.L., Anhøj, J., Bisgaard, A.M., Ward, L. and Bisgaard, H.
Abstract: The study aimed to examine the changes in water distribution in the soft tissue during systemic steroid activity.A three-way cross-over, randomized, placebo-controlled, double-blind trial was used, including 4 weeks of fluticasone propionate pMDI 200 microg b.i.d. delivered via Babyhaler, budesonide pressurized metered dose inhaler (pMDI) 200 microg b.i.d. delivered via Nebuchamber and placebo. Spacers were primed before use. In total, 40 children aged 1-3 years, with mild intermittent asthma were included. Twenty-five of the children completed all three treatments. At the end of each treatment period body impedance and skin ultrasonography were measured.We measured changes in water content of the soft tissues by two methods. Skin ultrasonography was used to detect small changes in dermal water content, and bioelectrical impedance was used to assess body water content and distribution.We found an increase in skin density of the shin from fluticasone as measured by ultrasonography (p = 0.01). There was a tendency for a consistent elevation of impedance parameters from active treatments compared to placebo although overall this effect was not statistically significant (0.1 < p < 0.2). However, sub-analyses indicated a significant effect on whole-body and leg impedance from budesonide treatment (p < 0.05).Decreased growth during inhaled steroid treatment seems to partly reflect generalized changes in body water.
BibTeX:
@article{,
  author = {Heitmann, B. L. and Anhøj, J. and Bisgaard, A. M. and Ward, L. and Bisgaard, H.},
  title = {Changes in body water distribution during treatment with inhaled steroid in pre-school children.},
  journal = {Ann Hum Biol},
  school = {Research Unit for Dietary Studies and the Danish Epidemiology Science Centre at the Institute of Preventative Medicine, Copenhagen University Hospital, Copenhagen Denmark. blh@ipm.hosp.dk},
  year = {2004},
  volume = {31},
  number = {3},
  pages = {333--341},
  url = {http://dx.doi.org/10.1080/0301446042000208286},
  doi = {https://doi.org/10.1080/0301446042000208286}
}
Kocevar, V.S. Thomas 3rd, J. Variations in pediatric asthma hospitalization rates and costs between and within Nordic countries. 2004 Chest 15136376 6,044 40
Authors: Kocevar, V.S., Bisgaard, H., Jönsson, L., Valovirta, E., Kristensen, F., Yin, D.D. and Thomas 3rd, J.
BibTeX:
@article{,
  author = {Kocevar, Vasilisa Sazonov and Bisgaard, Hans and Jönsson, Linus and Valovirta, Erkka and Kristensen, Frederik and Yin, Donald D. and Thomas, 3rd, Joseph},
  title = {Variations in pediatric asthma hospitalization rates and costs between and within Nordic countries.},
  journal = {Chest},
  school = {Department of Pharmacy Practice, Purdue University, West Lafayette, IN, USA.},
  year = {2004},
  volume = {125},
  number = {5},
  pages = {1680--1684}
}
Bisgaard, H. Davies, P. Twelve-month safety and efficacy of inhaled fluticasone propionate in children aged 1 to 3 years with recurrent wheezing. 2004 Pediatrics 14754977 5,705 71
Authors: Bisgaard, H., Allen, D., Milanowski, J., Kalev, I., Willits, L. and Davies, P.
Abstract: Our aim was to compare the 12-month safety and efficacy of fluticasone propionate (FP) and sodium cromoglycate (SCG) in children aged 1 to 3 years with mild to moderate recurrent wheeze.The study was a randomized, parallel-group, open-label multicenter study of 625 children, aged 1 to 3 years, with recurrent wheeze randomized in a 3:1 ratio to treatment for 52 weeks with FP (100 microg twice daily) via metered-dose inhaler and Babyhaler spacer device or SCG (5 mg 4 times daily) via metered-dose inhaler and Nebuhaler spacer device, respectively.There was no significant difference in mean adjusted growth rates between the 2 groups: 84.0 mm/year in the FP group versus 86.4 mm/year in the SCG group (difference FP-SCG: -2.4 mm/year; 95% confidence interval: -6.6 to 1.8). Growth comparisons were independent of age, gender, previous use of steroid, or whether measured as length and/or height. Serum and urinary cortisol concentrations showed a statistically significant suppression of 10% and 14 respectively, but the number of patients with serum cortisol levels below the lower normal limit was reduced during the trial. Both treatments were well tolerated. The most common drug-related adverse events were cough (2% FP vs 1% SCG) and hoarseness (1% FP vs 0% SCG). One incident of cataract was observed at baseline and 1 after FP treatment; the latter had resolved after 12 months. The efficacy of FP was superior to SCG with fewer cases of symptom worsening, exacerbations, and requirements for oral steroid treatment and more symptom-free days and days without use of rescue treatment.Twelve months of treatment with inhaled FP (100 microg twice daily) in preschool children aged 1 to 3 years with recurrent wheeze has no effect on growth and no other clinically important side effects but is more efficacious than SCG.
BibTeX:
@article{,
  author = {Bisgaard, Hans and Allen, David and Milanowski, Janusz and Kalev, Ilia and Willits, Lisa and Davies, Patricia},
  title = {Twelve-month safety and efficacy of inhaled fluticasone propionate in children aged 1 to 3 years with recurrent wheezing.},
  journal = {Pediatrics},
  school = {Department of Pediatrics, Copenhagen University Hospital, Copenhagen, Denmark. Bisgaard@copsac.dk},
  year = {2004},
  volume = {113},
  number = {2},
  pages = {e87--e94}
}
Bisgaard, H. Effect of long-acting beta2 agonists on exacerbation rates of asthma in children. 2003 Pediatr Pulmonol 14520721 2,758 87
Authors: Bisgaard, H.
Abstract: The purpose of this analysis was to examine the effect of long-acting beta(2)-adrenoceptor agonists (LABAs) on the asthma exacerbation rate in pediatric patients. Randomized controlled trials (RCT) that included the use of LABAs to treat symptoms of pediatric asthma in children on inhaled corticosteroids, that reported asthma exacerbation rates, and that were published as full papers in peer-reviewed journals were retrieved from a search of the medical literature. Eight studies were identified that fulfilled these criteria. An exacerbation was defined as deterioration in a patient's asthma requiring a change in prescribed medication or not defined but reported as an asthma exacerbation or an asthma-related hospitalization. Analysis of data from the eight studies revealed no apparent protection from an asthma exacerbation among children on a LABA compared to patients on comparator treatment. The relative risk of an asthma exacerbation for LABA compared to placebo or short-acting beta(2)-adrenoceptor agonist (SABA) ranged from 0.95-1.86. The relative risk of hospitalization for asthma in patients treated with LABAs with regular maintenance with ICS ranged from 3.3-21.6 in the three studies that reported asthma-related hospitalizations. The lack of evidence for the control of asthma exacerbations in children regularly using a LABA should bring into question its general use as add-on therapy. Studies should be designed to directly explore the implications of these observations in pediatric patients.
BibTeX:
@article{,
  author = {Bisgaard, Hans},
  title = {Effect of long-acting beta2 agonists on exacerbation rates of asthma in children.},
  journal = {Pediatr Pulmonol},
  school = {Copenhagen Studies on Asthma in Childhood (COPSAC), Department of Pediatrics, Copenhagen University Hospital, Amtssygehuset i Gentofte, Copenhagen, Denmark. Bisgaard@copsac.dk},
  year = {2003},
  volume = {36},
  number = {5},
  pages = {391--398},
  url = {http://dx.doi.org/10.1002/ppul.10381},
  doi = {https://doi.org/10.1002/ppul.10381}
}
Sampson, A.P. Bisgaard, H. Effects of cysteinyl leukotrienes and leukotriene receptor antagonists on markers of inflammation. 2003 J Allergy Clin Immunol 12532086 13,081 0
Authors: Sampson, A.P., Pizzichini, E. and Bisgaard, H.
Abstract: The understanding that asthma pathophysiology includes an inflammatory component has spurred the more aggressive use of anti-inflammatory therapies and created a need for effective tools to measure inflammation. Biomarkers of airway inflammation proposed are obtained by methods that are direct but highly invasive (bronchial biopsy, bronchoalveolar lavage), moderately direct, and less invasive (indirect sputum, exhaled air, breath condensate) or indirect and least invasive (blood, urine). Several studies described in this review have implicated the cysteinyl leukotrienes (CysLTs) as inflammatory mediators in a wide range of diseases, implying that their biological activities reach far beyond acute bronchoconstriction, the activity traditionally ascribed to them. The validity of examining sputum for "biomarkers" has improved the understanding of asthma pathophysiology, optimization of asthma treatment and management, and investigation of the relation between CysLTs and airway inflammation in asthma. Nitric oxide is also a surrogate marker of asthma and reflects airway inflammation. The anti-inflammatory effects of the leukotriene receptor antagonists and the markers of their activity continue to grow.
BibTeX:
@article{,
  author = {Sampson, Anthony P. and Pizzichini, Emilio and Bisgaard, Hans},
  title = {Effects of cysteinyl leukotrienes and leukotriene receptor antagonists on markers of inflammation.},
  journal = {J Allergy Clin Immunol},
  school = {Respiratory Cell Division at Southampton General Hospital, Southampton, UK.},
  year = {2003},
  volume = {111},
  number = {1 Suppl},
  pages = {S49--59; discussion S59-61}
}
Meyer, K.A. Bisgaard, H. Response to montelukast among subgroups of children aged 2 to 14 years with asthma. 2003 J Allergy Clin Immunol 12704354 13,081 29
Authors: Meyer, K.A., Arduino, J.M., Santanello, N.C., Knorr, B.A. and Bisgaard, H.
Abstract: Determining who responds to asthma therapies, particularly leukotriene modifiers, continues to be explored.We sought to identify patient characteristics predictive of response to montelukast.We used data from 2 clinical trials in which children with asthma received either montelukast or placebo. Symptoms, beta-agonist use, and unanticipated health resource use caused by asthma were recorded in validated daily diaries for children 2 to 5 (n = 689) and 6 to 14 (n = 336) years old. We defined primary end points of days without asthma in 2- to 5-year-old patients (24 hours without symptoms, beta-agonist use, or asthma attack) and change in percent predicted FEV(1) in 6- to 14-year-old children. Asthma attack was defined by the use of rescue oral corticosteroids or by an unscheduled visit to a medical provider. Patients were grouped according to baseline characteristics, such as family history of asthma, personal history of allergy, frequency of asthma symptoms, eosinophilia, and concomitant use of inhaled corticosteroids or cromolyn. We examined the stratum-specific effects of montelukast on the percentage of days without asthma, change in percent predicted FEV(1), asthma attack, and a variety of secondary symptom and FEV(1) end points.We did not identify characteristics that predicted response to montelukast in either preschool or 6- to 14-year-old children. These findings were consistent across all symptom and FEV(1) outcomes. There was also no differential response to montelukast in either age group when asthma attack was the outcome.The patient characteristics studied do not appear to provide an indication of who will benefit most from treatment with montelukast.
BibTeX:
@article{,
  author = {Meyer, Katie A. and Arduino, Jean Marie and Santanello, Nancy C. and Knorr, Barbara A. and Bisgaard, Hans},
  title = {Response to montelukast among subgroups of children aged 2 to 14 years with asthma.},
  journal = {J Allergy Clin Immunol},
  school = {Department of Pulmonary-Immunology, Merck Research Laboratories, Rahway, USA.},
  year = {2003},
  volume = {111},
  number = {4},
  pages = {757--762}
}
Buchvald, F. Bisgaard, H. Heterogeneity of FeNO response to inhaled steroid in asthmatic children. 2003 Clin Exp Allergy 14656363 5,264 40
Authors: Buchvald, F., Eiberg, H. and Bisgaard, H.
Abstract: Nitric oxide in exhaled air is regarded as an inflammation marker, and may be used to monitor the anti-inflammatory control from inhaled corticosteroids (ICSs). However, this response to ICSs exhibits a heterogeneous pattern.The study aimed to describe the independent variables associated with the heterogeneity in the response of exhaled nitric oxide to ICSs.Exhaled nitric oxide (FeNO), lung function, bronchial hyper-responsiveness (BHR), specific IgE to common inhalant allergens, blood eosinophils, other atopic manifestations and variants in nitric oxide synthethase 1 (NOS1) gene were studied in a double-blind, placebo-controlled crossover comparison of budesonide (BUD) Turbohaler 1600 mcg daily vs. placebo in asthmatic schoolchildren.Forty children were included in the study from a screening of 184 asthmatic children with moderately persistent asthma, well controlled on regular BUD 400 mcg daily: 20 children with normal FeNO and 20 with raised FeNO. FeNO, BHR and forced expiratory volume in 1 s improved significantly after BUD 1600 mcg (BUD1600). However, FeNO after ICS treatment exhibited a Gaussian distribution and FeNO was significantly raised in 15 children. Allergy and BHR, but none of the other independent variables under study were significantly related to FeNO after BUD1600.Exhaled nitric oxide exhibited a heterogeneous response to ICS in asthmatic schoolchildren. Allergy and BHR were driving FeNO level independently of high-dose steroid treatment. This should be considered when using FeNO for steroid dose titration and monitoring of ICS anti-inflammatory control in asthmatic children.
BibTeX:
@article{,
  author = {Buchvald, F. and Eiberg, H. and Bisgaard, H.},
  title = {Heterogeneity of FeNO response to inhaled steroid in asthmatic children.},
  journal = {Clin Exp Allergy},
  school = {Department of Paediatrics, Rigshospitalet, National University Hospital, Copenhagen, Denmark.},
  year = {2003},
  volume = {33},
  number = {12},
  pages = {1735--1740}
}
Buchvald, F. Bisgaard, H. Comparisons of the complementary effect on exhaled nitric oxide of salmeterol vs montelukast in asthmatic children taking regular inhaled budesonide. 2003 Ann Allergy Asthma Immunol 14533665 3,728 32
Authors: Buchvald, F. and Bisgaard, H.
Abstract: Inhaled, long-acting beta2-agonists or antileukotrienes are alternatives as add-on therapy for asthmatic children taking regular inhaled steroids. Any complementary effects would be relevant to the choice between these alternatives. Exhaled nitric oxide (FeNO) may reflect these effects.To compare the control of FeNO provided by salmeterol or montelukast add-on therapy in asthmatic children undergoing regular maintenance treatment with a daily dose of 400 microg of budesonide.The study included children with increased FeNO despite regular treatment with budesonide, 400 microg/d, and normal lung function. Montelukast, 5 mg/d, salmeterol, 50 microg twice daily, or placebo was compared as add-on therapy to budesonide, 400 microg, in a randomized, double-blind, double-dummy, crossover study.Twenty-two children completed the trial. The geometric mean FeNO level was 20 ppb (95% confidence interval [CI], 15-27 ppb) after salmeterol, which was significantly higher than after montelukast (mean, 15 ppb; 95% CI, 11-18 ppb; P = 0.002) and placebo (mean, 15 ppb; 95% CI, 10-21 ppb; P = 0.03). There was no difference in FeNO between the montelukast and placebo groups. Mean forced expiratory volume in 1 second (FEV1) was significantly increased after salmeterol (mean, 2.63 L; 95% CI, 2.34-2.91 L) compared with placebo (mean, 2.48 L; 95% CI, 2.19-2.77 L). Montelukast (mean, 2.57 L; 95% CI, 2.33-2.80 L) was no different than placebo.The FeNO levels were significantly higher after salmeterol add-on treatment compared with both placebo and montelukast add-on treatment. Salmeterol significantly improved lung function (FEV1) compared with placebo and nonsignificantly compared with montelukast. Montelukast failed to reduce FeNO and improve lung function compared with placebo in this group of children taking regular budesonide, 400 microg.
BibTeX:
@article{,
  author = {Buchvald, Frederik and Bisgaard, Hans},
  title = {Comparisons of the complementary effect on exhaled nitric oxide of salmeterol vs montelukast in asthmatic children taking regular inhaled budesonide.},
  journal = {Ann Allergy Asthma Immunol},
  school = {Department of Pediatrics, Rigshospitalet, National University Hospital, Copenhagen, Denmark.},
  year = {2003},
  volume = {91},
  number = {3},
  pages = {309--313},
  url = {http://dx.doi.org/10.1016/S1081-1206(10)63536-3},
  doi = {https://doi.org/10.1016/S1081-1206(10)63536-3}
}
Bjermer, L. Polos, P.G. Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults: one year, double blind, randomised, comparative trial. 2003 BMJ 14563743 20,785 142
Authors: Bjermer, L., Bisgaard, H., Bousquet, J., Fabbri, L.M., Greening, A.P., Haahtela, T., Holgate, S.T., Picado, C., Menten, J., Dass, S.B., Leff, J.A. and Polos, P.G.
Abstract: To assess the effect of montelukast versus salmeterol added to inhaled fluticasone propionate on asthma exacerbation in patients whose symptoms are inadequately controlled with fluticasone alone. Design and setting A 52 week, two period, double blind, multicentre trial during which patients whose symptoms remained uncontrolled by inhaled corticosteroids were randomised to add montelukast or salmeterol.Patients (15-72 years; n = 1490) had a clinical history of chronic asthma for > or = 1 year, a baseline forced expiratory volume in one second (FEV1) value 50-90% predicted, and a beta agonist improvement of > or = 12% in FEV1.The primary end point was the percentage of patients with at least one asthma exacerbation.20.1% of the patients in the group receiving montelukast and fluticasone had an asthma exacerbation compared with 19.1% in the group receiving salmeterol and fluticasone; the difference was 1% (95% confidence interval -3.1% to 5.0. With a risk ratio (montelukast-fluticasone/salmeterol-fluticasone) of 1.05 (0.86 to 1.29), treatment with montelukast and fluticasone was shown to be non-inferior to treatment with salmeterol and fluticasone. Salmeterol and fluticasone significantly increased FEV1 before a beta agonist was used and morning peak expiratory flow compared with montelukast and fluticasone (P < or = 0.001), whereas FEV1 after a beta agonist was used and improvements in asthma specific quality of life and nocturnal awakenings were similar between the groups. Montelukast and fluticasone significantly (P = 0.011) reduced peripheral blood eosinophil counts compared with salmeterol and fluticasone. Both treatments were generally well tolerated.The addition of montelukast in patients whose symptoms remain uncontrolled by inhaled fluticasone could provide equivalent clinical control to salmeterol.
BibTeX:
@article{,
  author = {Bjermer, Leif and Bisgaard, Hans and Bousquet, Jean and Fabbri, Leonardo M. and Greening, Andrew P. and Haahtela, Tari and Holgate, Stephen T. and Picado, Cesar and Menten, Joris and Dass, S Balachandra and Leff, Jonathan A. and Polos, Peter G.},
  title = {Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults: one year, double blind, randomised, comparative trial.},
  journal = {BMJ},
  school = {Department of Respiratory Medicine and Allergology, University Hospital, SE-221 85 Lund, Sweden.},
  year = {2003},
  volume = {327},
  number = {7420},
  pages = {891},
  url = {http://dx.doi.org/10.1136/bmj.327.7420.891},
  doi = {https://doi.org/10.1136/bmj.327.7420.891}
}
Bisgaard, H. Virus, R.S. A randomized trial of montelukast in respiratory syncytial virus postbronchiolitis. 2003 Am J Respir Crit Care Med 12406832 13,204 159
Authors: Bisgaard, H., , S.G.o.M. and Virus, R.S.
Abstract: Infants often develop reactive airway disease after respiratory syncytial virus (RSV) bronchiolitis. Cysteinyl-leukotrienes (cys-LT) are released during RSV infection and may contribute to the inflammation. We hypothesized that a cys-LT receptor antagonist would ameliorate reactive airway disease subsequent to RSV bronchiolitis. One hundred and thirty infants who were 3 to 36 months old, hospitalized with acute RSV bronchiolitis, were randomized into a double-blind, parallel comparison of 5-mg montelukast chewable tablets or matching placebo given for 28 days starting within 7 days of symptom debut. Infants with a suspected history of asthma were excluded. One hundred sixteen infants provided diary card data for the treatment period. Median age was 9 months. Infants on montelukast were free of any symptoms on 22% of the days and nights compared with 4% of the days and nights in infants on placebo (p = 0.015). Daytime cough was significantly reduced on active treatment (p = 0.04). Exacerbations were significantly delayed from montelukast compared with placebo (p < 0.05). In conclusion, cys-LT antagonist treatment reduces lung symptoms subsequent to RSV bronchiolitis.
BibTeX:
@article{,
  author = {Bisgaard, Hans and , Study Group on Montelukast and Respiratory Syncytial Virus},
  title = {A randomized trial of montelukast in respiratory syncytial virus postbronchiolitis.},
  journal = {Am J Respir Crit Care Med},
  school = {Copenhagen Studies on Asthma in Childhood (COPSAC), Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. Bisgaard@copsac.dk},
  year = {2003},
  volume = {167},
  number = {3},
  pages = {379--383}
}
Anhøj, J. Bisgaard, H. Systemic activity of inhaled steroids in 1- to 3-year-old children with asthma. 2002 Pediatrics 11875168 5,705 46
Authors: Anhøj, J., Bisgaard, A.M. and Bisgaard, H.
Abstract: To study the systemic activity of inhaled steroids in young children.Forty children with mild asthma aged 1 to 3 years were studied in a 3-way crossover, randomized, placebo-controlled, double-blind trial. Treatment with inhaled fluticasone propionate, 200 microg twice daily delivered via pressurized metered-dose inhaler (pMDI) and Babyhaler (FP400), was compared with budesonide, 200 microg twice daily delivered via pMDI and NebuChamber (BUD400), and to placebo. The Babyhaler was primed before use. Knemometry was used to detect systemic steroid activity. It was performed with a hand-held knemometer after 1 and 4 weeks of treatment. The increase in lower-leg length within this 3-week period was used as the outcome measure. The intention-to-treat population was analyzed by analysis of variance.The increases in the lower-leg length during placebo, BUD400, and FP400 treatments were 85, 45, and 34 microm/d, respectively (adjusted mean). The growth in lower-leg length was significantly reduced from both steroid treatments. The difference between BUD400 and placebo was -40 microm/d (n = 25; 95% confidence interval [CI]: -8 to -72). The difference between FP400 and placebo was -51 microm/d (n = 26; 95% CI: -19 to -83). The difference between FP and BUD was -11 microm/d and was not statistically significant (n = 28; 95% CI: 20 to -42).FP and BUD are both systemically active in children 1 to 3 years old when administered for 4 weeks from their dedicated spacer devices in daily doses of 400 microg with no difference between the 2 steroid regimens. These findings call for studies of clinical side effects from these treatments of preschool children.
BibTeX:
@article{,
  author = {Anhøj, Jacob and Bisgaard, Anne Marie and Bisgaard, Hans},
  title = {Systemic activity of inhaled steroids in 1- to 3-year-old children with asthma.},
  journal = {Pediatrics},
  school = {Pulmonary Service, Department of Paediatrics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.},
  year = {2002},
  volume = {109},
  number = {3},
  pages = {E40}
}
Bisgaard, H. Efficacy of steroid treatments in the asthmatic preschool child. 2002 Allergy 12371911 7,361 4
Authors: Bisgaard, H.
BibTeX:
@article{,
  author = {Bisgaard, H.},
  title = {Efficacy of steroid treatments in the asthmatic preschool child.},
  journal = {Allergy},
  school = {Department of Paediatrics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.},
  year = {2002},
  volume = {57 Suppl 74},
  pages = {32--41}
}
Benn, C.S. Melbye, M. Maternal vaginal microflora during pregnancy and the risk of asthma hospitalization and use of antiasthma medication in early childhood. 2002 J Allergy Clin Immunol 12110824 13,081 71
Authors: Benn, C.S., Thorsen, P., Jensen, J.S., Kjaer, B.B., Bisgaard, H., Andersen, M., Rostgaard, K., Björkstén, B. and Melbye, M.
Abstract: Infants with wheezing and allergic diseases have a microflora that differs from that of healthy infants. The fetus acquires microorganisms during birth when exposed to the maternal vaginal microflora. It is therefore conceivable that the maternal vaginal microflora might influence the establishment of the infant flora and, as a consequence, the development of wheezing and allergic diseases.We sought to study the associations between the composition of the maternal vaginal microflora and the development of wheezing and asthma in childhood.We performed a population-based cohort study in Denmark. Vaginal samples for bacterial analysis were obtained during pregnancy. A total of 2927 women (80% of the invited women) completed the study and had 3003 live infants. Infant wheezing was assessed as one or more hospitalizations for asthma between 0 and 3 years of age. Asthma was assessed as use of 3 or more packages of antiasthma medication between 4 and 5 years of age.Maternal vaginal colonization with Ureaplasma urealyticum during pregnancy was associated with infant wheezing (odds ratio [OR], 2.0; 95% CI, 1.2-3.6), but not with asthma, during the fifth year of life. Maternal colonization with staphylococci (OR, 2.2; 95% CI, 1.4-3.4) and use of antibiotics in pregnancy (OR, 1.7; 95% CI, 1.1-2.6) were associated with asthma during the fifth year of life.The composition of the maternal vaginal micro-flora might be associated with wheezing and asthma in the offspring up to 5 years of age.
BibTeX:
@article{,
  author = {Benn, Christine Stabell and Thorsen, Poul and Jensen, Jørgen Skov and Kjaer, Birgitte Boysen and Bisgaard, Hans and Andersen, Morten and Rostgaard, Klaus and Björkstén, Bengt and Melbye, Mads},
  title = {Maternal vaginal microflora during pregnancy and the risk of asthma hospitalization and use of antiasthma medication in early childhood.},
  journal = {J Allergy Clin Immunol},
  school = {Department of Epidemiology Research, Danish Epidemiology Science Centre, Statens Serum Institut, Copenhagen, Denmark.},
  year = {2002},
  volume = {110},
  number = {1},
  pages = {72--77}
}
Baraldi, E. de Jongste, J.C. Measurement of exhaled nitric oxide in children, 2001. 2002 Eur Respir J 12166573 10,569 280
Authors: Baraldi, E., de Jongste, J.C. and , E.R.S.T.S.(E.R.S.T.S.T.F.
Abstract: Measurement of fractional exhaled nitric oxide in exhaled air is an exciting innovative technique that gives new insights in to the pathophysiology of lung disease and asthma in particular, with many potential clinical applications. Careful standardisation of measurement techniques will facilitate the use of this new measurement in paediatric respiratory medicine: this Task Force was set up for this purpose. Methodologies, for use in all age groups, are already available and there are abundant questions relating to interpretation and application of fractional exhaled nitric oxide waiting to be addressed. Noninvasiveness and instantaneous results potentially make it a suitable monitoring instrument for use in children. Exhaled nitric oxide measurement has definitely found its way into clinical research in paediatric respiratory medicine. Evidence for clinically-useful applications is accumulating, and the merits of this new technique must now be demonstrated in larger studies, using standardised methodology in an appropriate setting.
BibTeX:
@article{,
  author = {Baraldi, E. and de Jongste, J. C. and , European Respiratory Society/American Thoracic Society (E. R. S/A. T. S) Task Force},
  title = {Measurement of exhaled nitric oxide in children, 2001.},
  journal = {Eur Respir J},
  school = {Dept. of Paediatrics, Padova, Italy. eugi@pediatria.unipd.it},
  year = {2002},
  volume = {20},
  number = {1},
  pages = {223--237}
}
Zach, M.S. Long Range Planning Committee Paediatric respiratory training in Europe: syllabus and centres. 2002 Eur Respir J 12503721 10,569 18
Authors: Zach, M.S. Bisgaard, H., and Long Range Planning Committee, P.A.o.t.E.R.S.C.o.P.R.T.i.E.E.B.o.P.
BibTeX:
@article{,
  author = {Zach, M. S. and , Long Range Planning Committee, Paediatric Assembly of the European Respiratory Society, Committee on Paediatric Respiratory Training in Europe, European Board of Paediatrics},
  title = {Paediatric respiratory training in Europe: syllabus and centres.},
  journal = {Eur Respir J},
  school = {Klinische Abteilung für Pulmonologie/Allergologie, Univ. Klinik für Kinder und Jugendheilkunde Graz, Auenbruggerplatz 30, A-8036 Graz, Austria. maximilian.zach@kfunigraz.ac.at},
  year = {2002},
  volume = {20},
  number = {6},
  pages = {1587--1593}
}
Lipworth, B.J. Bisgaard, H. Effect of plastic spacer handling on salbutamol lung deposition in asthmatic children. 2002 Br J Clin Pharmacol 12445036 3,493 15
Authors: Lipworth, B.J., Lee, D.K.C., Anhøj, J. and Bisgaard, H.
Abstract: To study the effects of electrostatics in a plastic spacer on the lung deposition of salbutamol in asthmatic children.Twenty-five children (5-12 years) with mild asthma were given salbutamol hydrofluoroalkane pressurized metered dose inhaler 400 micro g via a 750 ml plastic spacer on separate days. Blood samples were taken for plasma salbutamol at 5, 10, 15 and 20 min after inhalation to measure lung bioavailability as a surrogate for relative lung dose. With immediate inhalation following actuation, a new rinsed spacer (NewRinsed ) was compared with a used spacer after repeated daily use (Used ), a spacer rinsed after repeated use (UsedRinsed ) and a spacer primed with benzalkonium chloride to avoid electrostatics (Primed1). In addition, spacers were evaluated using a 15 s inhalation delay following actuation with primed (PrimedDelay) and rinsed (RinsedDelay) spacers. Data were log transformed and expressed as geometric mean fold difference for the average plasma salbutamol concentration (Cav) over 20 min.There were significant differences (P < 0.05) in Cav (as geometric mean fold difference and 95% CI) between Primed1 vs NewRinsed 1.92 fold (95% CI 1.15, 3.20) and between Used vs NewRinsed 1.75 fold (1.11, 2.76). There were no significant differences comparing Primed1, Used or UsedRinsed. There were also significant differences (P < 0.05) between Primed1 vs PrimedDelay 2.34 fold (1.31, 4.19), or vs RinsedDelay 3.59 fold (2.15, 5.99); and for Used vs PrimedDelay 2.14 fold (1.24, 3.69), or vs RinsedDelay 3.28 fold (2.13, 5.04).The relative lung dose of salbutamol from a plastic spacer may differ considerably depending on spacer handling suggesting that nonelectrostatic spacers may be the best way forward.
BibTeX:
@article{,
  author = {Lipworth, Brian J. and Lee, Daniel K C. and Anhøj, Jacob and Bisgaard, Hans},
  title = {Effect of plastic spacer handling on salbutamol lung deposition in asthmatic children.},
  journal = {Br J Clin Pharmacol},
  school = { Allergy Research Group, Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, UK. b.j.lipworth@dundee.ac.uk},
  year = {2002},
  volume = {54},
  number = {5},
  pages = {544--547}
}
Bisgaard, H. Pathophysiology of the cysteinyl leukotrienes and effects of leukotriene receptor antagonists in asthma. 2001 Allergy 11421935 7,361 52
Authors: Bisgaard, H.
Abstract: Cysteinyl leukotrienes, synthesized de novo from cell membrane phospholipids, are proinflammatory mediators that play an important role in the pathophysiology of asthma. These mediators are among the most potent of bronchoconstrictors and cause vasodilation, increased microvascular permeability, exudation of macromolecules and edema. The cysteinyl leukotrienes also have potent chemoattractant properties for eosinophils, causing an influx of eosinophils into the airway mucosa, which further fuels the inflammatory process. In addition, the cysteinyl leukotrienes are potent secretagogues and reduce ciliary motility, which may hinder mucociliary clearance. Asthmatic patients demonstrate increased production of cysteinyl leukotrienes during naturally occurring asthma and acute asthma attacks as well as after allergen and exercise challenge. The leukotriene receptor antagonists montelukast, zafirlukast and pranlukast inhibit bronchoconstriction in asthmatic patients undergoing allergen, exercise, cold air or aspirin challenge. They attenuate the hallmarks of asthmatic inflammation, including eosinophilia in the airway mucosa and peripheral blood. Moreover, exhaled nitric oxide concentrations, another correlate of airway inflammation, are decreased during montelukast treatment in children. Cysteinyl leukotriene synthesis is not blocked by corticosteroid therapy. This important observation suggests that the leukotriene receptor antagonists represent a novel therapeutic approach, one that may provide benefits that are additive with corticosteroid therapy. This supposition is supported by clinical observations that treatment with leukotriene receptor antagonists significantly improve asthma control when added to inhaled corticosteroid therapy. Moreover, the bronchodilator properties of the leukotriene receptor antagonists are additive with those of beta agonists. These data provide strong support for the use of leukotriene receptor antagonists for treating asthma.
BibTeX:
@article{,
  author = {Bisgaard, H.},
  title = {Pathophysiology of the cysteinyl leukotrienes and effects of leukotriene receptor antagonists in asthma.},
  journal = {Allergy},
  school = {Department of Paediatrics, University Hospital of Copenhagen, Cophenhagen, Denmark. bisgaard@rh.dk},
  year = {2001},
  volume = {56 Suppl 66},
  pages = {7--11}
}
Bisgaard, H. Persistent wheezing in very young preschool children reflects lower respiratory inflammation. 2001 Am J Respir Crit Care Med 11371382 13,204 16
Authors: Bisgaard, H.
BibTeX:
@article{,
  author = {Bisgaard, H.},
  title = {Persistent wheezing in very young preschool children reflects lower respiratory inflammation.},
  journal = {Am J Respir Crit Care Med},
  year = {2001},
  volume = {163},
  number = {6},
  pages = {1290--1291},
  url = {http://dx.doi.org/10.1164/ajrccm.163.6.ed1801b},
  doi = {https://doi.org/10.1164/ajrccm.163.6.ed1801b}
}
Bisgaard, H. Leukotriene modifiers in pediatric asthma management. 2001 Pediatrics 11158473 5,705 74
Authors: Bisgaard, H.
Abstract: Cysteinyl leukotrienes (Cys-LTs) are mediators released in asthma and virus-induced wheezing. Corticosteroids appear to have little or no effect on this release in vivo. Cys-LTs are both direct bronchoconstrictors and proinflammatory substances that mediate several steps in the pathophysiology of chronic asthma, including inflammatory cell recruitment, vascular leakage, and possibly airway remodeling. Blocking studies show that Cys-LTs are pivotal mediators in the pathophysiology of asthma. Cys-LTs are key components in the early and late allergic airway response and also contribute to bronchial obstruction after exercise and hyperventilation of cold, dry air in asthmatics. LT modifiers reduce airway eosinophil numbers and exhaled nitric oxide levels. Together these findings support an important role for the Cys-LTs in the asthma airway inflammation. Cys-LT receptor antagonists (Cys-LTRA) are generally well-tolerated. Phase III randomized, controlled clinical trials (RCT) show that LT modifiers are moderately effective, apparently with a particular between-patient variability in their clinical response. The clinical effects of LT modifiers are additive to those of beta-agonists and corticosteroids. The onset of action of LT modifiers is within 1 to several days, and not rapid enough to make them useful as rescue treatment. Although LT modifiers possess some antiinflammatory activity, they cannot substitute for corticosteroids for inflammation control. LT modifiers are alternatives to long-acting beta-agonists as complementary treatment to inhaled corticosteroids in pediatric asthma management because they provide bronchodilation and bronchoprotection without development of tolerance, and complement the antiinflammatory activity unchecked by steroids. In addition, the Cys-LTRA montelukast has been shown to ameliorate asthmatic symptoms and provide bronchoprotection in asthmatic preschool children from 2 years of age, which is of particular importance in this difficult-to-manage group of asthmatics. Given their efficacy, antiinflammatory activity, oral administration, and safety, LT modifiers will play an important role in the treatment of asthmatic children.
BibTeX:
@article{,
  author = {Bisgaard, H.},
  title = {Leukotriene modifiers in pediatric asthma management.},
  journal = {Pediatrics},
  school = {Department of Paediatrics, Copenhagen University Hospital, Copenhagen, Denmark. bisgaard@copsac.dk},
  year = {2001},
  volume = {107},
  number = {2},
  pages = {381--390}
}
Roorda, R.J. Maden, C. Response of preschool children with asthma symptoms to fluticasone propionate. 2001 J Allergy Clin Immunol 11590379 13,081 64
Authors: Roorda, R.J., Mezei, G., Bisgaard, H. and Maden, C.
Abstract: Many uncertainties remain in the diagnosis and treatment of preschool children with asthma symptoms.We sought to determine the subgroups of preschool children (aged 12-47 months) with recurrent asthma symptoms most likely to respond to inhaled fluticasone propionate (200 microg/d).Subgroups of pooled data from 2 similar 12-week multicenter studies were analyzed.Children with frequent symptoms (symptoms on > or =3 days per week and a total of > or =75% days with symptoms during the 4-week run-in period; n = 169) showed a significantly greater increase in days without symptoms after fluticasone propionate treatment (0% to 45 compared with after placebo treatment (0% to 25 P =.005). Children with a family history of asthma (n = 213) also had a significantly greater increase in days without symptoms after fluticasone propionate (11% to 54 compared with after placebo (7% to 35 P =.002) and a significantly higher proportion of exacerbation-free patients (61% to 76 P =.02). Children with less frequent symptoms, no family history of asthma, or both showed no significant treatment effect. There seemed to be no association between response to fluticasone propionate and history of rhinitis or eczema or the number of previous exacerbations.Children with frequent symptoms, a family history of asthma, or both showed the greatest response to fluticasone propionate treatment. These findings may help to predict treatment outcome and guide the management of preschool children with recurrent asthma symptoms.
BibTeX:
@article{,
  author = {Roorda, R. J. and Mezei, G. and Bisgaard, H. and Maden, C.},
  title = {Response of preschool children with asthma symptoms to fluticasone propionate.},
  journal = {J Allergy Clin Immunol},
  school = {Department of Pediatrics, Isala Klinieken, De Weezenlanden Hospital, Zwolle, The Netherlands.},
  year = {2001},
  volume = {108},
  number = {4},
  pages = {540--546},
  url = {http://dx.doi.org/10.1067/mai.2001.118789},
  doi = {https://doi.org/10.1067/mai.2001.118789}
}
Nielsen, K.G. Bisgaard, H. Discriminative capacity of bronchodilator response measured with three different lung function techniques in asthmatic and healthy children aged 2 to 5 years. 2001 Am J Respir Crit Care Med 11520714 13,204 136
Authors: Nielsen, K.G. and Bisgaard, H.
Abstract: The primary aim of this study was to quantify and compare bronchodilator responsiveness in healthy and asthmatic children aged 2 to 5 yr. The secondary aim of the study was to compare discriminative capacity (i.e., sensitivity, specificity, and predictive values of the reversibility test for the diagnosis of asthma) for each of the lung function tests applied in the study. Specific airway resistance (sRaw) as measured by whole-body plethysmography, respiratory resistance as measured with the interrupter technique (Rint), and respiratory resistance and reactance at 5 Hz (Rrs5, Xrs5, respectively) as measured with the impulse oscillation technique were assessed before and 20 min after inhalation of terbutaline from a pressurized metered-dose inhaler via a metal spacer by 92 children (37 healthy controls and 55 asthmatic subjects). The study of healthy children followed a randomized, double-blind, crossover design, whereas the study of asthmatic children was open. Baseline lung function was significantly decreased in asthmatic children as compared with healthy control subjects as reflected by all techniques used in the study. sRaw, Rint, and Rrs5, but not Xrs5, improved significantly with terbutaline as compared with placebo in healthy control subjects. Lung function improved to a significantly greater extent in asthmatic children than in control subjects as reflected by all methods. sRaw provided the best discriminative power of such a bronchodilator response, with a sensitivity of 66% and specificity of 81% at the cutoff level of a 25% decrease in sRaw after bronchodilator administration. In conclusion, bronchodilator response measured by sRaw allows a separation of asthmatic from healthy young children. This may help define asthma in this clinically difficult-to-manage group of young wheezy children. The sensitivity and specificity of the other methods used in the study were less than those of sRaw.
BibTeX:
@article{,
  author = {Nielsen, K. G. and Bisgaard, H.},
  title = {Discriminative capacity of bronchodilator response measured with three different lung function techniques in asthmatic and healthy children aged 2 to 5 years.},
  journal = {Am J Respir Crit Care Med},
  school = {Department of Pediatrics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.},
  year = {2001},
  volume = {164},
  number = {4},
  pages = {554--559},
  url = {http://dx.doi.org/10.1164/ajrccm.164.4.2006119},
  doi = {https://doi.org/10.1164/ajrccm.164.4.2006119}
}
Nielsen, K.G. Bisgaard, H. Bronchodilation and bronchoprotection in asthmatic preschool children from formoterol administered by mechanically actuated dry-powder inhaler and spacer. 2001 Am J Respir Crit Care Med 11463597 13,204 24
Authors: Nielsen, K.G. and Bisgaard, H.
Abstract: We evaluated the bronchodilatory and the bronchoprotective effect of the long-acting beta(2)-agonist formoterol administered as dry powder from a mechanically actuated dry-powder inhaler (DPI) using spacer in 12 asthmatic children 2 to 5 yr of age. Lung function was measured as the specific airway resistance (sRaw) in a whole body plethysmograph. Hyperventilation of cold, dry air was used as bronchial challenge, and the responsiveness was estimated as change in sRaw. The bronchoprotective effect of formoterol Turbohaler 9 microg was compared with salbutamol 200 microg and placebo at 15 min, 4 and 8 h postdose in a randomized, double-blind, placebo-controlled, crossover study. All treatments were administered from DPI (Turbohaler) actuated mechanically into a spacer. Formoterol and salbutamol caused similar and significant bronchodilation at the first measurement 3 min postdose. Formoterol offered a sustained and stable bronchodilation for at least 8 h. Salbutamol provided significant bronchodilation for less than 4 h. Formoterol caused significant bronchoprotection of 80% for at least 8 h compared with placebo, and from 4 h onward compared with salbutamol. Bronchoprotection from salbutamol lasted less than 4 h. In conclusion, formoterol administered as dry powder in a single dose provided rapid and sustained bronchodilation and clinically significant bronchoprotection for at least 8 h in 2- to 5-yr-old asthmatic children. Furthermore, this study suggests that mechanical actuation of DPI using a spacer is effective for aerosol treatment of young asthmatic children.
BibTeX:
@article{,
  author = {Nielsen, K. G. and Bisgaard, H.},
  title = {Bronchodilation and bronchoprotection in asthmatic preschool children from formoterol administered by mechanically actuated dry-powder inhaler and spacer.},
  journal = {Am J Respir Crit Care Med},
  school = {Department of Pediatrics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.},
  year = {2001},
  volume = {164},
  number = {2},
  pages = {256--259},
  url = {http://dx.doi.org/10.1164/ajrccm.164.2.2011121},
  doi = {https://doi.org/10.1164/ajrccm.164.2.2011121}
}
Knorr, B. Bratton, D.L. Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. 2001 Pediatrics 11533366 5,705 192
Authors: Knorr, B., Franchi, L.M., Bisgaard, H., Vermeulen, J.H., LeSouef, P., Santanello, N., Michele, T.M., Reiss, T.F., Nguyen, H.H. and Bratton, D.L.
Abstract: The greatest prevalence of asthma is in preschool children; however, the clinical utility of asthma therapy for this age group is limited by a narrow therapeutic index, long-term tolerability, and frequency and/or difficulty of administration. Inhaled corticosteroids and inhaled cromolyn are the most commonly prescribed controller therapies for young children with persistent asthma, although very young patients may have difficulty using inhalers, and dose delivery can be variable. Moreover, reduced compliance with inhaled therapy relative to orally administered therapy has been reported. One potential advantage of montelukast is the ease of administering a once-daily chewable tablet; additionally, no tachyphylaxis or change in the safety profile has been evidenced after up to 140 and 80 weeks of montelukast therapy in adults and pediatric patients aged 6 to 14 years, respectively. To our knowledge, this represents the first large, multicenter study to address the effects of a leukotriene receptor antagonist in children younger than 5 years of age with persistent asthma, as well as one of the few asthma studies that incorporated end points validated for use in preschool children.Our primary objective was to determine the safety profile of montelukast, an oral leukotriene receptor antagonist, in preschool children with persistent asthma. Secondarily, the effect of montelukast on exploratory measures of asthma control was also studied. DESIGN AND STATISTICAL ANALYSIS: We conducted a double-blind, multicenter, multinational study at 93 centers worldwide: including 56 in the United States, and 21 in countries in Africa, Australia, Europe, North America, and South America. In this study, we randomly assigned 689 patients (aged 2-5 years) to 12 weeks of treatment with placebo (228 patients) or 4 mg of montelukast as a chewable tablet (461 patients) after a 2-week placebo baseline period. Patients had a history of physician-diagnosed asthma requiring use of beta-agonist and a predefined level of daytime asthma symptoms. Caregivers answered questions twice daily on a validated, asthma-specific diary card and, at specified times during the study, completed a validated asthma-specific quality-of-life questionnaire. Physicians and caregivers completed a global evaluation of asthma control at the end of the study. Efficacy end points included: daytime and overnight asthma symptoms, daily use of beta-agonist, days without asthma, frequency of asthma attacks, number of patients discontinued because of asthma, need for rescue medication, physician and caregiver global evaluations of change, asthma-specific caregiver quality of life, and peripheral blood eosinophil counts. Although exploratory, the efficacy end points were predefined and their analyses were written in a data analysis plan before study unblinding. At screening and at study completion, a complete physical examination was performed. Routine laboratory tests were drawn at screening and weeks 6 and 12, and submitted to a central laboratory for analysis. Adverse effects were collected from caregivers at each clinic visit. An intention-to-treat approach, including all patients with a baseline measurement and at least 1 postrandomization measurement, was performed for all efficacy end points. An analysis-of-variance model with terms for treatment, study center and stratum (inhaled/nebulized corticosteroid use, cromolyn use, or none) was used to estimate treatment group means and between-group differences and to construct 95% confidence intervals. Treatment-by-age, -sex, -race, -radioallergosorbent test, -stratum, and -study center interactions were evaluated by including each term separately. Fisher's exact test was used for between-group comparisons of the frequency of asthma attacks, discontinuations from the study because of worsening asthma, need for rescue medication, and the frequencies of adverse effects. Because of an imbalance in baseline values for eosinophil counts for the 2 treatment groups, an analysis of covariance was performed on the eosinophil change from baseline with the patient's baseline as covariate.Of the 689 patients enrolled, approximately 60% were boys and 60% were white. Patients were relatively evenly divided by age: 21 24 30 and 23% were aged 2, 3, 4, and 5 years, respectively. For 77% of the patients, asthma symptoms first developed during the first 3 years of life. During the placebo baseline period, patients had asthma symptoms on 6.1 days/week and used beta-agonist on 6.0 days/week.In over 12 weeks of treatment of patients aged 2 to 5 years, montelukast administered as a 4-mg chewable tablet produced significant improvements compared with placebo in multiple parameters of asthma control including: daytime asthma symptoms (cough, wheeze, trouble breathing, and activity limitation); overnight asthma symptoms (cough); the percentage of days with asthma symptoms; the percentage of days without asthma; the need for beta-agonist or oral corticosteroids; physician global evaluations; and peripheral blood eosinophils. The clinical benefit of montelukast was evident within 1 day of starting therapy. Improvements in asthma control were consistent across age, sex, race, and study center, and whether or not patients had a positive radioallergosorbent test. Montelukast demonstrated a consistent effect regardless of concomitant use of inhaled/nebulized corticosteroid or cromolyn therapy. Caregiver global evaluations, the percentage of patients experiencing asthma attacks, and improvements in quality-of-life scores favored montelukast, but were not significantly different from placebo. There were no clinically meaningful differences between treatment groups in overall frequency of adverse effects or of individual adverse effects, with the exception of asthma, which occurred significantly more frequently in the placebo group. There were no significant differences between treatment groups in the frequency of laboratory adverse effects or in the frequency of elevated serum transaminase levels. Approximately 90% of the patients completed the study.Oral montelukast (4-mg chewable tablet) administered once daily is effective therapy for asthma in children aged 2 to 5 years and is generally well tolerated without clinically important adverse effects. Similarly, in adults and children aged 6 to 14 years, montelukast improves multiple parameters of asthma control. Thus, this study confirms and extends the benefit of montelukast to younger children with persistent asthma.
BibTeX:
@article{,
  author = {Knorr, B. and Franchi, L. M. and Bisgaard, H. and Vermeulen, J. H. and LeSouef, P. and Santanello, N. and Michele, T. M. and Reiss, T. F. and Nguyen, H. H. and Bratton, D. L.},
  title = {Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years.},
  journal = {Pediatrics},
  school = {Departments of Pulmonary-Immunology, Epidemiology, and Biostatistics, Merck Research Laboratories, Rahway, New Jersey 07065, USA. barbara_knorr@merck.com},
  year = {2001},
  volume = {108},
  number = {3},
  pages = {E48}
}
Bisgaard, H. Schiøtz, P.O. [Pediatric pulmonology]. 2001 Ugeskr Laeger 11816914 0 0
Authors: Bisgaard, H., Pedersen, S.E. and Schiøtz, P.O.
Abstract: Paediatric pulmonology (paediatric respiratory medicine) concerns such lung diseases in children as asthma, pneumonia, cystic fibrosis, primary ciliary dyskinesia, chronic interstitial pneumonia, bronchopulmonary dysplasia and congenital abnormalities. This specialty has been approved as an official subsection of the European Confederation of Specialists in Paediatrics (CESP) and acknowledged by the European Union of Medical Specialists (UEMS). A training syllabus has been defined and training centres in all EU countries, including Denmark, have been identified and approved by the local paediatric organisations. The training syllabus emphasises routine in the clinical diagnosis and treatment of the diseases, as well as methods such as lung function in all age groups, bronchoscopy, biopsy, and others. This article summarises the status of this specialty, and the training syllabus, and highlights key research questions.
BibTeX:
@article{,
  author = {Bisgaard, H. and Pedersen, S. E. and Schiøtz, P. O.},
  title = {[Pediatric pulmonology].},
  journal = {Ugeskr Laeger},
  school = {H:S Rigshospitalet, børneafdelingen. Bisgaard@copsac.dk},
  year = {2001},
  volume = {163},
  number = {46},
  pages = {6391--6395}
}
Buchvald, F. Bisgaard, H. FeNO measured at fixed exhalation flow rate during controlled tidal breathing in children from the age of 2 yr. 2001 Am J Respir Crit Care Med 11254527 13,204 59
Authors: Buchvald, F. and Bisgaard, H.
Abstract: We have outlined a new method to measure exhaled nitric oxide on-line at fixed flow rate during controlled tidal breathing (FeNO [controlled]) in young children aged 2 yr and older. FeNO(controlled) measures NO on-line during operator-controlled tidal breathing. The operator targets the exhaled flow of the child within preset limits of 0.4-0.6 L/s by continuously adjusting an expiratory resistance. FeNO(controlled) is estimated during end exhalation. We have validated this method against the reference method of the single breath on-line (SBOL) maneuvre (FeNO[SBOL]) and compared it with NO in mixed exhaled air collected in a bag (FeNO [mixed]). Sixty-seven children were studied: 16 school children and 51 children aged 2-5 yr; 14 of the young children were healthy, 22 had asthma treated with regular inhaled budesonide, and 15 had mild episodic wheeze treated with inhaled terbutaline as necessary. FeNO (controlled) showed good agreement with FeNO(SBOL) (factor difference 0.7-1.4), whereas FeNO(mixed) showed poor agreement with FeNO(SBOL) (factor difference 0.51-5.37). FeNO(controlled) (mean [95% confidence interval]) was 6 ppb (4-8 ppb) in young children with asthma, 5 ppb (3-7 ppb) in young children with mild episodic wheeze, and 3 ppb (2-4 ppb) in healthy control subjects (asthma versus control subjects: p = 0.006; episodic wheeze versus control subjects: p = 0.057). FeNO(controlled) increased from 4 ppb (2-7 ppb) to 13 ppb (10-18 ppb) (p < 0.0001) when the mean daily maintenance dose of budesonide was tapered in nine young children with asthma. FeNO(controlled) is feasible in young children from age 2 and shows better agreement with FeNO(SBOL) than FeNO(mixed). FeNO(controlled) covaries with asthma disease severity and steroid dose. FeNO(controlled) is therefore suggested as a noninvasive diagnostic tool for monitoring asthma disease activity in young children with asthma from the age of 2 yr.
BibTeX:
@article{,
  author = {Buchvald, F. and Bisgaard, H.},
  title = {FeNO measured at fixed exhalation flow rate during controlled tidal breathing in children from the age of 2 yr.},
  journal = {Am J Respir Crit Care Med},
  school = {Department of Paediatrics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.},
  year = {2001},
  volume = {163},
  number = {3 Pt 1},
  pages = {699--704},
  url = {http://dx.doi.org/10.1164/ajrccm.163.3.2004233},
  doi = {https://doi.org/10.1164/ajrccm.163.3.2004233}
}
Bisgaard, H. Olsen, N.A. Cost-effectiveness of fluticasone propionate administered via metered-dose inhaler plus babyhaler spacer in the treatment of asthma in preschool-aged children. 2001 Chest 11742910 6,044 16
Authors: Bisgaard, H., Price, M.J., Maden, C. and Olsen, N.A.
Abstract: To evaluate the cost-effectiveness of inhaled fluticasone propionate (FP) in children aged 12 to 47 months with asthma symptoms.A retrospective economic analysis conducted from the perspective of the Danish health-care system, based on clinical data from a 12-week study.Thirty-three outpatient centers in nine countries.Two hundred thirty-seven children aged 12 to 47 months with documented history of recurrent wheeze or asthma symptoms.Two dosages of FP, 100 microg/d and 200 microg/d, and placebo administered in two divided doses via a metered-dose inhaler and a Babyhaler (Glaxo Wellcome; Middlesex, UK) spacer device.Effectiveness in terms of asthma exacerbations, control of cough and wheeze symptoms, symptom-free days, overall direct costs of asthma management in Danish kroner at 1999 prices, and mean and incremental cost-effectiveness ratios.FP, 200 microg/d, was significantly more effective than placebo treatment in terms of the proportion of exacerbation-free patients (73.7% vs 59.8 p = 0.025) and patients experiencing a > or = 25% improvement in cough symptoms (57.9% vs 39.0 p = 0.018). The costs per exacerbation-free patient, per patient with a > or = 25% improvement in cough and wheeze symptoms from baseline, and per symptom-free day were lower in the FP groups than in the placebo group. The incremental cost-effectiveness ratios for these end points indicated that the additional benefits of FP, 200 microg/d, were achieved at a lower overall cost compared with placebo treatment.From the perspective of the Danish health-care system, FP, 100 microg bid, administered via the Babyhaler inhalation device was cost-effective relative to standard therapy with bronchodilators alone.
BibTeX:
@article{,
  author = {Bisgaard, H. and Price, M. J. and Maden, C. and Olsen, N. A.},
  title = {Cost-effectiveness of fluticasone propionate administered via metered-dose inhaler plus babyhaler spacer in the treatment of asthma in preschool-aged children.},
  journal = {Chest},
  school = {Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. Bisgaard@copsac.dk},
  year = {2001},
  volume = {120},
  number = {6},
  pages = {1835--1842}
}
Bisgaard, H. Bisgaard, H. [Do we follow guidelines for the treatment of asthma in children?]. 2000 Ugeskr Laeger 11107939 0 0
Authors: Bisgaard, H.
BibTeX:
@article{,
  author = {Bisgaard, H.},
  title = {[Do we follow guidelines for the treatment of asthma in children?].},
  journal = {Ugeskr Laeger},
  year = {2000},
  volume = {162},
  number = {45},
  pages = {6051}
}
Bisgaard, H. Bisgaard, H. Role of leukotrienes in asthma pathophysiology. 2000 Pediatr Pulmonol 10922142 2,758 36
Authors: Bisgaard, H.
Abstract: Inflammation is an essential component of asthma pathophysiology. While beta(2)-agonists are often used for short-term relief of acute bronchospasm, anti-inflammatory agents are required for the long-term management of chronic inflammation in this disease. Corticosteroids have emerged as the first-line anti-inflammatory therapy for asthma management. However, in some patients, especially children, the high doses of corticosteroids that may be required to control features of hyperresponsiveness, including exercise-induced asthma, raise safety concerns. Thus, there is a need for complementary anti-inflammatory, steroid-sparing agents in asthma therapy. Several inflammatory mediators have been targeted in an attempt to thwart this inflammatory process, but so far with little success. The cysteinyl leukotrienes (CysLT), LTC(4), LTD(4), and LTE(4), have been shown to be essential mediators in asthma, making them obvious targets for therapy. These cysteinyl leukotrienes, previously known as the slow-reacting substance of anaphylaxis (SRS-A), mediate many of the features of asthma, including bronchial constriction, bronchial hyperreactivity, edema, and eosinophilia. Data show that selective cysteinyl leukotriene receptor antagonists (CysLTRAs) effectively reverse these pathologic changes. Corticosteroids do not inhibit the production of CysLTs in vivo, suggesting that CysLTRAs and corticosteroids affect different targets. The bronchodilator properties of CysLTRAs seem to be additive to those of beta(2)-agonists and corticosteroids. These data suggest that CysLTs are important therapeutic targets in the management of inflammation in asthma.
BibTeX:
@article{,
  author = {Bisgaard, H.},
  title = {Role of leukotrienes in asthma pathophysiology.},
  journal = {Pediatr Pulmonol},
  school = {Department of Pediatrics, National University Hospital, Rigshospitalet, Copenhagen, Denmark. Bisgaard@RH.DK},
  year = {2000},
  volume = {30},
  number = {2},
  pages = {166--176}
}
Bisgaard, H. Bisgaard, H. Long-acting beta(2)-agonists in management of childhood asthma: A critical review of the literature. 2000 Pediatr Pulmonol 10686044 2,758 95
Authors: Bisgaard, H.
Abstract: This review assesses the evidence regarding the use of long-acting beta(2)-agonists in the management of pediatric asthma. Thirty double-blind, randomized, controlled trials on the effects of formoterol and salmeterol on lung function in asthmatic children were identified. Single doses of inhaled salmeterol or formoterol cause prolonged bronchodilatation (>12 h) and extended bronchoprotection against exercise-induced bronchoconstriction in children, some children achieving full protection for more than 12 h. Heterogeneity in bronchoprotection has been observed, and individual dose-titration may be attempted. The onset of action of formoterol is comparable to salbutamol, while salmeterol has a slower onset of action. Partial tolerance develops when long-acting beta(2)-agonists are used as regular treatment, including cross-tolerance to short-acting beta(2)-agonists. Regular treatment with salmeterol in children with or without corticosteroids provides statistically significant bronchodilatation, but the degree of improvement in lung function or bronchoprotection against exercise and nonspecific irritants is small with regular use. There is no evidence of anti-inflammatory effects from inhaled long-acting beta(2)-agonists, which is reflected by unchanged or increased bronchial hyperreactivity and no reduction of exacerbation rates. The evidence does not support a recommendation for long-acting beta(2)-agonists as monotherapy, nor does it support their general use as regular add-on therapy. In conclusion, long-acting beta(2)-agonists provide effective bronchodilatation and bronchoprotection when used as intermittent, single-dose treatment of asthma in children, but not when used as regular treatment. Future studies should examine the positioning of long-acting beta(2)-agonists as an "as needed" rescue medication instead of short-acting beta(2)-agonists for pediatric asthma management.
BibTeX:
@article{,
  author = {Bisgaard, H.},
  title = {Long-acting beta(2)-agonists in management of childhood asthma: A critical review of the literature.},
  journal = {Pediatr Pulmonol},
  school = {Department of Pediatrics, National University Hospital, Rigshospitalet, Copenhagen, Denmark. Bisgaard@rh.dk},
  year = {2000},
  volume = {29},
  number = {3},
  pages = {221--234}
}
Nielsen, K.G. Bisgaard, H. The effect of inhaled budesonide on symptoms, lung function, and cold air and methacholine responsiveness in 2- to 5-year-old asthmatic children. 2000 Am J Respir Crit Care Med 11029368 13,204 105
Authors: Nielsen, K.G. and Bisgaard, H.
Abstract: We hypothesized that measurement of lung function (LF) and bronchial hyperresponsiveness (BHR) could serve as supplemental tools in evaluating the efficacy of treatment with inhaled corticosteroids in asthmatic children aged 2 to 5 yr. We studied 38 children (mean age: 53 mo; range: 35 to 71 mo) with moderately severe asthma in a single-center, randomized, double-blind, parallel-group, placebo-controlled study involving 8 wk of treatment. Budesonide (BUD) 400 microgram twice daily was administered via a pressurized metered-dose inhaler and metal spacer device. Symptom scores (SSc) and use of short-acting beta(2)-agonist were monitored with diary cards. LF in awake children was measured as the specific airway resistance (sRaw), using whole-body plethysmography; as resistance by the interrupter technique (Rint); and as resistance and reactance at 5 Hz (Rrs5, Xrs5) by the impulse oscillation technique. Cold air challenge (CACh) and methacholine challenge (MCh) were used to assess BHR. Children in the BUD group experienced significantly fewer night- and daytime symptoms (p < 0.05) and more symptom-free days (p < 0.05), but not nights (p = 0.07), than children in the placebo group. Daytime (p < 0.05) but not nighttime (p = 0.09) use of rescue medication and asthma exacerbation rates (3.7 versus 9.3 exacerbations/yr) (p = 0.006) were both in favor of BUD. LF measured with the Rint technique, Rrs5, and Xrs5 were significantly improved by BUD. BHR as measured by CACh improved significantly with BUD, whereas no improvement was found on MCh. In conclusion, inhaled BUD at a total dose of 800 microgram daily significantly improved SSc, asthma exacerbation rates, lung function, and BHR as assessed by CACh in asthmatic children aged 2 to 5 yr.
BibTeX:
@article{,
  author = {Nielsen, K. G. and Bisgaard, H.},
  title = {The effect of inhaled budesonide on symptoms, lung function, and cold air and methacholine responsiveness in 2- to 5-year-old asthmatic children.},
  journal = {Am J Respir Crit Care Med},
  school = {Department of Pediatrics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.},
  year = {2000},
  volume = {162},
  number = {4 Pt 1},
  pages = {1500--1506},
  url = {http://dx.doi.org/10.1164/ajrccm.162.4.2002019},
  doi = {https://doi.org/10.1164/ajrccm.162.4.2002019}
}
Nielsen, K.G. Bisgaard, H. Lung function response to cold air challenge in asthmatic and healthy children of 2-5 years of age. 2000 Am J Respir Crit Care Med 10852748 13,204 74
Authors: Nielsen, K.G. and Bisgaard, H.
Abstract: The aim of the study was to assess feasibility, sensitivity, specificity, predictive value, and repeatability of cold, dry air challenge (CACh) as a diagnostic test for asthma in young children 2 to 5 yr of age. Response to a 4-min single-step isocapnic CACh was measured in 38 asthmatics and 29 control subjects. Specific airway resistance (sRaw) by whole body plethysmography was the primary outcome. In addition, lung function was measured as respiratory resistance by the interrupter technique (Rint) and respiratory resistance and reactance at 5 Hz (Rrs5, Xrs5) by the impulse oscillation technique. At baseline, lung function measures differed significantly between asthmatics and healthy control subjects. CACh was readily performed in young children. Response was expressed as change from baseline in numbers of within-subject standard deviation (SDw). Hyperresponsiveness defined as change in lung function of more than 3 SDw was detected by sRaw in 26 of 38 asthmatics versus 2 of 29 control subjects, by Rint in 12 of 38 asthmatics versus 1 of 29 control subjects, by Xrs5 in 9 of 38 asthmatics versus zero of 29 control subjects and by Rrs5 in 7 of 38 asthmatics versus 1 of 29 control subjects. Thus sRaw had the highest sensitivity (68. Specificity ranged from 93 to 100%. The correlation coefficient between sRaw responses to CACh repeated within 8 wk was 96%. In conclusion, CACh is feasible in young children age 2 to 5 yr. Whole body plethysmography (sRaw) was superior in separating asthmatics from healthy control subjects. Change in sRaw in response to CACh may be used as a diagnostic test for asthma in young children.
BibTeX:
@article{,
  author = {Nielsen, K. G. and Bisgaard, H.},
  title = {Lung function response to cold air challenge in asthmatic and healthy children of 2-5 years of age.},
  journal = {Am J Respir Crit Care Med},
  school = {Department of Pediatrics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.},
  year = {2000},
  volume = {161},
  number = {6},
  pages = {1805--1809},
  url = {http://dx.doi.org/10.1164/ajrccm.161.6.9905098},
  doi = {https://doi.org/10.1164/ajrccm.161.6.9905098}
}
Mygind, N. Bisgaard, H. Leukotrienes, leukotriene receptor antagonists, and rhinitis. 2000 Allergy 10843421 7,361 14
Authors: Mygind, N., Dahl, R. and Bisgaard, H.
BibTeX:
@article{,
  author = {Mygind, N. and Dahl, R. and Bisgaard, H.},
  title = {Leukotrienes, leukotriene receptor antagonists, and rhinitis.},
  journal = {Allergy},
  school = {Department of Respiratory Diseases, Aarhus University Hospital, Denmark.},
  year = {2000},
  volume = {55},
  number = {5},
  pages = {421--424}
}
Klug, B. Bisgaard, H. Observer variability of lung function measurements in 2-6-yr-old children. 2000 Eur Respir J 11028662 10,569 28
Authors: Klug, B., Nielsen, K.G. and Bisgaard, H.
Abstract: The aim of this study was to assess the within-observer and between-observer variability of lung function measurements in children aged 2-6 yrs. Two observers examined 22 asthmatic children independently according to a predefined protocol. Each observer obtained duplicate measurements of respiratory resistance by the interrupter technique (Rint), respiratory resistance (Rrs,5) and reactance (Xrs,5) at 5 Hz by the impulse oscillation technique and the specific airway resistance (sRaw) by whole body plethysmography. The within-subject SD (SDw) was not significantly different in the two observers. The ratio SDw between observers/mean SDw within observers was 0.94, 1.25, 1.35 and 2.86 for Xrs,5, Rrs,5, sRaw and Rint, respectively, indicating greater between-observer variability of the latter. The systematic difference between observers assessed by the difference between observer means (expressed as a percentage of their mean value) was 11, 7, 6 and 2% for Xrs,5, sRaw, Rrs,5 and Rint, respectively. These differences were statistically significant, except that for Rint. In conclusion, specific airway resistance, impulse oscillation technique and respiratory resistance assessed by the interrupter technique measurements in young children are subject to influence by the observer, and the random variability between observers appears to be particularly great for respiratory resistance assessed by the interrupter technique. The authors suggest that the between-observer variability should be investigated when evaluating novel methods for testing lung function.
BibTeX:
@article{,
  author = {Klug, B. and Nielsen, K. G. and Bisgaard, H.},
  title = {Observer variability of lung function measurements in 2-6-yr-old children.},
  journal = {Eur Respir J},
  school = {Dept of Paediatrics 5003, National Uninversity Hospital, Rigshospitalet, Copenhagen, Denmark.},
  year = {2000},
  volume = {16},
  number = {3},
  pages = {472--475}
}
Bisgaard, H. Nielsen, K.G. Bronchoprotection with a leukotriene receptor antagonist in asthmatic preschool children. 2000 Am J Respir Crit Care Med 10903240 13,204 80
Authors: Bisgaard, H. and Nielsen, K.G.
Abstract: We hypothesized that a leukotriene receptor antagonist (LTRA) could provide bronchoprotection against the cold, dry air-induced response in asthmatic preschool children. In a randomized, double-blind, placebo-controlled crossover study, we examined the effect of the specific LTRA montelukast at 5 mg/d for 2 d on the bronchoconstriction induced by hyperventilation of cold, dry air in 13 asthmatic children 3 to 5 yr old. The bronchoconstriction was measured as the specific airway resistance (sRaw) in a whole-body plethysmograph before and 4 min after challenge with cold, dry air. The repeatability of the bronchoprotection was examined by repeating the placebo-controlled study in six of the 13 children. sRaw increased by an average of 46% (95% confidence interval [CI]: 30 to 63 after placebo treatment and 17% (95% CI: 3 to 31 after montelukast (p < 0.01). Eight of the children were receiving regular treatment with budesonide delivered by an inhaler with a spacer in a mean daily dose of 350 microg, but the bronchoprotection provided by montelukast was independent of concurrent steroid treatment. There was no convincing evidence of failure to respond, and the protective effect of montelukast was consistent upon repeated testing (p = 0. 02). We conclude that the LTRA montelukast provided clinically significant bronchoprotection against the effect of hyperventilation of cold dry air in asthmatic children 3 to 5 yr old. The bronchoprotection appeared to be homogeneous among the children, and seemed independent of steroid treatment. This suggests that LTRAs may be of therapeutic use in limiting clinical symptoms of asthma in young children.
BibTeX:
@article{,
  author = {Bisgaard, H. and Nielsen, K. G.},
  title = {Bronchoprotection with a leukotriene receptor antagonist in asthmatic preschool children.},
  journal = {Am J Respir Crit Care Med},
  school = {Department of Pediatrics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. Bisgaard@RH.DK},
  year = {2000},
  volume = {162},
  number = {1},
  pages = {187--190},
  url = {http://dx.doi.org/10.1164/ajrccm.162.1.9910039},
  doi = {https://doi.org/10.1164/ajrccm.162.1.9910039}
}
Bjermer, L. Leff, J.A. Montelukast or salmeterol combined with an inhaled steroid in adult asthma: design and rationale of a randomized, double-blind comparative study (the IMPACT Investigation of Montelukast as a Partner Agent for Complementary Therapy-trial). 2000 Respir Med 10921768 3,217 27
Authors: Bjermer, L., Bisgaard, H., Bousquet, J., Fabbri, L.M., Greening, A., Haahtela, T., Holgate, S.T., Picado, C. and Leff, J.A.
Abstract: Asthma patients who continue to experience symptoms despite taking regular inhaled corticosteroids represent a management challenge. Leukotrienes play a key role in asthma pathophysiology, and since pro-inflammatory leukotrienes are poorly suppressed by corticosteroids it seems rational to add a leukotriene receptor antagonist (LTRA) when a low to moderate dose of inhaled corticosteroids does not provide sufficient disease control. Long acting beta2-agonist (LABA) treatment represents an alternative to LTRAs and both treatment modalities have been shown to provide additional disease control when added to corticosteroid treatment. To compare the relative clinical benefits of adding either a LTRA or a LABA to asthma patients inadequately controlled by inhaled corticosteroids, a randomized, double-blind, multi-centre, 48-week study will be initiated at approximately 120 centres throughout Europe, Latin America, Middle East, Africa and the Asia-Pacific region in early 2000. The study will compare the oral LTRA montelukast with the inhaled LABA salmeterol, each administered on a background of inhaled fluticasone, on asthma attacks, quality of life, lung function, eosinophil levels, healthcare utilization, and safety, in approximately 1200 adult asthmatic patients. The requirements for study enrollment include a history of asthma, FEV1 or PEFR values between 50% and 90% of the predicted value together with > or = 12% improvement in FEV1 after beta-agonist administration, a minimum pre-determined level of asthma symptoms and daily beta-agonist medication. The study will include a 4-week run-in period, during which patients previously taking inhaled corticosteroids are switched to open-label fluticasone (200 microg daily), followed by a 48-week double-blind, treatment period in which patients continuing to experience abnormal pulmonary function and daytime symptoms are randomized to receive montelukast (10 mg once daily) and salmeterol placebo, or inhaled salmeterol (100 microg daily) and montelukast placebo. All patients will continue with inhaled fluticasone (200 microg daily). During the study, asthma attacks, overnight asthma symptoms, and morning peak expiratory flow rate will be assessed using patient diary cards; quality of life will also be assessed using an asthma-specific quality-of life questionnaire. The results of this study are expected to provide physicians with important clinical evidence to help them make a rational and logical treatment choice for asthmatic patients experiencing breakthrough symptoms on inhaled corticosteroids.
BibTeX:
@article{,
  author = {Bjermer, L. and Bisgaard, H. and Bousquet, J. and Fabbri, L. M. and Greening, A. and Haahtela, T. and Holgate, S. T. and Picado, C. and Leff, J. A.},
  title = {Montelukast or salmeterol combined with an inhaled steroid in adult asthma: design and rationale of a randomized, double-blind comparative study (the IMPACT Investigation of Montelukast as a Partner Agent for Complementary Therapy-trial).},
  journal = {Respir Med},
  school = {Department of Lung Medicine, University Hospital, Trondheim, Norway. Leif.Bjermer@medisin.ntnu.no},
  year = {2000},
  volume = {94},
  number = {6},
  pages = {612--621},
  url = {http://dx.doi.org/10.1053/rmed.2000.0806},
  doi = {https://doi.org/10.1053/rmed.2000.0806}
}
Bisgaard, H. Bisgaard, H. Towards improved aerosol devices for the young child. 1999 Pediatr Pulmonol Suppl 10093104 2,758 1
Authors: Bisgaard, H.
BibTeX:
@article{,
  author = {Bisgaard, H.},
  title = {Towards improved aerosol devices for the young child.},
  journal = {Pediatr Pulmonol Suppl},
  school = {Dept Paediatrics, University Hospital, Rigshospitalet, Copenhagen, Denmark. Bisgaard@RH.DK},
  year = {1999},
  volume = {18},
  pages = {78}
}
Bisgaard, H. Bisgaard, H. Future options for aerosol delivery to children. 1999 Allergy 10422756 7,361 13
Authors: Bisgaard, H.
Abstract: There is an increasing awareness of the importance of reliable aerosol delivery, with emphasis on the dose delivered to the lungs, optimal clinical control, cost-effectiveness, and safety in children. Dose prescription should relate to the expected lung dose rather than the factory-dispensed dose, as at present. The device determines the lung dose. Clearly, therefore, the device should be considered an integral part of the prescription. Drug approval processes should clearly specify the device, and discourage the use of other devices. This would rationalize the choice of devices. Important new insights into factors essential for drug delivery to the airways have been acquired in recent years. Nasal inhalation increases systemic bioavailability, reduces lung dose, and adds to its variability; hence, face masks to prevent nasal breathing have been developed. Similarly, dead space in the inspiratory line causes a proportional reduction in lung dose; hence, attention should be paid to reducing such dead space. Plastics in spacers cause a rapid loss of drug due to electrostatic attraction of the aerosol. The residence time of the aerosol, i.e., the time available for inhalation, is increased in nonelectrostatic spacers, allowing less compliant children enough time to obtain a full dose. Eliminating the electrostatic charge can change the lung dose by several times; hence, nonelectrostatic materials should be used in future spacer devices. Compliance is the biggest problem in drug delivery to children. The inhaler design process should be reversed, adapting technology to the child. Interactive microchip technology should provide intelligent devices that react to correct handling and breathing maneuvers. An intelligent nebulizer has been developed that adapts nebulization to the child's breathing pattern, nebulizing only during inhalation and avoiding loss of aerosol during exhalation. An automatic device (AirPac) has been developed that transforms a dry-powder inhaler, Turbuhaler, into a spacer. In addition to the general advantages of spacer treatment, this device offers the advantage of a drug aerosol delivered without use of propellants or additives. The mechanical actuation ensures highly repeatable drug delivery. Finally, a nonelectrostatic, tower-shaped spacer provides a stable aerosol, which remains airborne for a prolonged period. The spacer is equipped with a face mask that prevents nasal breathing. Such features should improve our ability to treat young children with inhaled drug aerosols.
BibTeX:
@article{,
  author = {Bisgaard, H.},
  title = {Future options for aerosol delivery to children.},
  journal = {Allergy},
  school = {Department of Paediatrics, National University Hospital, Copenhagen, Denmark. Bisgaard@RH.DK},
  year = {1999},
  volume = {54 Suppl 49},
  pages = {97--103}
}
Zak, M. Bisgaard, H. A mathematical model of aerosol holding chambers. 1999 J Aerosol Med 10623335 0 14
Authors: Zak, M., Madsen, J., Berg, E., Bülow, J. and Bisgaard, H.
Abstract: A mathematical model of aerosol delivery from holding chambers (spacers) was developed incorporating tidal volume (VT), chamber volume (Vch), apparatus dead space (VD), effect of valve insufficiency and other leaks, loss of aerosol by immediate impact on the chamber wall, and fallout of aerosol in the chamber with time. Four different spacers were connected via filters to a mechanical lung model, and aerosol delivery during "breathing" was determined from drug recovery from the filters. The formula correctly predicted the delivery of budesonide aerosol from the AeroChamber (Trudell Medical, London, Ontario, Canada), NebuChamber (Astra, Södirtälje, Sweden) and Nebuhaler (Astra) adapted for babies. The dose of fluticasone proportionate delivered by the Babyhaler (Glaxco Wellcome, Oxbridge, Middlesex, UK) was 80% of that predicted, probably because of incomplete priming of this spacer. Of the above-mentioned factors, initial loss of aerosol by impact on the chamber wall is most important for the efficiency of a spacer. With a VT of 195 mL, the AeroChamber and Babyhaler were emptied in two breaths, the NebuChamber in four breaths, and the Nebuhaler in six breaths. Insufficiencies of the expiratory valves were demonstrated by comparison of pressure flow curves during "inspiratory" flow with and without occluded expiratory openings. Insufficient inspiratory valves were demonstrated by comparison of "expiratory" pressure flow curves with and without occluded inspiratory openings. With children breathing through the spacers, mask pressure variations were generally on the same order as that seen with the mechanical respiratory, supporting the clinical relevance of the in vitro findings.
BibTeX:
@article{,
  author = {Zak, M. and Madsen, J. and Berg, E. and Bülow, J. and Bisgaard, H.},
  title = {A mathematical model of aerosol holding chambers.},
  journal = {J Aerosol Med},
  school = {Department of Pediatrics, Rigshospitalet, Copenhagen, Denmark.},
  year = {1999},
  volume = {12},
  number = {3},
  pages = {187--196},
  url = {http://dx.doi.org/10.1089/jam.1999.12.187},
  doi = {https://doi.org/10.1089/jam.1999.12.187}
}
Nikander, K. Bisgaard, H. Impact of constant and breath-synchronized nebulization on inhaled mass of nebulized budesonide in infants and children. 1999 Pediatr Pulmonol 10495335 2,758 16
Authors: Nikander, K. and Bisgaard, H.
Abstract: The aim of the present study was to compare the output of a breath-synchronized jet nebulizer to a conventional constant output nebulizer over a fixed period of time in terms of inhaled mass of budesonide, i.e., the amount of budesonide deposited on a filter interposed between the nebulizer and the face mask. One hundred and sixty-five asthmatic children (103 boys) were enrolled in this open, randomized, crossover trial. Their age ranged from 6 months to 7.9 years, height from 69 to 132 cm, and weight from 8.2 to 31.3 kg. Their duration of asthma ranged from less than 1 to 7 years. Budesonide suspension, 0.5 mg mL-1, 2 mL, was used. With 5 min of constant output nebulization, the mean inhaled mass of budesonide in percent of the nominal dose was 11.4% in the youngest children and 14.9% in the 7-year-old children. Expressed in percent of the total output of budesonide, i.e., the amount that left the nebulizer as an aerosol, the inhaled mass ranged from 34.6-48.6%. Thus, 51.4-65.4% of the total output was deposited on the expiratory filter. With 5 min of breath-synchronized nebulization, the mean inhaled mass ranged from 10.5-14.9% of the nominal dose. For the youngest patients less than 3-4 years of age, it was approximately 80-90% of the total output. For the older patients the inhaled mass was approximately 95% of the total output, i.e., only small amounts of budesonide were deposited on the expiratory filter. For both modes of nebulization the between-subject variation in inhaled mass was large: up to 6-fold in the young children and 3-4-fold in the older ones. The results of the present study showed that the inhaled mass of budesonide was significantly age-dependent with both modes of nebulization, i.e., the inhaled mass was less in younger children. Breath-synchronized nebulization resulted in reduced waste of drug during expiration.
BibTeX:
@article{,
  author = {Nikander, K. and Bisgaard, H.},
  title = {Impact of constant and breath-synchronized nebulization on inhaled mass of nebulized budesonide in infants and children.},
  journal = {Pediatr Pulmonol},
  school = {D, Lund, Sweden. kurt.nikander@draco.se.astra.com},
  year = {1999},
  volume = {28},
  number = {3},
  pages = {187--193}
}
Mygind, N. Dahl, R. Simultaneous treatment of rhinitis and asthma by nasal inhalation of corticosteroid from a spacer. 1999 Allergy 10565489 7,361 4
Authors: Mygind, N., Bisgaard, H. and Dahl, R.
BibTeX:
@article{,
  author = {Mygind, N. and Bisgaard, H. and Dahl, R.},
  title = {Simultaneous treatment of rhinitis and asthma by nasal inhalation of corticosteroid from a spacer.},
  journal = {Allergy},
  school = {Department of Respiratory Diseases, Aarhus University Hospital, Denmark.},
  year = {1999},
  volume = {54 Suppl 57},
  pages = {132--135}
}
Klug, B. Bisgaard, H. Lung function and short-term outcome in young asthmatic children. 1999 Eur Respir J 10596711 10,569 23
Authors: Klug, B. and Bisgaard, H.
Abstract: The aims of this study were to investigate lung function in 2-5-yr-old stable asthmatic children consecutively referred from general practitioners and to analyse the outcome on the basis of their requirement for antiasthmatic treatment and symptoms after 1.6-4.5 yrs. Lung function was measured in 110 children with a mean+/-SD age of 3.8+/-1.0 yrs using the interruptor technique (resistance assessed using the interruptor technique (Rint)), whole body plethysmography (specific airway resistance (sRaw) and respiratory resistance (Rrs,5)and reactance at 5 Hz (Xrs,5) using the impulse oscillation technique. Rint, sRaw, Xrs,5 and Rrs,5 were suggestive of impaired lung function in 44 14 11% and 7.5% of the children, respectively, with a predominance of children aged 2-3 yrs. Sixty-five per cent were treated with inhaled steroids, and 35% were treated only with beta2-agonists as needed; lung function was not significantly different between these two groups. Outcome after 2.9+/-0.7 yrs was not significantly different between children with Rint measurements above and those children with Rint measurements within the reference range at enrolment. Of these children, 58 and 59% were currently on antiasthmatic treatment, and 40% and 49% had current symptoms, respectively. Impairment of lung function may be a common finding in stable young asthmatic children, but apparently this is not a risk factor for persistence of asthmatic symptoms.
BibTeX:
@article{,
  author = {Klug, B. and Bisgaard, H.},
  title = {Lung function and short-term outcome in young asthmatic children.},
  journal = {Eur Respir J},
  school = {Dept of Pediatrics 5003, National University Hospital, Rigshospitalet, Copenhagen, Denmark.},
  year = {1999},
  volume = {14},
  number = {5},
  pages = {1185--1189}
}
Bisgaard, H. Møller, H. Changes in risk of hospital readmission among asthmatic children in Denmark, 1978-93. 1999 BMJ 10417085 20,785 21
Authors: Bisgaard, H. and Møller, H.
BibTeX:
@article{,
  author = {Bisgaard, H. and Møller, H.},
  title = {Changes in risk of hospital readmission among asthmatic children in Denmark, 1978-93.},
  journal = {BMJ},
  school = {Department of Paediatrics, Rigshospitalet, National University Hospital, DK-2100 Copenhagen, Denmark. Bisgaard@RH.DK},
  year = {1999},
  volume = {319},
  number = {7204},
  pages = {229--230}
}
Bisgaard, H. Oj, J.A. NO in exhaled air of asthmatic children is reduced by the leukotriene receptor antagonist montelukast. 1999 Am J Respir Crit Care Med 10508811 13,204 167
Authors: Bisgaard, H., Loland, L. and Oj, J.A.
Abstract: Nitric oxide in exhaled air (FENO) is increased in asthmatic children, probably reflecting aspects of airway inflammation. We have studied the effect of the leukotriene receptor antagonist (LTRA) montelukast on FENO with a view to elucidate potential anti-inflammatory properties of LTRAs. Twenty-six asthmatic children 6 to 15 yr of age completed a double-blind crossover trial of 2 wk of treatment with 5 mg montelukast once daily versus placebo. FENO was measured during single-breath exhalation at a constant flow rate of 0.1 to 0.13 L/s against a resistance of 10 kPa/L/s. Eleven children were receiving maintenance treatment with inhaled steroids during the study (mean daily dose, 273 microgram), whereas the other 15 used only inhaled beta(2)-agonists as required. The within-subject coefficient of variation of FENO over a 2-wk interval for the 26 children was 38%. FENO was significantly reduced by 20% after the 2-wk treatment with montelukast as compared with placebo as well as compared with baseline. This effect occurred rapidly with a 15% fall in FENO within 2 d. The effect of montelukast on FENO was independent of concurrent steroid treatment. The effect on FENO is probably not caused by bronchodilatation since FENO increased significantly after inhalation of terbutaline. In conclusion, FENO in asthmatic children was significantly decreased from montelukast, which corroborates anti- inflammatory properties of LTRA.
BibTeX:
@article{,
  author = {Bisgaard, H. and Loland, L. and Oj, J. A.},
  title = {NO in exhaled air of asthmatic children is reduced by the leukotriene receptor antagonist montelukast.},
  journal = {Am J Respir Crit Care Med},
  school = {Department of Paediatrics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Bisgaard@RH.DK},
  year = {1999},
  volume = {160},
  number = {4},
  pages = {1227--1231},
  url = {http://dx.doi.org/10.1164/ajrccm.160.4.9903004},
  doi = {https://doi.org/10.1164/ajrccm.160.4.9903004}
}
Bisgaard, H. Maden, C. The effect of inhaled fluticasone propionate in the treatment of young asthmatic children: a dose comparison study. 1999 Am J Respir Crit Care Med 10390389 13,204 134
Authors: Bisgaard, H., Gillies, J., Groenewald, M. and Maden, C.
Abstract: The response in asthmatic young children to inhaled steroids within the usual pediatric dose range is unknown. We therefore evaluated the dose-related response in young children with moderate asthma to inhaled fluticasone propionate (FP) (delivered via the Babyhaler spacer device) within the pediatric dose range. A total of 237 children (mean age 28 mo, range 12 to 47) with moderate asthmatic symptoms were studied in this multicenter, randomized, double-blind, parallel group, placebo-controlled study of 12 wk treatment following a 4-wk run-in period. The median use of rescue medication was 1 dose in 2 d during the run-in period. FP 50 micrograms twice daily (FP100) and 100 micrograms twice daily (FP200) was compared with placebo inhaled from a pressurized metered-dose inhaler (pMDI) and the Babyhaler spacer device. With FP200 there was a statistically significant improvement from baseline, as compared with the placebo group, in 8 of 10 diary card parameters, including the three symptom domains of wheeze, cough, and breathlessness, and use of rescue medication. FP100 produced a significant reduction in 5 of these 10 parameters, whereas no significant differences were found between the FP200 and FP100. The numbers of patients with at least one exacerbation during treatment with placebo, FP100, and FP200 were 37 26 and 20 respectively. This difference between placebo and FP200, as well as the dose-related order was significant (p < 0.05). Both FP doses were as well tolerated as placebo over the 12 wk treatment with a similar incidence of adverse effects. Asthmatic symptoms in 1- to 3-yr-old children responded in a significant and dose-related manner to treatment with FP within a pediatric dose range.
BibTeX:
@article{,
  author = {Bisgaard, H. and Gillies, J. and Groenewald, M. and Maden, C.},
  title = {The effect of inhaled fluticasone propionate in the treatment of young asthmatic children: a dose comparison study.},
  journal = {Am J Respir Crit Care Med},
  school = {Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. Bisgaard@RH.DK},
  year = {1999},
  volume = {160},
  number = {1},
  pages = {126--131},
  url = {http://dx.doi.org/10.1164/ajrccm.160.1.9811024},
  doi = {https://doi.org/10.1164/ajrccm.160.1.9811024}
}
Anhøj, J. Lipworth, B.J. Effect of electrostatic charge in plastic spacers on the lung delivery of HFA-salbutamol in children. 1999 Br J Clin Pharmacol 10215759 3,493 32
Authors: Anhøj, J., Bisgaard, H. and Lipworth, B.J.
Abstract: The effect of the electrostatic charge in plastic spacers in vivo on drug delivery to the lung of hydrofluoroalkane (HFA) salbutamol spray was studied in children.Five children, aged 7-12 years, were included in a 3-way crossover randomised single-blind trial. Salbutamol HFA spray was delivered on 3 different study days from plastic spacers with mouthpiece. Pre-treatment of the spacers differed between study days: (a) Non-electrostatic 350 ml Babyhaler (coated with benzalkonium chloride) (b) New 350 ml Babyhaler (rinsed in water), and (c) New 145 ml AeroChamber (rinsed in water). Plasma salbutamol was measured before and 5, 10, 15 and 20 min after inhalation of four single puffs of 100 microg salbutamol. Cmax and Cav (5-20min) were calculated as a reflection of lung dose.For Cmax: (A) Non-electrostatic Babyhaler 4.3 ng ml(-1) (B) New Babyhaler 1.9 ng ml(-1) (C) New AeroChamber 1.6 ng ml(-1): AvsB (95% CI for difference 0.5-4.5 ng ml(-1)), A vs C (95% CI for difference 0.7-4.8 ng ml(-1)). The geometric mean ratio for A:B was 2.4 fold, and for A:C was 2.9 fold. The values for Cav were similar with ratios for A:B of 2.4 fold, and A: C of 4.1 fold. The nonelectrostatic Babyhaler delivered a significantly (P<0.05) higher lung dose (for both Cmax and Cav) than either of the other two spacers.The electrostatic charge in plastic spacers reduces lung dose in children by more than two-fold. This is clinically significant and the use of potentially electrostatically charged spacers should be avoided.
BibTeX:
@article{,
  author = {Anhøj, J. and Bisgaard, H. and Lipworth, B. J.},
  title = {Effect of electrostatic charge in plastic spacers on the lung delivery of HFA-salbutamol in children.},
  journal = {Br J Clin Pharmacol},
  school = {Department of Paediatrics, National University Hospital, Copenhagen, Denmark.},
  year = {1999},
  volume = {47},
  number = {3},
  pages = {333--336}
}
Bisgaard, H. Bisgaard, H. Automatic actuation of a dry powder inhaler into a nonelectrostatic spacer. 1998 Am J Respir Crit Care Med 9476867 13,204 29
Authors: Bisgaard, H.
Abstract: This article describes a new "automatic spacer" device, which has been developed to improve the delivery of inhaled medication to young children. In the device, a dry powder inhaler (DPI) is mechanically actuated into a nonelectrostatic spacer, producing an aerosol cloud of fine drug particles (aerodynamic diameter, < 4.7 microm) with a long half-life. The new device combines the principal advantages of the conventional spacer and the DPI. It has the potential to provide a high ratio between lung dose and pharyngeal dose, without need for coordination or forced inhalation, and it avoids exposure of the patient to the additives and propellants used in pressurized metered dose inhalers. Studies with the prototype device show a high yield of fine drug particles in the aerosol (mass median aerodynamic diameter, 2.8 microm), a high repeatability of drug delivery owing to the mechanical nature of the actuation (relative standard deviation, 12, and a prolonged residence time of the fine particle aerosol (half-life of the fallout of the fine particles, 82 s). These features should prove advantageous in the treatment of young children with inhaled medication.
BibTeX:
@article{,
  author = {Bisgaard, H.},
  title = {Automatic actuation of a dry powder inhaler into a nonelectrostatic spacer.},
  journal = {Am J Respir Crit Care Med},
  school = {Pulmonary Service, Department of Pediatrics, Rigshospitalet, National University Hospital, Copenhagen, Denmark. Bisgaard@RH.DK},
  year = {1998},
  volume = {157},
  number = {2},
  pages = {518--521},
  url = {http://dx.doi.org/10.1164/ajrccm.157.2.9705025},
  doi = {https://doi.org/10.1164/ajrccm.157.2.9705025}
}
Berg, E. Bisgaard, H. In vitro performance of three combinations of spacers and pressurized metered dose inhalers for treatment in children. 1998 Eur Respir J 9727804 10,569 41
Authors: Berg, E., Madsen, J. and Bisgaard, H.
Abstract: The performance of pressurized metered dose inhalers (pMDIs) and spacers in correct dose recommendations is important, but limited information on dose delivery and fine-particle dose from different combinations of spacers and pMDIs is available. In this study, three combinations of spacers and pMDIs were investigated: NebuChamber and AeroChamber with budesonide pMDI and Babyhaler with fluticasone propionate pMDI. Doses were withdrawn onto a filter either with a breathing simulator (dose to ventilator) or with constant flow (maximal dose). The fine-particle dose was assessed with a cascade impactor (Andersen Sampler). The effect of repeated use and cleaning of the spacers on the passive fallout of aerosol within the spacers was determined by evacuating the dose on a filter 2, 5, 10 and 30 s after actuating the spray. The drugs were quantified by liquid chromatography. The NebuChamber delivered the highest doses, both maximal dose and dose to ventilator. The recovered doses (means+/-SD) were 55+/-6% and 51+/-2 respectively, of the delivered dose from the pMDI. The corresponding results for the Babyhaler were 41+/-7% and 24+/-4% and for the Aerochamber 27+/-3% and 17+/-3%. The passive fallout of aerosol, determined as half-life (t1/2) was around approximately 30 s for the NebuChamber, 9-15 s for the Babyhaler and approximately 10 s for the AeroChamber. The present study confirms that there are significant differences in dose output from different combinations of pressurized metered dose inhalers and spacers, with the NebuChamber giving the highest dose, both as delivered dose and in droplets <4.7 microm. Interactions with the spacer material, dead space in the inspiratory line and entrainment of air during inhalation due to inefficient valve control could account for these differences.
BibTeX:
@article{,
  author = {Berg, E. and Madsen, J. and Bisgaard, H.},
  title = {In vitro performance of three combinations of spacers and pressurized metered dose inhalers for treatment in children.},
  journal = {Eur Respir J},
  school = {D, Analytical Chemistry, Astra Draco AB, Lund, Sweden.},
  year = {1998},
  volume = {12},
  number = {2},
  pages = {472--476}
}
Pedersen, W. Mygind, N. Nasal inhalation of budesonide from a spacer in children with perennial rhinitis and asthma. 1998 Allergy 9574880 7,361 24
Authors: Pedersen, W., Hjuler, I., Bisgaard, H. and Mygind, N.
Abstract: The standard treatment of allergic rhinitis and asthma consists of topical corticosteroids administered intranasally and inhaled through the mouth. Although this therapy is highly effective, and side-effects are few and mild, it may be possible further to improve the therapeutic index and patient compliance with the treatment. In the present study, we evaluated a nasal inhalation system used for the simultaneous treatment of rhinitis and asthma. In principle, it results in an airway deposition of the corticosteroid similar to that of inhaled allergens. Twenty-four children with perennial rhinitis and asthma inhaled budesonide through the nose from a pressurized aerosol, attached to a spacer device, in a double-blind, placebo-controlled, crossover study. Compared with placebo, budesonide treatment resulted in a significant reduction of nasal symptoms (P<0.01) and of asthma symptoms (P<0.05), and in an increase of nasal peak inspiratory flow (P < 0.001) and of oral peak expiratory flow (P=0.01). There were no differences between budesonide and placebo in local side-effects, such as dry nose, nosebleed, and hoarseness. We conclude that nasal inhalation of a corticosteroid from a spacer offers a simple and effective treatment for both rhinitis and asthma in children, but it is an open question whether the nasal inhalation system can improve the ratio of antirhinitis/antiasthma effects to side-effects.
BibTeX:
@article{,
  author = {Pedersen, W. and Hjuler, I. and Bisgaard, H. and Mygind, N.},
  title = {Nasal inhalation of budesonide from a spacer in children with perennial rhinitis and asthma.},
  journal = {Allergy},
  school = {Department of Paediatrics, Gentofte Hospital, Hellerup, Denmark.},
  year = {1998},
  volume = {53},
  number = {4},
  pages = {383--387}
}
Nielsen, K.G. Bisgaard, H. Clinical effect of Diskus dry-powder inhaler at low and high inspiratory flow-rates in asthmatic children. 1998 Eur Respir J 9551737 10,569 52
Authors: Nielsen, K.G., Auk, I.L., Bojsen, K., Ifversen, M., Klug, B. and Bisgaard, H.
Abstract: In vitro studies with the Diskus inhaler at low and high flow rates show consistent doses of drug as fine particles <4.7 microm. The present study was designed to ascertain whether this in vitro flow independency translates into flow-independent clinical effect when the device is used by patients at low (30 L x min[-1]) and high (90 L x min[-1]) flow rates. A pilot study in 129 children aged 3-10 yrs demonstrated that 99% of children of 3 yrs and above can generate a flow > or = 30 L x min(-1) through the device, while 26% performed > or = 90 L x min(-1). Eighteen children aged 8-15 yrs with exercise induced asthma inhaled placebo or salmeterol 50 microg at either 30 L x min(-1) or 90 L x min(-1). Exercise challenges were carried out 1 h and 12 h after dosing. The maximum percentage fall in forced expiratory volume in one second (FEVI) after exercise 12 h after treatment was significantly less after salmeterol at either flow rates as compared to placebo. There was no significant difference in the protection from salmeterol on the day of low-flow inhalation versus the day of high-flow inhalation. Consistent in vitro fine particle dosing from the Diskus inhaler translates into a consistent clinical effect at low and high flow rates in children.
BibTeX:
@article{,
  author = {Nielsen, K. G. and Auk, I. L. and Bojsen, K. and Ifversen, M. and Klug, B. and Bisgaard, H.},
  title = {Clinical effect of Diskus dry-powder inhaler at low and high inspiratory flow-rates in asthmatic children.},
  journal = {Eur Respir J},
  school = {Dept of Paediatrics, National University Hospital, Copenhagen, Denmark.},
  year = {1998},
  volume = {11},
  number = {2},
  pages = {350--354}
}
Klug, B. Bisgaard, H. Specific airway resistance, interrupter resistance, and respiratory impedance in healthy children aged 2-7 years. 1998 Pediatr Pulmonol 9635934 2,758 143
Authors: Klug, B. and Bisgaard, H.
Abstract: We report data on respiratory function in healthy children aged 2-7 years in whom we measured respiratory resistance by the interrupter technique (Rint); total respiratory impedance (Zrs), respiratory resistance (Rrs), and reactance (Xrs) by the impulse oscillation technique; and specific airway resistance (sRaw) by a modified procedure method in the whole body plethysmograph. Measurements were attempted in 151 children and were successfully obtained in 121 children with a mean (SD) age of 5.3 (1.5) years; no measurements were possible in 30 children (mean age 3 (0.9) years). The repeatability of measurements was independent of the age of the subjects, and the within-subject coefficient of variation was 11.1 8.1 10.8 and 10.2% for sRaw, Rint, Zrs, and Rrs at 5 Hz (Rrs5), respectively. All lung function indices were linearly related to age, height, and weight. A significant negative correlation with age, height, and weight was found for Rint, Zrs, and Rrs5. Xrs5 was positively correlated to age and body size. The mean values of Rint, Rrs5, Xrs5, and Zrs in children younger and older than 5 years were 1.04, 1.38, -0.5, and 1.48 kPa x L(-1) x s and 0.9, 1.18, -0.37, and 1.23 kPa x L(-1) x s, respectively. sRaw showed no significant correlation with body size or age and the mean sRaw in children younger and older than 5 years was 1.09 and 1.13 kPa x s, respectively. None of the indices of respiratory function differed between boys and girls. Xrs and Rrs exhibited a significant frequency dependence in the range of 5-35 Hz. The techniques applied in this study require minimal cooperation and allow measurement of lung function in 80% of our population of awake young children. Further studies are needed to evaluate the potentials of the presently established reference values for clinical and epidemiological purposes.
BibTeX:
@article{,
  author = {Klug, B. and Bisgaard, H.},
  title = {Specific airway resistance, interrupter resistance, and respiratory impedance in healthy children aged 2-7 years.},
  journal = {Pediatr Pulmonol},
  school = {Department of Pediatrics, National University Hospital, Rigshospitalet, Copenhagen, Denmark.},
  year = {1998},
  volume = {25},
  number = {5},
  pages = {322--331}
}
Bisgaard, H. Munch, E. Comparative study of budesonide as a nebulized suspension vs pressurized metered-dose inhaler in adult asthmatics. 1998 Respir Med 9519224 3,217 35
Authors: Bisgaard, H., Nikander, K. and Munch, E.
Abstract: The study objective was to compare the effect of budesonide administered as a nebulized suspension as compared to a spray with a spacer in adult asthmatics. In a double-blind, double-dummy crossover study, 26 adult patients with moderately severe unstable asthma were randomized to three 4-week treatment periods with budesonide 0.8 mg b.i.d. administered by a pressurized metered-dose inhaler (pMDI) with spacer (Nebuhaler) and budesonide 1 mg and 4 mg b.i.d. administered by a Pari Inhalier Boy jet nebulizer. The nebulizer was activated only during inspiration. The total mass output was similar from the two devices but their fraction of small particles differed by a factor of 2 in favour of pMDI. Effect was evaluated from daily home measurements of peak expiratory flow (PEF), need of beta 2-agonist and symptom scores. Plasma cortisol and budesonide levels were measured in a subgroup of 10 patients. A consistent trend showed the nebulizer treatment to be at least as efficient as the pMDI plus spacer treatment. In actual fact, the apparent order of effect was: 4 mg nebulized suspension treatment > or = 1 mg nebulized suspension treatment > or = 0.8 mg pMDI with spacer treatment. Plasma budesonide and plasma cortisol also exhibited dose-related levels independent of device. The adverse effects reported appeared to be related to the dose rather than delivery device. Accordingly, the effect was related to total mass output, rather than to the small particle fraction of the budesonide aerosol. These results attest to the efficiency of jet-nebulized budesonide suspension, and indicate nebulized budesonide to be equipotent to standard budesonide therapy delivered by pMDI with Nebuhaler, provided nebulization is synchronized with inspiration and no loss of aerosol occurs during expiration.
BibTeX:
@article{,
  author = {Bisgaard, H. and Nikander, K. and Munch, E.},
  title = {Comparative study of budesonide as a nebulized suspension vs pressurized metered-dose inhaler in adult asthmatics.},
  journal = {Respir Med},
  school = {Department of Paediatrics, National University Hospital, Rigshospitalet, Copenhagen, Denmark.},
  year = {1998},
  volume = {92},
  number = {1},
  pages = {44--49}
}
Borum, S. Mygind, N. Experimentally induced nasal hypersecretion does not reduce the efficacy of intranasal levocabastine. 1998 Rhinology 9923056 2,350 2
Authors: Borum, S., Nielsen, K., Bisgaard, H. and Mygind, N.
Abstract: In allergic rhinitis, a nasal H1-antihistamine spray seems to be well suited for usage on an as-needed basis, because it has a quick onset of action, and many patients prefer to take medicine only when they have symptoms. It is a prerequisite, however, that nasal hypersecretion during a rhinitis episode does not significantly reduce the efficacy of intranasal treatment by washing away the drug before it reaches the H1-histamine receptors. In order to investigate this problem, we have induced nasal hypersecretion with a methacholine challenge in one experiment and in four experiments we have washed the nasal cavities 0.5 min. before, 5 min. before, 0.5 min. after and 5 min. after intranasal use of the H1-antagonist, levocabastine. The symptom response to a subsequent histamine challenge was used as the effect parameter. Levocabastine reduced the number of histamine-induced sneezes with 81% (p < 0.0001) and the secretion weight with 62% (p < 0.001) compared with placebo. Neither methacholine-induced hypersecretion nor washing the nose with saline reduced the efficacy of the antihistamine spray. We conclude that experimentally induced nasal hypersecretion does not reduce the efficacy of the antihistamine spray, and probably the same applies to rhinorrhea during an acute episode of allergic rhinitis.
BibTeX:
@article{,
  author = {Borum, S. and Nielsen, K. and Bisgaard, H. and Mygind, N.},
  title = {Experimentally induced nasal hypersecretion does not reduce the efficacy of intranasal levocabastine.},
  journal = {Rhinology},
  school = {Department of Pediatrics, National University Hospital, Copenhagen, Denmark.},
  year = {1998},
  volume = {36},
  number = {4},
  pages = {153--155}
}
Bisgaard, H. Burnell, P.K. Fine particle mass from the Diskus inhaler and Turbuhaler inhaler in children with asthma. 1998 Eur Respir J 9648964 10,569 77
Authors: Bisgaard, H., Klug, B., Sumby, B.S. and Burnell, P.K.
Abstract: The study aimed to investigate dose consistency and particle distribution from the dry powder inhalers Diskus and Turbuhaler. Full profiles of inhalation pressure versus time were recorded in 18 4 yr old and 18 8 yr old asthmatic children through Diskus and Turbuhaler inhalers. These data were used in an inhalation profile simulator to assess drug delivery from both a Diskus inhaler and a Turbuhaler inhaler, and in particular to assess the proportion of drug emitted in the coarse (>4.7 microm) and fine (<4.7 microm) particle size range from each type of inhaler. The inhalation profile more accurately represents the changes in flow rate over time through the device than the constant flow rate usually applied with an impactor alone. The aerosol cloud was released before the peak inspiratory effort had been achieved and accordingly the early part and not the peak of the inspiratory performance is a determinant of the quality of the aerosol. The mean (SD) amount of drug in large particles (>4.7 microm), fine particles (<4.7 microm) and very fine particles (<2.1 microm) in percentage of label claim from the Fluticasone Diskus was 72 (5), 15 (2) and 2 (1) from the 4 yr old children and 71 (3), 18 (2) and 2 (1) from the 8 yr old children, respectively. Similar particle fractions from the Budesonide Turbuhaler were 35 (9), 21 (10) and 7 (5) from 4 yr old children and 30 (7), 32 (9) and 12 (6) from 8 yr old children. In conclusion, the Diskus inhaler provides an improved dose consistency through the varying age groups and inspiratory flow performances when compared to the Turbuhaler in terms of the proportion of the dose emitted at each particle size. This improvement is at the expense of a low fine particle mass and a high proportion of coarse particles from the Diskus as compared with the Turbuhaler.
BibTeX:
@article{,
  author = {Bisgaard, H. and Klug, B. and Sumby, B. S. and Burnell, P. K.},
  title = {Fine particle mass from the Diskus inhaler and Turbuhaler inhaler in children with asthma.},
  journal = {Eur Respir J},
  school = {Dept of Paediatrics, Pulmonary Service, National University Hospital, Rigshospitalet, Copenhagen, Denmark.},
  year = {1998},
  volume = {11},
  number = {5},
  pages = {1111--1115}
}
Nielsen, K.G. Bisgaard, H. Flow-dependent effect of formoterol dry-powder inhaled from the Aerolizer. 1997 Eur Respir J 9311511 10,569 54
Authors: Nielsen, K.G., Skov, M., Klug, B., Ifversen, M. and Bisgaard, H.
Abstract: The output and size distribution of aerosols from dry powder inhalers are dependent on the flow rate through the device. Therefore, in an in vivo study, we examined the flow-dependency of the effect of formoterol when delivered from a dry powder inhaler, the Aerolizer, in a flow range relevant to schoolchildren. In a preliminary study comprising 126 asthmatic children aged 3-10 yrs, the relationship between age and peak inspiratory flow (PIF) rate through the Aerolizer was determined. Mean PIF was 104 L.min-1 and all children aged > 5 yrs performed a PIF > 60 L.min-1. Sixteen children aged 8-15 yrs with exercise-induced asthma (EIA) took part in the main trial comparing the protective effect of 12 micrograms formoterol inhaled at 60 and 120 L.min-1. The effect from high and low inspiratory flow was judged from the protective effect against EIA 12 h after drug administration. The decrease in forced expiratory volume in one second (FEV1) after exercise was 34% on the placebo day, but only 15% when formoterol was inhaled at the high flow rate. This difference was statistically significant. The decrease in FEV1 was 23% after treatment with formoterol inhaled at the low flow rate, that was not significantly different from placebo or from high-flow formoterol treatment. These clinical findings correspond with the in vitro findings of flow-dependent fine particle mass from the Aerolizer, and corroborate the relationship between fine particle mass of aerosol and clinical effect. The results indicate a flow-dependent effect of formoterol dry powder inhaled from the Aerolizer, within the range of inspiratory flow rate obtainable by school-children. This questions its applicability in children with asthma.
BibTeX:
@article{,
  author = {Nielsen, K. G. and Skov, M. and Klug, B. and Ifversen, M. and Bisgaard, H.},
  title = {Flow-dependent effect of formoterol dry-powder inhaled from the Aerolizer.},
  journal = {Eur Respir J},
  school = {Dept of Paediatrics, National University Hospital, Copenhagen, Denmark.},
  year = {1997},
  volume = {10},
  number = {9},
  pages = {2105--2109}
}
Klug, B. Bisgaard, H. Measurement of the specific airway resistance by plethysmography in young children accompanied by an adult. 1997 Eur Respir J 9230254 10,569 62
Authors: Klug, B. and Bisgaard, H.
Abstract: The purpose of this study was to evaluate a procedure for measurement of specific airway resistance (sRaw) by whole body plethysmography in young awake children accompanied by an adult. sRaw was measured by a single-step procedure, omitting the measurement of the thoracic gas volume. The frequency dependency of sRaw was investigated and the accuracy of simulating body temperature, atmospheric pressure and saturation with water vapour (BTPS) conditions by electronic compensation was assessed. One hundred and thirty one children with asthma were studied. In 57 children (mean (SD) age 5.6 (1.8) yrs) who performed measurements with and without an accompanying adult, the mean value of sRaw was 1.45 (0.36) and 1.44 (0.38) kPa x s, respectively, with a mean difference of 0.008 (0.152) kPa x s, and mean within-subject coefficients of variations (CV) of 8% and 10 respectively. In 52 children (mean age 3.3 (0.8) yrs), for whom measurements made only in the presence of an accompanying adult, the CV was 8.5%. No measurements could be obtained in 22 children (17 (mean age 2.8 (0.5) yrs). Measurements exhibited a significant frequency dependency, and electronic BTPS compensation substantially overestimated SRaw. In conclusion, the use of electronic compensation for simulating body temperature, atmospheric pressure and saturation with water vapour introduces a bias that affects the accuracy of the estimate of specific airway resistance. Nevertheless, plethysmographic measurements with and without an accompanying adult yielded comparable and equally repeatable estimates of specific airway resistance. The single-step plethysmographic procedure with an accompanying adult is a clinically useful method for evaluating airway function in children too young to perform plethysmographic measurements alone.
BibTeX:
@article{,
  author = {Klug, B. and Bisgaard, H.},
  title = {Measurement of the specific airway resistance by plethysmography in young children accompanied by an adult.},
  journal = {Eur Respir J},
  school = {National University Hospital, Rigshospitalet, Copenhagen, Denmark.},
  year = {1997},
  volume = {10},
  number = {7},
  pages = {1599--1605}
}
Klug, B. Bisgaard, H. Repeatability of methacholine challenges in 2- to 4-year-old children with asthma, using a new technique for quantitative delivery of aerosol. 1997 Pediatr Pulmonol 9141113 2,758 24
Authors: Klug, B. and Bisgaard, H.
Abstract: To determine the repeatability of bronchial responsiveness in awake young children, two methacholine challenge tests were performed on separate days in 16 children with stable asthma (mean age, 3 3/4 years). Methacholine was administered using a new method for quantitative delivery of aerosol that eliminates the effect of dilution of the aerosol by entrainment of air and enables quantitative delivery of aerosol according to body weight. Respiratory function was monitored by measurement of respiratory resistance by the interrupter technique (Rint), respiratory resistance and reactance at 5 Hz (Rrs5, Xrs5) by the impulse oscillation technique, transcutaneous measurements of oxygen (PtcO2), and specific airway resistance (sRaw). Repeatability was evaluated by determining the provocative dose that caused a defined percentage of change relative to baseline (PD Rint PD30, Rrs5 PD30, Xrs5 PD80, PtcO2 PD10, and sRaw PD80. Repeatability was estimated from the difference between the PD% obtained at the time of the two tests. Using the numeric value of these differences, the repeatability of Xrs5 PD60, PtcO2 PD10, and sRaw PD50 was [mean (SD)]: [0.8 (0.5)] [0.5 (0.4)] and [0.7 (0.6)] doubling doses, respectively. Rint PD30 and Rrs5 PD30 proved to be less reproducible: [1.2 (1)] and [1.6 (0.9)] doubling doses, respectively. The new method of aerosol delivery offers a means of standardizing the bronchoconstrictor stimulus, and the results show that estimates of bronchial responsiveness in young children can be obtained reproducibly within one doubling dose of methacholine.
BibTeX:
@article{,
  author = {Klug, B. and Bisgaard, H.},
  title = {Repeatability of methacholine challenges in 2- to 4-year-old children with asthma, using a new technique for quantitative delivery of aerosol.},
  journal = {Pediatr Pulmonol},
  school = {Department of Pediatrics, National University, Copenhagen, Denmark.},
  year = {1997},
  volume = {23},
  number = {4},
  pages = {278--286}
}
Ellerman, A. Bisgaard, H. Longitudinal study of lung function in a cohort of primary ciliary dyskinesia. 1997 Eur Respir J 9387968 10,569 167
Authors: Ellerman, A. and Bisgaard, H.
Abstract: Patients with primary ciliary dyskinesia (PCD) have pronounced stasis of their respiratory secretions and therefore recurrent lower airway infections, which raises concerns for the development of lung function. Twenty four patients with PCD have been studied prospectively with a standardized regime in our clinic for 2-16 yrs with clinic visits, including spirometry 2-4 times per year, daily physiotherapy and monthly sputum cultures with subsequent specific antibiotic treatment. Lung function was significantly lower in the 12 PCD patients entering the cohort as adults when compared to the PCD patients entering as children (forced vital capacity (FVC) 70 versus 85% predicted; forced expiratory volume in one second (FEV1) 59 versus 72% pred). The lung damage did not relate to the type of ciliary dyskinesia. During the subsequent surveillance of the groups for a median of 14 and 7 yrs, respectively, the lung function remained stable in most patients. It is concluded that primary ciliary dyskinesia is accompanied by a progressive deterioration in lung function if undertreated, but lung function can be maintained with appropriate antibiotic treatment and regular physiotherapy. This emphasizes the need for early diagnosis of primary ciliary dyskinesia.
BibTeX:
@article{,
  author = {Ellerman, A. and Bisgaard, H.},
  title = {Longitudinal study of lung function in a cohort of primary ciliary dyskinesia.},
  journal = {Eur Respir J},
  year = {1997},
  volume = {10},
  number = {10},
  pages = {2376--2379}
}
Bisgaard, H. Koch, C. Controlled trial of inhaled budesonide in patients with cystic fibrosis and chronic bronchopulmonary Psuedomonas aeruginosa infection. 1997 Am J Respir Crit Care Med 9351621 13,204 55
Authors: Bisgaard, H., Pedersen, S.S., Nielsen, K.G., Skov, M., Laursen, E.M., Kronborg, G., Reimert, C.M., Høiby, N. and Koch, C.
Abstract: The efficacy and safety of anti-inflammatory treatment with inhaled glucocorticosteroids in patients with cystic fibrosis (CF) and complicating chronic Pseudomonas aeruginosa (P.a.) lung infection was studied in a placebo-controlled, parallel, double-blind single center trial. Active treatment consisted of budesonide dry powder, 800 microg twice daily, delivered from a Turbuhaler. The study period covered two successive 3-mo intervals between elective courses of intravenous anti-Pseudomonas antibiotics. Fifty-five patients entered the study, with a mean age of 20 yr and a mean FEV1 of 63% of predicted. Analysis of all patients entered, irrespective of trial adherence ("intention to treat"), showed a decrease in FEV1 in the first period of -0.032 L in patients on budesonide versus -0.187 L in patients on placebo (p = 0.08). The corresponding figures for the patients adhering to the protocol during the first period were -0.017 L versus -0.198 L (p < 0.05, confidence interval of the difference: -0.035 to +0.327 L). For all patients entered, as well as for patients adhering to the trial, there was always a trend in favor of budesonide, as judged by changes in FEV1 and FVC in both 3-mo periods. None of the patients had asthma, but the patients on budesonide had a mean improvement in histamine reactivity of +1.15 dose steps over the entire 6-mo period, as opposed to +0.017 dose steps in patients on placebo (p < 0.05). There was also a significant (p = 0.01) correlation between pre-trial histamine reactivity and the change in FEV1 in the first period in patients on budesonide. We conclude that inhaled glucocorticosteroids can be of short-term benefit in patients with CF and chronic P.a. infection and that those patients most likely to benefit from this treatment are patients with hyperreactive airways. Prolonged studies in larger number of patients are necessary to determine the long-term efficacy of this treatment.
BibTeX:
@article{,
  author = {Bisgaard, H. and Pedersen, S. S. and Nielsen, K. G. and Skov, M. and Laursen, E. M. and Kronborg, G. and Reimert, C. M. and Høiby, N. and Koch, C.},
  title = {Controlled trial of inhaled budesonide in patients with cystic fibrosis and chronic bronchopulmonary Psuedomonas aeruginosa infection.},
  journal = {Am J Respir Crit Care Med},
  school = {Department of Pediatrics, National University Hospital, Rigshospitalet, Copenhagen, Denmark.},
  year = {1997},
  volume = {156},
  number = {4 Pt 1},
  pages = {1190--1196},
  url = {http://dx.doi.org/10.1164/ajrccm.156.4.9612044},
  doi = {https://doi.org/10.1164/ajrccm.156.4.9612044}
}
Bisgaard, H. Schiøtz, P.O. [Steroid treatment of asthmatic children]. 1997 Ugeskr Laeger 9417698 0 0
Authors: Bisgaard, H., Pedersen, S.E. and Schiøtz, P.O.
BibTeX:
@article{,
  author = {Bisgaard, H. and Pedersen, S. E. and Schiøtz, P. O.},
  title = {[Steroid treatment of asthmatic children].},
  journal = {Ugeskr Laeger},
  year = {1997},
  volume = {159},
  number = {47},
  pages = {6971}
}
Bisgaard, H. Bisgaard, H. What dose fraction represents the respirable dose? 1997 Respir Med 9474363 3,217 4
Authors: Bisgaard, H.
BibTeX:
@article{,
  author = {Bisgaard, H.},
  title = {What dose fraction represents the respirable dose?},
  journal = {Respir Med},
  school = {Department of Paediatrics, National University Hospital, Rigshospitalet, Copenhagen, Denmark.},
  year = {1997},
  volume = {91 Suppl A},
  pages = {20--21}
}
Bisgaard, H. Bisgaard, H. Use of inhaled corticosteroids in pediatric asthma. 1997 Pediatr Pulmonol Suppl 9316099 2,758 25
Authors: Bisgaard, H.
Abstract: Inhaled corticosteroids reduce asthma symptoms and exacerbations, improve lung function, and reduce airway inflammation and bronchial hyperreactivity more effectively than other treatments. However, inhaled corticosteroids may be unable to return lung function and bronchial hyperreactivity to normal when introduced for moderately severe asthma. This finding highlights the need to improve treatment strategy in pediatric asthma. The natural progression of persistent asthma may lead to loss of lung function and chronic bronchial hyperreactivity for children and adults. There is evidence to suggest that asthma acts via a chronic inflammatory process that causes remodeling of the airways with mucosal thickening and smooth muscle hypertrophy. An optimal treatment strategy would be one aimed at reducing the ongoing airway inflammation. Inhaled steroids ameliorate the inflammation, whereas this has not been documented for any other treatment. Delayed introduction of inhaled steroids appears to result in reduced improvement in lung function compared with the early use of inhaled steroids. This improved response from the earlier use of inhaled steroids appears to be valid at any stage of the disease. Therefore, a change in treatment strategy toward earlier introduction of corticosteroids may impede airway remodeling, bronchial hyperreactivity, and airway damage. No other treatment has been found to affect the course of the disease. Systemic side-effects, particularly inhibition of growth in asthmatic children using inhaled corticosteroids, do not seem to be cause for concern. Growth retardation has not been reported when inhaled corticosteroid doses of < or = 400 micrograms daily are individually tailored to each child's needs. The ongoing change in treatment strategy toward the earlier use of inhaled steroids in childhood asthma, as reflected in current revisions of various treatment strategies, therefore seems well founded.
BibTeX:
@article{,
  author = {Bisgaard, H.},
  title = {Use of inhaled corticosteroids in pediatric asthma.},
  journal = {Pediatr Pulmonol Suppl},
  school = {Department of Pediatrics, National University Hospital, Copenhagen, Denmark.},
  year = {1997},
  volume = {15},
  pages = {27--33}
}
Bisgaard, H. Bisgaard, H. Demands on spacer devices for young children. 1997 Pediatr Pulmonol Suppl 9443268 2,758 4
Authors: Bisgaard, H.
BibTeX:
@article{,
  author = {Bisgaard, H.},
  title = {Demands on spacer devices for young children.},
  journal = {Pediatr Pulmonol Suppl},
  school = {Dept. Pediatrics, Pulmonary Service, Rigshospitalet, National University Hospital, Copenhagen, Denmark.},
  year = {1997},
  volume = {16},
  pages = {188--189}
}
Bisgaard, H. Bisgaard, H. Delivery of inhaled medication to children. 1997 J Asthma 9428291 1,746 61
Authors: Bisgaard, H.
BibTeX:
@article{,
  author = {Bisgaard, H.},
  title = {Delivery of inhaled medication to children.},
  journal = {J Asthma},
  school = {Department of Pediatrics, Rigshospitalet National University Hospital, Copenhagen, Denmark.},
  year = {1997},
  volume = {34},
  number = {6},
  pages = {443--467},
  url = {http://dx.doi.org/10.3109/02770909709055389},
  doi = {https://doi.org/10.3109/02770909709055389}
}
Bisgaard, H. Bisgaard, H. Delivery options for inhaled therapy in children under the age of 6 years. 1997 J Aerosol Med 10165122 0 3
Authors: Bisgaard, H.
BibTeX:
@article{,
  author = {Bisgaard, H.},
  title = {Delivery options for inhaled therapy in children under the age of 6 years.},
  journal = {J Aerosol Med},
  school = {National University Hospital, Department of Paediatrics, Copenhagen, Denmark.},
  year = {1997},
  volume = {10 Suppl 1},
  pages = {S37--S40}
}
Nysom, K. Hertz, H. Lung function after allogeneic bone marrow transplantation for leukaemia or lymphoma. 1996 Arch Dis Child 8669960 /a> 3,265 37
Authors: Nysom, K., Holm, K., Hesse, B., Ulrik, C.S., Jacobsen, N., Bisgaard, H. and Hertz, H.
Abstract: Longitudinal data were analysed on the lung function of 25 of 29 survivors of childhood leukaemia or lymphoma, who had been conditioned with cyclophosphamide and total body irradiation before allogeneic bone marrow transplantation, to test whether children are particularly vulnerable to pulmonary damage after transplantation. None developed chronic graft-versus-host disease. Transfer factor and lung volumes were reduced immediately after bone marrow transplantation, but increased during the following years. However, at the last follow up, 4-13 years (median 8) after transplantation, patients had significantly reduced transfer factor, total lung capacity, and forced vital capacity (-1.0, -1.2, and -0.8 SD score, respectively), and increased ratio of forced expiratory volume in one second to forced vital capacity (+0.9 SD score). None of the patients had pulmonary symptoms, and changes were unrelated to their age at bone marrow transplantation. In conclusion, patients had subclinical restrictive pulmonary disease at a median of eight years after total body irradiation and allogeneic bone marrow transplantation.
BibTeX:
@article{,
  author = {Nysom, K. and Holm, K. and Hesse, B. and Ulrik, C. S. and Jacobsen, N. and Bisgaard, H. and Hertz, H.},
  title = {Lung function after allogeneic bone marrow transplantation for leukaemia or lymphoma.},
  journal = {Arch Dis Child},
  school = {National University Hospital Rigshospitalet, Copenhagen, Denmark.},
  year = {1996},
  volume = {74},
  number = {5},
  pages = {432--436}
}
Klug, B. Bisgaard, H. Measurement of lung function in awake 2-4-year-old asthmatic children during methacholine challenge and acute asthma: a comparison of the impulse oscillation technique, the interrupter technique, and transcutaneous measurement of oxygen versus whole-body plethysmography. 1996 Pediatr Pulmonol 8726154 2,758 141
Authors: Klug, B. and Bisgaard, H.
Abstract: This study evaluated three techniques for testing of lung function in young awake children. We compared measurements by the forced or impulse oscillation technique (IOS), the interrupter technique (IT), and transcutaneous measurements of oxygen (tcPo2) with concomitant measurements of specific airway resistance (sRaw) during methacholine challenge in 20 stable asthmatic children, 2-4 years old. Measurements were performed with all techniques after each dose of methacholine and after inhalation of a bronchodilator. Measurements were carried out during tidal breathing using a face-mask with a built-in mouthpiece. The ranking of sensitivity was as follows: sRaw > IOS, respiratory reactance at 5 Hz (Xrs5) > tcPo2 > interrupter resistance (Rint) > IOS, respiratory resistance at 5 Hz (Rrs5). The sensitivity of sRaw and Xrs5 was not significantly different, but both were significantly more sensitive than Rint and Rrs5; the sensitivity of tcPo2, Rint, and Rrs5 was not significantly different. Measurements in eight of the subjects performed during an episode of acute asthma yielded comparable results in regard to the sensitivity of the techniques. Measurements improved significantly after bronchodilator administration; however, the response to bronchodilator tended to be less during acute asthma and was best demonstrated by a deterioration of tcPo2. All the evaluated techniques reliably reflect short-term changes in respiratory function and can provide clinically useful estimates of airway function. The techniques are non-invasive, are not dependent on the active co-operation or sedation of the subjects, and therefore are well suited for routine use in young children.
BibTeX:
@article{,
  author = {Klug, B. and Bisgaard, H.},
  title = {Measurement of lung function in awake 2-4-year-old asthmatic children during methacholine challenge and acute asthma: a comparison of the impulse oscillation technique, the interrupter technique, and transcutaneous measurement of oxygen versus whole-body plethysmography.},
  journal = {Pediatr Pulmonol},
  school = {Department of Pediatrics, National University Hospital, Copenhagen, Denmark.},
  year = {1996},
  volume = {21},
  number = {5},
  pages = {290--300},
  url = {http://dx.doi.org/3.0.CO;2-R},
  doi = {3.0.CO;2-R}
}
Klug, B. Bisgaard, H. Assessment of bronchial hyperresponsiveness in preschool children: methodological issues. 1996 Pediatr Allergy Immunol 9156724 3,775 3
Authors: Klug, B. and Bisgaard, H.
BibTeX:
@article{,
  author = {Klug, B. and Bisgaard, H.},
  title = {Assessment of bronchial hyperresponsiveness in preschool children: methodological issues.},
  journal = {Pediatr Allergy Immunol},
  school = {Department of Pediatrics, National University Hospital, Copenhagen, Denmark.},
  year = {1996},
  volume = {7},
  number = {9 Suppl},
  pages = {25--27}
}
Daugbjerg, P. Bisgaard, H. Duration of action of formoterol and salbutamol dry-powder inhalation in prevention of exercise-induced asthma in children. 1996 Acta Paediatr 8816204 2,043 24
Authors: Daugbjerg, P., Nielsen, K.G., Skov, M. and Bisgaard, H.
Abstract: The aim of this study was to evaluate the effect and tolerability of formoterol 12 micrograms on exercise-induced asthma in children for 12 h as compared to the effect of salbutamol 400 micrograms and placebo. The drugs were inhaled as dry powder from a flow-dependent metered-dose inhaler (DP-MDI). Sixteen asthmatic children took part in a double-blind placebo-controlled within-patient single-centre trial. On each study day the patients were given one of the drugs or placebo in random order, and standardized exercise tests were performed after 3 and 12 h. At a pretrial test the children had demonstrated a median maximum percentage fall of 38% (range 22-79 in forced expiratory volume in 1 s after exercise challenge. Formoterol showed a median percentage protection of 77% and 70% at 3 and 12 h postexercise, respectively, as compared to 46% and 13% with salbutamol. No side-effects were observed. Formoterol 12 micrograms administered as dry powder offers significantly better protection against exercise-induced asthma after 3 and 12 h as compared to salbutamol 400 micrograms and placebo.
BibTeX:
@article{,
  author = {Daugbjerg, P. and Nielsen, K. G. and Skov, M. and Bisgaard, H.},
  title = {Duration of action of formoterol and salbutamol dry-powder inhalation in prevention of exercise-induced asthma in children.},
  journal = {Acta Paediatr},
  school = {Department of Paediatrics, National University Hospital, Rigshospitalet, Copenhagen, Denmark.},
  year = {1996},
  volume = {85},
  number = {6},
  pages = {684--687}
}
Bisgaard, H. Pedersen, S. Safety of treatment. 1996 Eur Respir J Suppl 8962615 10,569 7
Authors: Bisgaard, H. and Pedersen, S.
Abstract: Data concerning safety of treatment in schoolchildren cannot be extrapolated to preschool children due to differences in growth velocity and metabolism. The safety issue in preschool children is further complicated by insufficient knowledge of the optimal dose, and the lung delivery from the devices available. Systemic activity has often been studied as a marker of adverse clinical effect. However, with improving technology, systemic activity can be detected within the range of the normal biological feedback system, where it is of no clinical importance. Therefore, systemic activity is not synonymous with clinically relevant side-effects. Side-effects should be assessed in specific clinical studies. Effect on growth velocity is a potential side-effect of major interest. Knemometry is a sensitive measure of short-term growth of the lower leg length in schoolchildren as well as in preschool children, which enables precise measurements of systemic activity, but it is not a measure of statural growth. The only clinically relevant outcome measure of human growth is the final height in relation to expected final height, allowing for gender and midparental height differences. In addition to effects on statural height, osteoperosis is an important potential side-effect. The importance of bone density during preschool age for final adult bone mineral density needs to be studied. Cataract formation is a side-effect associated with systemic steroid treatment and may be of special consideration during treatment with nebulized steroids, which may expose the eyes to high doses. Thrush, dysphonia and local skin atrophy in steroid-exposed areas are potential local side-effects, and yet the incidence in young children is unknown and dependent on the device used for delivery. When considering adverse effects of treatment, the risk of side-effects from undertreatment should always be observed.
BibTeX:
@article{,
  author = {Bisgaard, H. and Pedersen, S.},
  title = {Safety of treatment.},
  journal = {Eur Respir J Suppl},
  school = {Rigshospitalet/National University Hospital, Dept of Paediatrics, GGK-5002, Kopenhamn, Denmark.},
  year = {1996},
  volume = {21},
  pages = {28s--34s}
}
Bisgaard, H. Bisgaard, H. Drug delivery from inhaler devices. 1996 BMJ 8876085 20,785 0
Authors: Bisgaard, H.
BibTeX:
@article{,
  author = {Bisgaard, H.},
  title = {Drug delivery from inhaler devices.},
  journal = {BMJ},
  year = {1996},
  volume = {313},
  number = {7062},
  pages = {895--896}
}
Bisgaard, H. Klug, B. Lung function measurement in awake young children. 1995 Eur Respir J 8666102 10,569 187
Authors: Bisgaard, H. and Klug, B.
Abstract: The aim of the study was to evaluate methods applicable in a clinical setting for monitoring of changes in lung function in awake young children. Impedance measurements by the impulse oscillation technique (ZIOS), respiratory resistance measurements by the interrupter technique (Rint) and transcutaneous measurements of oxygen tension (Ptc,O2) were compared with concomitant measurements of specific airway resistance (sRaw) and forced expiratory volume in one second (FEV1) by whole body plethysmography and spirometry, respectively, during methacholine challenge in 21 young children aged 4-6 yrs, with suspected asthma. Measurements with each technique were repeated after each challenge step. A special face-mask was developed with an integrated mouthpiece which ensured mouth breathing during the measurements. The order of sensitivity of the techniques to assess methacholine-induced changes in lung function was ZIOS > sRaw > Ptc,O2 > FEV1 > Rint. ZIOS was significantly more sensitive than all subsequent methods, and Ptc,O2 was significantly more sensitive than FEV1. ZIOS, sRaw and Rint, but not Ptc,O2 and FEV1, detected the subclinical increase in bronchial muscle tone in the children during baseline, which was revealed by the significantly reduced airway obstruction after inhalation of a beta 2-agonist as compared to baseline. It is concluded that ZIOS, Rint and Ptc,O2 change in parallel with sRaw and FEV1 and with a comparable sensitivity during simultanoeous measurements of the response to methacholine in young children aged 4-6 yrs. This implies that ZIOS, Rint and Ptc,O2 provide convenient indices of changes in lung function. Their combined use will be useful for monitoring airway diseases of young children.
BibTeX:
@article{,
  author = {Bisgaard, H. and Klug, B.},
  title = {Lung function measurement in awake young children.},
  journal = {Eur Respir J},
  school = {Dept of Pediatrics, National University Hospital, Rigshospitalet, Copenhagen, Denmark.},
  year = {1995},
  volume = {8},
  number = {12},
  pages = {2067--2075}
}
Bisgaard, H. Berg, E. A non-electrostatic spacer for aerosol delivery. 1995 Arch Dis Child 7492160 3,265 95
Authors: Bisgaard, H., Anhøj, J., Klug, B. and Berg, E.
Abstract: A pear shaped non-electrostatic spacer, composed of steel with a volume of 250 ml and equipped with a facemask containing integrated inlet and outlet valves for inspiration and expiration, was compared with three plastic spacers. The plastic spacers were primed with repeated puffs from a budesonide pressurised metered dose inhaler (p-MDI) to minimise the electrostatic charge on the plastic. The procedure prolonged the half life (t1/2) of the aerosol in the Nebuhaler from nine to 32 seconds. A normal cleaning procedure reduced the aerosol t1/2 back to baseline. The t1/2 of the aerosol in the metal spacer was 27 seconds and independent of the use of p-MDI. In vitro the maximum dose of budesonide from a p-MDI, expressed as a percentage of the nominal dose, was 56% from the non-electrostatic spacer, 61% from the Nebuhaler, 45% from the Babyhaler, and 30% from the AeroChamber. In 124 children, age 6 months to 6 years, suspected to have asthma the non-electrostatic spacer delivered a mean total dose of budesonide aerosol of 39% of the nominal dose, which was significantly higher than the Babyhaler (28, the Nebuhaler (21, and the AeroChamber (19. These differences were most pronounced in children younger than 4 years. The improved dose delivery from the small volume non-electrostatic spacer is probably related to the non-electrostatic spacer material and the valves which assured unidirectional airflow from the spacer without adding any dead space in the inspiratory channel. The non-electro-static spacer should improve the cost effectiveness of aerosol treatment and, as the counteracting effects of proming and recharging of the plastic from cleaning are avoided, should deliver a more reliable dose.
BibTeX:
@article{,
  author = {Bisgaard, H. and Anhøj, J. and Klug, B. and Berg, E.},
  title = {A non-electrostatic spacer for aerosol delivery.},
  journal = {Arch Dis Child},
  school = {Department of Paediatrics, National University Hospital, Copenhagen, Denmark.},
  year = {1995},
  volume = {73},
  number = {3},
  pages = {226--230}
}
Bisgaard, H. Bisgaard, H. A metal aerosol holding chamber devised for young children with asthma. 1995 Eur Respir J 7656962 10,569 72
Authors: Bisgaard, H.
Abstract: The low tidal volume and flow in preschool children may reduce the efficiency of aerosol delivery from a pressurized metered-dose inhaler (pMDI) through a traditional holding chamber. A prototype small-volume steel holding chamber with two one-way valves was devised to prolong aerosol availability in the chamber and to ensure unidirectional airflow. Dead space between the valves was minimized to less than 2 ml. The dose-delivery and rate of passive disappearance of a budesonide pMDI aerosol were compared between this prototype and the large-volume, single-valved plastic Nebuhaler, in 164 asthmatic children less than 8 yrs of age. In vitro, the half life of aerosol disappearance in the steel prototype and the plastic Nebuhaler was > 30 s and 9 s, respectively. In vivo, the prototype delivered an age-independent mean dose of 38% of the nominal dose, and the Nebuhaler delivered an age-dependent mean dose, ranging from 42% of the nominal dose in children > or = 4 yrs to 19% of the nominal dose in infants. We conclude that the use of plastic for holding chambers may influence dose-delivery, and single-valve control may cause age-dependent dose-delivery. Reproducible age-independent drug-delivery may be achieved by pMDI aerosol inhaled through a small-volume metal holding chamber with separate inlet and outlet valves and minimized dead space. This holding chamber would improve the possibilities of aerosol therapy for young children.
BibTeX:
@article{,
  author = {Bisgaard, H.},
  title = {A metal aerosol holding chamber devised for young children with asthma.},
  journal = {Eur Respir J},
  school = {Dept of Paediatrics, National University Hospital, Copenhagen, Denmark.},
  year = {1995},
  volume = {8},
  number = {5},
  pages = {856--860}
}
Bisgaard, H. Nikander, K. Use of budesonide Turbuhaler in young children suspected of asthma. 1994 Eur Respir J 8005258 10,569 24
Authors: Bisgaard, H., Pedersen, S. and Nikander, K.
Abstract: The question addressed in this study was the ability of young children to use a dry-powder inhaler, Turbuhaler. One hundred and sixty five children suspected of asthma, equally distributed in one year age-groups from 6 months to 8 yrs, inhaled from a Pulmicort Turbuhaler, 200 micrograms budesonide-dose-1, through a filter. The amount of drug trapped by the filter was used as a measure of drug released to the patient. None of the children had prior experience in the use of a Turbuhaler, but they were instructed carefully, together with their parents, in the clinic. The median dose released revealed an age-dependent increase, with a considerable scatter. Accordingly, the dose delivered could not be predicted in these young children. The limitation to effective use in young children appeared to be lack of sufficient co-operation, rather than physical limitations, as even some very young children appeared to obtain a sufficient activation of the device. It is likely that repeated training at home may improve these findings. In conclusion, our results indicate that dry-powder inhalers are not reliable in all circumstances for treatment of young children, and that careful and repeated tuition is required if such devices are to be used.
BibTeX:
@article{,
  author = {Bisgaard, H. and Pedersen, S. and Nikander, K.},
  title = {Use of budesonide Turbuhaler in young children suspected of asthma.},
  journal = {Eur Respir J},
  school = {Dept of Paediatrics, State University Hospital, Copenhagen, Denmark.},
  year = {1994},
  volume = {7},
  number = {4},
  pages = {740--742}
}
Bisgaard, H. Bisgaard, H. Clinical efficacy of nebulized drugs. 1994 J Aerosol Med 10147079 0 2
Authors: Bisgaard, H.
Abstract: There is a mandatory need for effortless drug administration to young children since the prevalence among them of recurrent wheezing is a 15-20%. It is becoming increasingly evident that many of these children respond dramatically well to beta2-agonists and topical steroids; accordingly this sub-group of children should be treated as asthmatics. The dose of topical steroids is critical as opposed to that of beta2-agonists which are often administered in doses well above the minimal effective dose. Budesonide suspension has proven its efficacy in adults in a study of 21 patients with asthma treated with budesonide suspension delivered from a nebulizer activated during inspiration versus metered dose inhalation (MDI) via a large-volume spacer. Nebulized in this manner the suspension exhibited a dose-dependent effect, apparently equipotent to the MDI administration as evaluated from daily peak expiratory flow measurements and symptom scoring. Continuous nebulization of budesonide in 18 schoolchildren with bronchial asthma similarly showed a dose-dependent improvement of lung function and symptom score, though in a 1:2 potency ratio as compared to MDI administration, probably due to loss of nebulized aerosol during expiration. In a subsequent study of 23 young children unresponsive to beta2-agonist therapy, nebulized budesonide was without demonstrable effect. Recently, a study of 31 young children with steroid-dependent asthma demonstrated a significant improvement from continuous nebulization of budesonide 1mg twice daily. In conclusion, the efficacy of nebulized budesonide has been convincingly demonstrated in patients with reversible symptoms of asthma.(ABSTRACT TRUNCATED AT 250 WORDS)
BibTeX:
@article{,
  author = {Bisgaard, H.},
  title = {Clinical efficacy of nebulized drugs.},
  journal = {J Aerosol Med},
  school = {Department of Paediatrics, State University Hospital, Copenhagen, Denmark.},
  year = {1994},
  volume = {7},
  number = {Suppl 1},
  pages = {S33--S37}
}
Sprogøe-Jakobsen, U. Bisgaard, H. [Formoterol--a prolonged-action beta 2 agonist]. 1993 Ugeskr Laeger 7901931 0 0
Authors: Sprogøe-Jakobsen, U., Viktrup, L. and Bisgaard, H.
BibTeX:
@article{,
  author = {Sprogøe-Jakobsen, U. and Viktrup, L. and Bisgaard, H.},
  title = {[Formoterol--a prolonged-action beta 2 agonist].},
  journal = {Ugeskr Laeger},
  year = {1993},
  volume = {155},
  number = {44},
  pages = {3582--3585}
}
Grønborg, H. Mygind, N. Early and late nasal symptom response to allergen challenge. The effect of pretreatment with a glucocorticosteroid spray. 1993 Allergy 8457038 7,361 30
Authors: Grønborg, H., Bisgaard, H., Rømeling, F. and Mygind, N.
Abstract: We challenged 30 pollen-sensitive volunteers with allergen, recorded symptoms and signs over a 10-h period, and rechallenged them after 24 h, in order to characterize the early and late allergic symptom response in the nose. The challenge was performed after topical pretreatment with the glucocorticosteroid budesonide (200 micrograms twice daily) for 14 d and with placebo in a double-blind, cross-over trial. The early response, consisting of sneezing, discharge, and blockage, was followed by a weak late response, consisting of a few sneezes and nose-blowings, and of a sustained nasal blockage. These symptoms did not have a well-defined peak in time, and a biphasic symptom curve could not be identified. The rechallenge response showed increased nasal responsiveness. The degree of budesonide effect on the early response varied, depending on the symptom; there was a marked effect on sneezing (72% reduction; P < 0.01), a moderate effect on discharge (37% reduction; P < 0.01), and a slight effect on blockage (17% reduction of nasal inspiratory peak flow rate; P < 0.02). The degree of inhibition of the rechallenge response was similar to the effect on the initial early response. The effect on the late response was very pronounced for all symptoms and signs (97% reduction of sneezes, 76% reduction of nose-blowings, 96% reduction of blockage; P < 0.01). In conclusion, we found it difficult in the individual subject to identify a well-defined late symptom response by criteria similar to those employed to characterize the late response in the bronchi. The effect of budesonide was more marked on sneezing than on blockage, and the drug was considerably more effective on the late response than on the early response.
BibTeX:
@article{,
  author = {Grønborg, H. and Bisgaard, H. and Rømeling, F. and Mygind, N.},
  title = {Early and late nasal symptom response to allergen challenge. The effect of pretreatment with a glucocorticosteroid spray.},
  journal = {Allergy},
  school = {Department of Otorhinolaryngology, Rigshospitalet, Copenhagen, Denmark.},
  year = {1993},
  volume = {48},
  number = {2},
  pages = {87--93}
}
Bisgaard, H. Schiøtz, P.O. [Treatment of asthmatic bronchitis in small children with steroid inhalation]. 1993 Ugeskr Laeger 8421881 0 2
Authors: Bisgaard, H. and Schiøtz, P.O.
BibTeX:
@article{,
  author = {Bisgaard, H. and Schiøtz, P. O.},
  title = {[Treatment of asthmatic bronchitis in small children with steroid inhalation].},
  journal = {Ugeskr Laeger},
  school = {Paediatrisk afdeling, Rigshospitalet, København.},
  year = {1993},
  volume = {155},
  number = {3},
  pages = {181--182}
}
Bisgaard, H. Bisgaard, H. Systemic activity of inhaled topical steroid in toddlers studied by knemometry. 1993 Acta Paediatr 8155929 2,043 0
Authors: Bisgaard, H.
Abstract: The short-term linear growth rate of the lower leg in toddlers was measured and evaluated in order to study the possible effect of inhaled budesonide on this factor in toddlers with mild recurrent wheezing. The short-term linear growth rate of the lower leg was measured weekly using a hand-held knemometer. Eighteen toddlers aged 13-36 months (mean 27 months) with a history of recurrent wheezing requiring inhaled topical steroids, but without need of regular medication during the months prior to the study, were studied. The children were randomized blindly through three consecutive treatment periods of four weeks with placebo or budesonide in daily doses of 200 micrograms and 800 micrograms administered as a pressurized aerosol inhaled via a spacer with a face mask. Twenty-nine percent (median) of the nominal dose was delivered at the mouth of the children. Three children were withdrawn because of exacerbations and one because of non-compliance. The precision of the measurement procedure was 51 microns/day. The mean growth rate during placebo, low-dose and high-dose steroid treatment was 92 microns/day, 114 microns/day and 46 microns/day respectively. The growth rate during the high-dose treatment was suppressed significantly compared to placebo treatment (95% CI -76 microns/day to -17 microns/day), whereas the growth rate during low-dose steroid treatment was indistinguishable from placebo treatment (95% CI -7 to +52 microns/day). In conclusion, measurement of short-term linear growth rate by knemometry in toddlers is a fast and gentle method with a high level of precision.(ABSTRACT TRUNCATED AT 250 WORDS)
BibTeX:
@article{,
  author = {Bisgaard, H.},
  title = {Systemic activity of inhaled topical steroid in toddlers studied by knemometry.},
  journal = {Acta Paediatr},
  school = {Department of Paediatrics, Rigshospitalet, State University Hospital of Copenhagen, Denmark.},
  year = {1993},
  volume = {82},
  number = {12},
  pages = {1066--1071}
}
Fogh, J. Bisgaard, H. A specific assay for leukotriene B4 in human whole blood. 1992 J Pharmacol Toxicol Methods 1338371 2,405 4
Authors: Fogh, J., Poulsen, L.K. and Bisgaard, H.
Abstract: Leukotrienes (LTs) are potent mediators of inflammatory and allergic responses, and are present in biological fluids in minute amounts, that is, in the picogram range. The aim of this study was to develop and validate a method for determination of LTB4 synthesized in vitro in human whole blood. Heparinized blood was stimulated with calcium-ionophore A23187 at 37 degrees C. After 30 min cells were separated by centrifugation. LTB4 was analyzed by radioimmunoassay (RIA). When sample preparation was restricted to protein precipitation with acetone, interference was demonstrated by lack of parallelism between standard and sample dilution curves. Purification was, therefore, extended by combinations of the following steps: 1) protein precipitation, 2) lipid extractions, and 3) high-performance liquid chromatography (HPLC). One of two commercially available LTB4 standards was found to contain multiple components, several of which were immunoreactive in RIA. Even for the standard containing pure LTB4, interference was demonstrated by lack of parallelism between sample and standard dilution curves. Testing eight combinations of varying purification steps, we found that only a three-step purification procedure, including 1) solid-phase extraction, 2) protein precipitation at -20 degrees C, and 3) HPLC, was able to eliminate interference in RIA. Using this procedure, the recovery was 78%. Stimulation of whole blood from normal subjects with calcium-ionophore showed optimal LTB4 production at 10 microM ionophore, yielding 6.6 ng LTB4/mL blood.
BibTeX:
@article{,
  author = {Fogh, J. and Poulsen, L. K. and Bisgaard, H.},
  title = {A specific assay for leukotriene B4 in human whole blood.},
  journal = {J Pharmacol Toxicol Methods},
  school = {Laboratory of Medical Allergology, National University Hospital, Copenhagen, Denmark.},
  year = {1992},
  volume = {28},
  number = {4},
  pages = {185--190}
}
Dein, T. Norn, S. Histamine release after nasal challenge with anti-IgE and Staphylococcus aureus in patients with allergic rhinitis. 1992 Pneumonol Alergol Pol 1284820 0 0
Authors: Dein, T., Kristensen, K.S., Bisgaard, H., Espersen, F., Clementsen, P., Permin, H., Skov, P.S. and Norn, S.
BibTeX:
@article{,
  author = {Dein, T. and Kristensen, K. S. and Bisgaard, H. and Espersen, F. and Clementsen, P. and Permin, H. and Skov, P. S. and Norn, S.},
  title = {Histamine release after nasal challenge with anti-IgE and Staphylococcus aureus in patients with allergic rhinitis.},
  journal = {Pneumonol Alergol Pol},
  school = {Depertment of Pharmacology, University of Copenhagen.},
  year = {1992},
  volume = {60 Suppl 2},
  pages = {22--26}
}
Clementsen, P. Norn, S. Bacteria-induced histamine release from human bronchoalveolar cells and blood leukocytes. 1991 Allergy 1708212 7,361 11
Authors: Clementsen, P., Milman, N., Struve-Christensen, E., Petersen, B.N., Pedersen, M., Bisgaard, H., Permin, H. and Norn, S.
Abstract: Histamine release induced by Staphylococcus aureus was examined in cells obtained by bronchoalveolar lavage (BAL) in non-atopic individuals. Approximately half of the individuals responded with mediator release to the bacterium, and the release was found to be time- and concentration dependent. No difference was found between the patients who responded and those who did not respond in regard to age, sex, smoker/non-smoker, % recovery of BAL-fluid, total cell count, differential cell counts, histamine content per mast cell, or diagnoses. Also stimulation of the BAL-cells with the calcium-ionophore A23187 resulted in histamine release. S. aureus-induced histamine release from basophils was examined in leukocyte suspensions obtained from the same individuals, and in all experiments release was found. The dose-response curves were similar to those obtained with BAL cells. The bacteria-induced mediator release from superficially lying cells in the airways epithelium might be of importance for the precipitation or exacerbation of bronchial asthma in respiratory tract infections.
BibTeX:
@article{,
  author = {Clementsen, P. and Milman, N. and Struve-Christensen, E. and Petersen, B. N. and Pedersen, M. and Bisgaard, H. and Permin, H. and Norn, S.},
  title = {Bacteria-induced histamine release from human bronchoalveolar cells and blood leukocytes.},
  journal = {Allergy},
  school = {Department of Pharmacology, University of Copenhagen, Denmark.},
  year = {1991},
  volume = {46},
  number = {1},
  pages = {45--51}
}
Bisgaard, H. Osterballe, O. Adrenal function in asthmatic children treated with inhaled budesonide. 1991 Acta Paediatr Scand 2035313 0 25
Authors: Bisgaard, H., Pedersen, S., Damkjaer Nielsen, M. and Osterballe, O.
Abstract: The effect of the inhaled topical steroid budesonide on adrenal function was evaluated in 33 children (aged 7-15 years) with moderate bronchial asthma. The trial was designed as a prospective single-blind study of the effect of budesonide in daily doses of 200 microgram through 400 microgram to 800 micrograms in three randomized consecutive periods of 8 weeks. The unstimulated diurnal production of cortisol was assessed by measurement of free cortisol in 24-hour urine samples at the end of each period. No significant dose-related suppression was found. The cortisol production did not differ significantly during treatment with 800 microgram budesonide as compared to treatment with 200 microgram budesonide (95% confidence interval: 74112. It is concluded, that budesonide is a topical steroid with a favourable ratio between topical and systemic effects in asthmatic children.
BibTeX:
@article{,
  author = {Bisgaard, H. and Pedersen, S. and Damkjaer Nielsen, M. and Osterballe, O.},
  title = {Adrenal function in asthmatic children treated with inhaled budesonide.},
  journal = {Acta Paediatr Scand},
  school = {Department of Paediatrics, University Hospital of Copenhagen, Denmark.},
  year = {1991},
  volume = {80},
  number = {2},
  pages = {213--217}
}
Bisgaard, H. Ohlsson, S.V. Inhaled budesonide for treatment of recurrent wheezing in early childhood. 1990 Lancet 1975851 47,831 131
Authors: Bisgaard, H., Munck, S.L., Nielsen, J.P., Petersen, W. and Ohlsson, S.V.
Abstract: 77 children, aged 11 to 36 months (mean 24) with moderately severe recurrent wheezing, were treated with budesonide pressurised aerosol 400 micrograms twice daily or placebo for 12 weeks in a double-blind, parallel-group trial. Aerosols were inhaled from a spacer with a facemask. Budesonide significantly improved symptom scores of wheezing, sleep disturbance, and patient happiness. The frequency of severe exacerbations that required a course of oral prednisolone was also significantly reduced. The treatment effect appeared to be fully established after 6-8 weeks and no side-effects could be ascribed to the active treatment. The findings indicate that young children below 3 years of age can inhale a pressurised aerosol from a spacer with a facemask. Use of topically active glucocorticosteroids with this simple device may reduce symptoms and distress in young children with moderately severe recurrent wheeze and dyspnoea, and possibly reduce their requirement for oral steroids.
BibTeX:
@article{,
  author = {Bisgaard, H. and Munck, S. L. and Nielsen, J. P. and Petersen, W. and Ohlsson, S. V.},
  title = {Inhaled budesonide for treatment of recurrent wheezing in early childhood.},
  journal = {Lancet},
  school = {Department of Paediatrics, University Hospital of Copenhagen, Denmark.},
  year = {1990},
  volume = {336},
  number = {8716},
  pages = {649--651}
}
Bisgaard, H. Venge, P. Allergen-induced increase of eosinophil cationic protein in nasal lavage fluid: effect of the glucocorticoid budesonide. 1990 J Allergy Clin Immunol 2185293 13,081 80
Authors: Bisgaard, H., Grønborg, H., Mygind, N., Dahl, R., Lindqvist, N. and Venge, P.
Abstract: It was our aim to study the effect of nasal allergen provocation on the concentration of eosinophil cationic protein (ECP) in nasal lavage fluid, with and without glucocorticoid pretreatment. Twenty grass-pollen sensitive volunteers were provoked outside the pollen season on 2 consecutive days after pretreatment for 2 weeks with the glucocorticoid, budesonide, as a nasal spray (400 micrograms/day) and with placebo with a double-blind, crossover design. Nasal lavage fluid was repeatedly collected during a 10-hour period to study both early and late-phase responses. 99mTechnetium-albumin was added to the lavage fluid, making it possible to calculate the amount of secretion and the degree of dilution. The results were as follows: (1) There was no correlation between ECP concentration and dilution factor in the individual samples. (2) The mean concentration of ECP in lavage fluid from untreated, prechallenge noses was 400 micrograms/L. (3) The ECP level did not increase during the early phase response. (4) There was a late occurring increase in the ECP concentration (6 to 24 hours). (5) This increase was completely inhibited by budesonide pretreatment. (6) The glucocorticoid therapy also reduced the prechallenge ECP concentration. In conclusion, allergen provocation in the nose results in a late occurring increase of ECP in nasal lavage fluid, and one of the therapeutic effects of topical glucocorticoid therapy may be an inhibition of the allergen-induced increase of this cytotoxic molecule.
BibTeX:
@article{,
  author = {Bisgaard, H. and Grønborg, H. and Mygind, N. and Dahl, R. and Lindqvist, N. and Venge, P.},
  title = {Allergen-induced increase of eosinophil cationic protein in nasal lavage fluid: effect of the glucocorticoid budesonide.},
  journal = {J Allergy Clin Immunol},
  school = {Department of Otorhinolaryngology, Rigshospitalet, Copenhagen, Denmark.},
  year = {1990},
  volume = {85},
  number = {5},
  pages = {891--895}
}
Lerche, A. Søndergaard, J. Prostaglandin E1 and prostaglandin F2 alpha in exudate in nickel allergy. 1989 Acta Derm Venereol 2566235 3,653 2
Authors: Lerche, A., Bisgaard, H., Kassis, V., Christensen, J.D. and Søndergaard, J.
Abstract: Ten nickel-allergic patients and 5 healthy control subjects participated in a study of the kinetics of the flux and concentration of migrated leukocytes and extracellular PGE1 and PGF2 alpha during a 48 h period, using a skin chamber technique. The patients were provided with two skin chambers, one with and one without nickel challenge. A higher flux of leukocytes, PGE1 and PGF2 alpha was observed during the second day of allergen exposure, while the concentrations probably due to dilution were unchanged or diminished, indicating an unspecific role of the prostaglandins during the contact allergic reaction. No correlations were found within the groups between the migration of leukocytes and the prostaglandin content.
BibTeX:
@article{,
  author = {Lerche, A. and Bisgaard, H. and Kassis, V. and Christensen, J. D. and Søndergaard, J.},
  title = {Prostaglandin E1 and prostaglandin F2 alpha in exudate in nickel allergy.},
  journal = {Acta Derm Venereol},
  school = {Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark.},
  year = {1989},
  volume = {69},
  number = {3},
  pages = {253--256}
}
Clementsen, P. Norn, S. Staphylococcus aureus and influenza A virus stimulate human bronchoalveolar cells to release histamine and leukotrienes. 1989 Agents Actions 2473614 0 24
Authors: Clementsen, P., Bisgaard, H., Pedersen, M., Permin, H., Struve-Christensen, E., Milman, N., Nüchel-Petersen, B. and Norn, S.
Abstract: Mediator release was examined from superficially lying cells in the airway epithelium obtained by bronchoalveolar lavage (BAL) in 13 non-atopic individuals. The BAL-cells were incubated (20 min, 37 degrees C) with Staphylococcus (Staph.) aureus or with human influenza A virus Staph. aureus was found to release histamine from cells from 7 of the 13 individuals and influenza A virus in 3 of 5 persons. Furthermore, Staph, aureus stimulated the BAL-cells to release leukotriene B4 in 7 of 11 subjects, whereas no release was found by influenza A virus in 7 examined persons. When cells from 4 persons were stimulated with Staph. aureus no release of leukotriene C4 was found. The mediator release caused by bacteria and virus might be of importance for the exacerbation of bronchial asthma in upper respiratory tract infections, since histamine is assumed to increase the epithelial permeability with entrance of allergens and other insulting particles, and leukotriene B4 facilitates airway inflammation.
BibTeX:
@article{,
  author = {Clementsen, P. and Bisgaard, H. and Pedersen, M. and Permin, H. and Struve-Christensen, E. and Milman, N. and Nüchel-Petersen, B. and Norn, S.},
  title = {Staphylococcus aureus and influenza A virus stimulate human bronchoalveolar cells to release histamine and leukotrienes.},
  journal = {Agents Actions},
  school = {Dept. of Pharmacology, University of Copenhagen, Denmark.},
  year = {1989},
  volume = {27},
  number = {1-2},
  pages = {107--109}
}
Bisgaard, H. Ohlsson, S. PEP-spacer: an adaptation for administration of MDI to infants. 1989 Allergy 2764262 7,361 5
Authors: Bisgaard, H. and Ohlsson, S.
BibTeX:
@article{,
  author = {Bisgaard, H. and Ohlsson, S.},
  title = {PEP-spacer: an adaptation for administration of MDI to infants.},
  journal = {Allergy},
  year = {1989},
  volume = {44},
  number = {5},
  pages = {363--364}
}
Bisgaard, H. Bisgaard, H. Sulphidoleukotrienes in human allergic diseases. 1989 Dan Med Bull 2651029 1,086 11
Authors: Bisgaard, H.
BibTeX:
@article{,
  author = {Bisgaard, H.},
  title = {Sulphidoleukotrienes in human allergic diseases.},
  journal = {Dan Med Bull},
  school = {University of Copenhagen, Denmark.},
  year = {1989},
  volume = {36},
  number = {2},
  pages = {142--159}
}
Lerche, A. Søndergaard, J. Lactoferrin, myeloperoxidase, lysozyme and eosinophil cationic protein in exudate in delayed type hypersensitivity. 1988 Allergy 2834974 7,361 11
Authors: Lerche, A., Bisgaard, H., Christensen, J.D., Venge, P., Dahl, R. and Søndergaard, J.
Abstract: A skin window technique was used to study the morphology of leucocytes in upper dermis and exudate during nickel challenge in patients with contact allergy to nickel. Contact allergic patients and healthy volunteers tested with a skin widow without addition of nickel to the chamber medium served as controls. The morphology of the leucocytes in dermis was studied in biopsies taken 8, 24, or 48 h after skin window application, and in a parallel test the morphology of the exudate was examined by sequential collection of the chamber medium during a 48 h period. The infiltrate in dermis of contact allergic patients with nickel challenge in the chamber medium showed a time-dependent increase of mononuclear cells, eosinophils and basophils and a concomitant decrease of polymorphonuclear granulocytes, characteristic of a combined specific and unspecific inflammation. The morphology of the exudate in contact allergic patients exposed to nickel showed a dominance of polymorphonuclear granulocytes throughout the study period, while mononuclear cells, eosinophils and basophils were detected at a much lower quantity and with a considerable delay. Further, we studied the kinetics of the leucocyte granule proteins: lactoferrin, myeloperoxidase, lysozyme and eosinophil cationic protein in exudate fluid in a parallel test. A significant higher flux was found for all during the second day of allergen exposure compared to contact allergic patients without allergen challenge as well as normal volunteers. The increased protein fluxes were not accompanied by an increased flux of polymorphonuclear granulocytes in the exudate.(ABSTRACT TRUNCATED AT 250 WORDS)
BibTeX:
@article{,
  author = {Lerche, A. and Bisgaard, H. and Christensen, J. D. and Venge, P. and Dahl, R. and Søndergaard, J.},
  title = {Lactoferrin, myeloperoxidase, lysozyme and eosinophil cationic protein in exudate in delayed type hypersensitivity.},
  journal = {Allergy},
  school = {Dept. of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark.},
  year = {1988},
  volume = {43},
  number = {2},
  pages = {139--145}
}
Bisgaard, H. Holgate, S.T. Leukotriene C4 and histamine in early allergic reaction in the nose. 1988 Allergy 3377145 7,361 25
Authors: Bisgaard, H., Robinson, C., Rømeling, F., Mygind, N., Church, M. and Holgate, S.T.
Abstract: We have examined the measurements of LTC4 and histamine in nasal lavage fluids and blown secretions as a possible model of the early mediator events during nasal allergy. A nasal challenge with grass pollen extract was undertaken on two separate occasions in 20 patients with a history of seasonal rhinitis and a positive immediate skin test to grass pollen. A 2 ml nasal lavage was performed before allergen challenge, and blown secretion collected separately 15 min after the provocation, followed by a final 2 ml nasal lavage. The dilution of nasal secretion by the lavage fluid was determined using 99mTc-labelled albumin as an exogenous marker added to the fluid. The amounts of admixture in the nasal lavages did not correlate to the concentrations of LTC4 and histamine, indicating that the variable amounts of nasal secretion in nasal lavage do not constitute a confounding variable for measurements of LTC4 and histamine. In the pre-challenge lavages, the median concentrations, of LTC4 and histamine were 1.7 and 52 nmol/l respectively. Following allergen challenge neither LTC4 nor histamine measured in nasal lavage showed any significant change from pre-challenge baseline values. However, measurements of both mediators in the blown secretion showed a significantly higher concentration than in the pre- or post-challenge lavage samples, compatible with transitory release during the acute allergic reaction. However, it seems doubtful whether measurements of LTC4 or histamine can be compared between blown secretion and nasal lavage fluid, even if the dilution factor is disregarded.(ABSTRACT TRUNCATED AT 250 WORDS)
BibTeX:
@article{,
  author = {Bisgaard, H. and Robinson, C. and Rømeling, F. and Mygind, N. and Church, M. and Holgate, S. T.},
  title = {Leukotriene C4 and histamine in early allergic reaction in the nose.},
  journal = {Allergy},
  school = {Department of Otorhinolaryngology, Rigshospitalet, Copenhagen, Denmark.},
  year = {1988},
  volume = {43},
  number = {3},
  pages = {219--227}
}
Bisgaard, H. Pelck, I. Adrenal function in children with bronchial asthma treated with beclomethasone dipropionate or budesonide. 1988 J Allergy Clin Immunol 3288682 13,081 99
Authors: Bisgaard, H., Damkjaer Nielsen, M., Andersen, B., Andersen, P., Foged, N., Fuglsang, G., Høst, A., Leth, C., Pedersen, M. and Pelck, I.
Abstract: The effect of inhaled beclomethasone dipropionate and budesonide on the adrenal function was studied in 30 children (aged 7 to 15 years) with mild bronchial asthma. The trial was designed as a prospective double-blind parallel study of the effect of stepwise increase of either beclomethasone dipropionate or budesonide from 200 micrograms through 400 micrograms, to 800 micrograms daily in three consecutive periods of 4 weeks. At the end of each period, the adrenal stress response was evaluated by measurements of serum cortisol and androstenedione during a short adrenocorticotropic hormone test. The unstimulated diurnal production of glucocorticosteroids was assessed by measurements of free cortisol in 24-hour urine samples. Free cortisol in urine was found a valid measure of the total diurnal excretion of cortisol metabolites, since it exhibited a good correlation to the fractional cortisol metabolites measured by gas chromatography. The adrenal response to adrenocorticotropic hormone stimulation was unaffected by treatment or dose. The unstimulated diurnal production of glucocorticosteroids demonstrated a highly significant dose-related suppression in response to the inhaled steroids. No significant difference was found between the two topical steroids (probability value 5.3, and yet the suppression was apparent in the group of children treated with beclomethasone dipropionate but not in the group of children treated with budesonide. Further studies are desirable in order to ascertain whether budesonide offers an improved ratio between beneficial anti-inflammatory effect and unwanted systemic activity.
BibTeX:
@article{,
  author = {Bisgaard, H. and Damkjaer Nielsen, M. and Andersen, B. and Andersen, P. and Foged, N. and Fuglsang, G. and Høst, A. and Leth, C. and Pedersen, M. and Pelck, I.},
  title = {Adrenal function in children with bronchial asthma treated with beclomethasone dipropionate or budesonide.},
  journal = {J Allergy Clin Immunol},
  school = {Department of Pediatrics, Rigshospitalet, Copenhagen, Denmark.},
  year = {1988},
  volume = {81},
  number = {6},
  pages = {1088--1095}
}
Stafanger, G. Koch, C. Effect of N-acetylcysteine on the human nasal ciliary activity in vitro. 1987 Eur J Respir Dis 3569447 0 10
Authors: Stafanger, G., Bisgaard, H., Pedersen, M., Mørkassel, E. and Koch, C.
Abstract: N-acetylcysteine (NAC) is widely used as a mucolytic agent, but the clinical and pharmacological effects of NAC are still unclear. It has recently been claimed in animal studies that NAC will stimulate ciliary beating frequency at low concentrations, while inhibiting beating at higher concentrations. Using a microphoto-oscillographic method combined with microperfusion technique, we studied the direct effect of NAC on human nasal cilia. NAC caused a direct dose- and time-related decrease in ciliary beating frequency, which was detectable at 2 mg/ml and reached statistically significant levels at 20 mg/ml. NAC at 200 mg/ml caused total cessation of movements within 15 s but this effect was completely reversible within 15 min of perfusion with medium alone. At no concentrations of NAC was beating frequency increased over base-line. NAC, however, had no effect on beating pattern. NAC seems to have a selective and fully reversible inhibitory effect on the beating frequency of human cilia in vitro.
BibTeX:
@article{,
  author = {Stafanger, G. and Bisgaard, H. and Pedersen, M. and Mørkassel, E. and Koch, C.},
  title = {Effect of N-acetylcysteine on the human nasal ciliary activity in vitro.},
  journal = {Eur J Respir Dis},
  year = {1987},
  volume = {70},
  number = {3},
  pages = {157--162}
}
Bisgaard, H. Pedersen, M. SRS-A leukotrienes decrease the activity of human respiratory cilia. 1987 Clin Allergy 3581463 0 56
Authors: Bisgaard, H. and Pedersen, M.
Abstract: We have studied the effects of the slow reacting substance of anaphylaxis (SRS-A) constituents leukotrienes (LT) C4 and D4 on the ciliary activity of human respiratory cells. The ciliary beat frequency on human nasal cells harvested by cell scraping from the inferior turbinate was measured in a blind design by a microphoto-oscillographic technique. A total of 740 ciliated cells from seventy-four cell scrapings were studied. Mean baseline of ciliary beat frequency was 10.2 Hz. The ciliary beat frequency exhibited a pronounced variability in the spontaneous changes between the cell scrapings, yet less so within cell samples from the cell scrapings. We, therefore, evaluated the effect of the test solutions relative to the spontaneous decrease found during simultaneous perfusion with control solution of samples from the same cell scrapings. LTC4, 3-300 nmol/l, caused a highly significantly dose-related decrease in the ciliary beat frequency by up to approximately 20% as compared to the corresponding control solution. The effect of LTC4 was significantly inhibited by the SRS-A receptor antagonist FPL 55712 (10 mumol/l), but not by indomethacin (10 mumol/l). LTD4, 300 nmol/l, also decreased the ciliary beat frequency. LTB4, which is a leukotriene, although without the sulphidopeptide side chain of the SRS-A leukotrienes, did not affect the ciliary beat frequency in a concentration of 100 nmol/l. This would seem to confirm the structure specificity of the elucidated effect of the SRS-A leukotrienes. Histamine (100 mumol/l) did not affect the ciliary beat frequency.(ABSTRACT TRUNCATED AT 250 WORDS)
BibTeX:
@article{,
  author = {Bisgaard, H. and Pedersen, M.},
  title = {SRS-A leukotrienes decrease the activity of human respiratory cilia.},
  journal = {Clin Allergy},
  year = {1987},
  volume = {17},
  number = {2},
  pages = {95--103}
}
Bisgaard, H. Mygind, N. Measurement of secretion in nasal lavage. 1987 Clin Sci (Lond) 3652626 4,936 27
Authors: Bisgaard, H., Krogsgaard, O.W. and Mygind, N.
Abstract: 1. The amount of admixture in nasal lavage fluids was determined by addition of 99mTc labelled albumin, providing a correction factor for measurements of cellular material and humoral substances in nasal lavage return as well as a quantitative measure of nasal secretions. 2. Albumin was chosen as marker molecule, since only negligible amounts were absorbed or adsorbed to the mucosa during the nasal lavage. 3. Labelling of the albumin with 99mTc ensured an accuracy of measurements only limited by the precision of the weighing. The isotope allowed for the determination of the amount of admixed secretion to be carried out on the whole sample of lavage fluid, thereby avoiding the necessity of complete admixture between marker and lavage fluid which would be pertinent to marker molecules measured chemically. The radiation from a nasal lavage is minimal and the procedure is fully acceptable for repeated use in humans. 4. The nasal lavage technique adopted allowed the return of 99.2% (median value) of the instilled volume. The area irrigated was visualized on a gamma-camera, and was demonstrated to cover an area larger than the area reached by challenge from a pumpspray, i.e. a large part of the nose, yet not the oropharynx. 5. A dose related increase in nasal secretion harvested by the nasal lavage in 10 persons challenged with histamine chloride could be demonstrated by this technique. 6. It is concluded that the use of 99mTc-albumin in a nasal washing provides a safe, simple and quick method for determination of the admixed nasal secretion with a remarkable degree of accuracy.(ABSTRACT TRUNCATED AT 250 WORDS)
BibTeX:
@article{,
  author = {Bisgaard, H. and Krogsgaard, O. W. and Mygind, N.},
  title = {Measurement of secretion in nasal lavage.},
  journal = {Clin Sci (Lond)},
  school = {Otopathological Laboratory, Rigshospitalet, Copenhagen, Denmark.},
  year = {1987},
  volume = {73},
  number = {2},
  pages = {217--222}
}
Bisgaard, H. Søndergaard, I. Nebulization and selective deposition of LTD4 in human lungs. 1987 Allergy 3631461 7,361 4
Authors: Bisgaard, H., Poulsen, L. and Søndergaard, I.
Abstract: The process of nebulization and deposition of LTD4 was studied in detail. The concentration of LTD4 in a saline solution decreased by approximately 90% after 2 min of nebulization in a DeVilbiss 35B ultrasonic nebulizer. This decrease was prevented by diluting LTD4 in a phosphate buffer, pH 7.4. Nebulization of tritiated LTD4 in this phosphate buffer did not cause any appreciable deterioration of the leukotriene, as demonstrated by an unchanged ratio between radioactivity and LTD4 concentration in the test solution before and after nebulization as well as in the condensed aerosol. The aerosol generated by the DeVilbiss 35B ultrasonic nebulizer was shown to generate particles with a mass median diameter of 1.3 microns (dry particle size). Interposition of a settling bag reduced the amount of large particles, reducing the mass median diameter to 0.84 microns (dry particle size). Nine healthy volunteers were challenged on separate days with 40 nmol LTD4 or 100 mumol histamine, and the changes in FEV1 and partial flow volume curves initiated at 50% of vital capacity (Vmax30) were measured. A relative diffuse deposition pattern was ensured by inhalation via a settling bag. These results were compared to challenges with a relatively central deposition pattern as ensured by inhalation directly from the nebulizer with brisk inhalation maneuvers. The diffuse deposition pattern caused minimal changes in FEV1 but pronounced effect in Vmax30. The effects of LTD4 and histamine on FEV1 and Vmax30 changed in parallel when the deposition of the mediators was changed to a more central pattern. This indicates that the two mediators do not differ with respect to any selective effects on different parts of the airways.
BibTeX:
@article{,
  author = {Bisgaard, H. and Poulsen, L. and Søndergaard, I.},
  title = {Nebulization and selective deposition of LTD4 in human lungs.},
  journal = {Allergy},
  year = {1987},
  volume = {42},
  number = {5},
  pages = {336--342}
}
Bisgaard, H. Groth, S. Bronchial effects of leukotriene D4 inhalation in normal human lung. 1987 Clin Sci (Lond) 2953527 4,936 19
Authors: Bisgaard, H. and Groth, S.
Abstract: The aim of the study was to investigate whether inhaled leukotriene (LT) D4 could mimic the characteristics of asthmatic patients after allergen-induced attack, i.e. a prolonged subclinical bronchial obstruction, an increased reactivity of the airways and a late reaction. The effects of LTD4 were compared with those of histamine and the mechanism of action sought. Thirty-three non-atopic individuals participated in the study. The two drugs were inhaled as an aerosol of small particles causing a relative peripheral deposition pattern in order to mimic the preferential involvement of peripheral airways in asthmatic patients out of attack. LTD4 caused a dose-dependent obstruction of the airways as measured by partial flow-volume curves and volume of trapped gas, yet only minor changes in forced expiratory volume in 1 s (FEV1) and peak expiratory flow rate. LTD4 was 1900-7000 times more potent than histamine. LTD4 inhalations were almost symptomless as opposed to the irritative and dyspnoeic symptoms seen after inhalation of histamine. The time duration for the induced change in partial flow-volume curves was the same for the two drugs. Approximately 30 min elapsed until the bronchial obstruction had decreased by 50% of the maximum effect, and no delayed reaction was observed within 10 h. The reactivity of the airways did not change during 10 h after inhalation of LTD4 as tested by repeated exercise challenges. Pretreatment with ipratropium bromide prevented the effect of LTD4 on FEV1, yet not on partial flow-volume curves. Pretreatment with either cimetidine and mepyramine or with indomethacin, did not affect the bronchial obstruction after LTD4.(ABSTRACT TRUNCATED AT 250 WORDS)
BibTeX:
@article{,
  author = {Bisgaard, H. and Groth, S.},
  title = {Bronchial effects of leukotriene D4 inhalation in normal human lung.},
  journal = {Clin Sci (Lond)},
  year = {1987},
  volume = {72},
  number = {5},
  pages = {585--592}
}
Bisgaard, H. Nyboe, J. Risk factors for wheezing during infancy. A study of 5,953 infants. 1987 Acta Paediatr Scand 3661172 0 52
Authors: Bisgaard, H., Dalgaard, P. and Nyboe, J.
Abstract: Risk factors for the development of wheezing during infancy were studied in 5,953 children. The data for the study were collected from a large prospective investigation of children born in 1959-61, who had attended a one-year follow-up examination. Wheezing was diagnosed when the symptom had been observed at least once during the first year of life, not in conjunction with pneumonia, epiglottitis or acute laryngitis. Logit analysis was used for the purpose of assessing the causal effect of environmental and other factors on the risk of wheezing among infants. The assessment of a risk factor by means of regression technique, requires certain other variables to be included in the regression model. A general rule concerning inclusion of other variables has been formulated and applied to the above data. The study demonstrated that the risk of wheezing was affected by a number of factors--particularly environmental. Poor social environment increases the risk of wheezing, as does the mother's smoking, and placement of the baby in day-care. Boys experienced wheezing more often than girls. Premature infants are more liable to develop wheezing than mature children. Remarkably, children born in the period April through September develop wheezing, but not bronchitis, more often than children born in October through March.
BibTeX:
@article{,
  author = {Bisgaard, H. and Dalgaard, P. and Nyboe, J.},
  title = {Risk factors for wheezing during infancy. A study of 5,953 infants.},
  journal = {Acta Paediatr Scand},
  school = {Unit for Prospective Paediatric Research, State University Hospital, Copenhagen, Denmark.},
  year = {1987},
  volume = {76},
  number = {5},
  pages = {719--726}
}
Bisgaard, H. Bisgaard, H. Laser Doppler flowmeter. 1987 Int J Dermatol 2960632 1,560 7
Authors: Bisgaard, H.
BibTeX:
@article{,
  author = {Bisgaard, H.},
  title = {Laser Doppler flowmeter.},
  journal = {Int J Dermatol},
  school = {Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark.},
  year = {1987},
  volume = {26},
  number = {8},
  pages = {511--512}
}
Bisgaard, H. Bisgaard, H. Vascular effects of leukotriene D4 in human skin. 1987 J Invest Dermatol 3805752 6,287 29
Authors: Bisgaard, H.
Abstract: Leukotriene D4 (LTD4) increased the blood flow rate in human skin, equipotent to histamine in the dose range of 3.1-200 pmol. The vasodilatation lasted for up to 60 min, and no late reactions occurred. Indomethacin did not affect the LTD4-induced blood flow rate. H1 and H2 antagonists reduced the increase in blood flow rate, but did not abolish the response to LTD4. Local nerve block inhibited the axon reflex-mediated flare component of the LTD4-induced blood flow rate, leaving a local red reaction. This local red reaction was not affected by H1 and H2 antagonists. These results indicate histamine as a mediator of the axon reflex, and show that LTD4 causes a direct vasodilatory effect that is not mediated via histamine or cyclooxygenase products. The laser-Doppler flowmeter was applied for dynamic studies of the vasopressor response in the skin during a Valsalva maneuver, and the relative changes in blood flow were confirmed by control estimates of the blood flow rate by a 133xenon washout method. The pressor response to a Valsalva maneuver was reversed by local nerve block, but not affected by LTD4. Therefore LTD4 did not interfere with the sympathetic activity on the cutaneous vessels. Leukotriene D4 caused a dose-dependent wheal reaction, equipotent to histamine in the dose range of 0.2-200 pmol. Only minor whealing occurred when the vasculature to the test arm was occluded before injection of LTD4 and the circulation restored 30 min later. Most of the LTD4 was apparently metabolized within this period. Subsequent injections of LTD4 into the same sites demonstrated the development of tachyphylaxis with respect to whealing. This evidence suggests that LTD4 cannot mediate sustained inflammation. The injections of LTD4 caused neither pain nor itching. In conclusion, the elucidated properties point to LTD4 as a possible mediator of microvascular changes during acute inflammation.
BibTeX:
@article{,
  author = {Bisgaard, H.},
  title = {Vascular effects of leukotriene D4 in human skin.},
  journal = {J Invest Dermatol},
  year = {1987},
  volume = {88},
  number = {2},
  pages = {109--114}
}
Kristensen, J.K. Søndergaard, J. New parameters for evaluation of blood flow in patients with leg ulcers. 1986 Acta Derm Venereol 2424219 3,653 8
Authors: Kristensen, J.K., Karlsmark, T., Bisgaard, H. and Søndergaard, J.
Abstract: Three new parameters have been introduced to provide data for quantitative evaluation of peripheral cutaneous blood flow in patients with leg ulcers. Reactive hyperemia was induced by occlusion of the blood flow for four minutes at the thigh-level. Blood flow was subsequently measured by laser-Doppler velocimetry in an unselected group of 14 patients with leg ulcers and a matched control group. The parameters used for evaluation was: 1) "peak flow" f(p), 2) divided by time to "peak flow" t(p), rendering a rate constant k (k = f(p)/t(p)) expressing the ability to increase blood flow abruptly in case of need. These parameters were all significantly reduced in the patients with leg ulcers, indicating that this simple and atraumatic technique was useful for discriminating blood flow values that may be relevant for healing time and with a sensitivity comparable to the measurements of distal systolic blood pressure. Distal systolic blood pressure measurements can still be considered to be of value when screening for arterial insufficiency in patients with leg ulcers. The values obtained were significantly lower in 36 patients with leg ulcers compared with 9 age-matched control persons.
BibTeX:
@article{,
  author = {Kristensen, J. K. and Karlsmark, T. and Bisgaard, H. and Søndergaard, J.},
  title = {New parameters for evaluation of blood flow in patients with leg ulcers.},
  journal = {Acta Derm Venereol},
  year = {1986},
  volume = {66},
  number = {1},
  pages = {62--65}
}
Fogh, H. Kristensen, J.K. [The Marstock method. A method for measuring sensitivity and pain thresholds]. 1986 Ugeskr Laeger 3787833 0 0
Authors: Fogh, H., Bisgaard, H. and Kristensen, J.K.
BibTeX:
@article{,
  author = {Fogh, H. and Bisgaard, H. and Kristensen, J. K.},
  title = {[The Marstock method. A method for measuring sensitivity and pain thresholds].},
  journal = {Ugeskr Laeger},
  year = {1986},
  volume = {148},
  number = {45},
  pages = {2916--2918}
}
Bisgaard, H. Bende, M. Effect of leukotriene D4 on nasal mucosal blood flow, nasal airway resistance and nasal secretion in humans. 1986 Clin Allergy 2427255 0 154
Authors: Bisgaard, H., Olsson, P. and Bende, M.
Abstract: The possible role of leukotriene D4 (LTD4) in nasal allergy was investigated in healthy volunteers. Nasal blood flow, nasal airway resistance, nasal discharge and nasal itching and sneezing were examined. LTD4 was found to induce a dose-response related increase in nasal mucosal blood flow as measured by laser-Doppler flowmetry. Histamine exhibited similar effects on blood flow in the same concentration range. Nasal airway resistance as recorded by rhinomanometry, increased in a dose-related manner after topical LTD4. Nasal secretion was obtained by nasal lavage and estimated from a dilution principle. Topical LTD4 did not increase the amount of nasal secretion, whereas a dose-related increase was found after topical histamine. LTD4 did not cause itching, sneezing or other irritative symptoms. In conclusion, LTD4 may play a role in nasal allergy by increasing blood flow and nasal airway resistance. Itching, sneezing and discharge, however, are apparently not caused by LTD4 but ca