Publications

COPSAC publications

First Author	Senior Author	All authors	Title	Year	Journal	PMID	Impact Factor	# Citations	Abstract	keywords
Lerche A	Søndergaard J	Lerche A, Bisgaard H, Christensen JD, Søndergaard J	Human leukocyte mobilization and morphology in nickel contact allergy using a skin chamber technique	1981	ACTA DERM-VENEREOL	6177163	3,653	3	An improved skin chamber technique has been devised and used for quantitative evaluation of the leukocyte mobilization rate (LMR). The method was applied in 10 nickel-hypersensitive patients exposed to nickel sulphate. Each patient served as his own control and for additional control purpose, 5 healthy individuals without nickel hypersensitivity were studied. The kinetics of the mobilized leukocytes were followed over a 48-hour period. After an initial lag phase of 2-4 hours, maximum migration was observed from the 24th to the 48th hour, with a wide interindividual variability in the number of mobilized cells at the time of maximum LMR response. The median cumulative leukocyte count was 1.412 x 10(6) leukocytes/cm2/48 h. In the same period a statistically significant increase in the basophils for all the nickel allergic patients was observed. In 8 out of 10 patients a statistically significant effect upon the lymphocytes could be demonstrated. Six of these 8 patients had an increased lymphocyte mobilization. Throughout the period the neutrophil granulocytes were the dominant cell type, although the number decreased as the number of basophils and lymphocytes increased. The chamber technique is a valuable means for quantitative evaluation of leukocyte mobilization and morphology in skin exudates during exposure to an allergen in delayed hypersensitivity reactions.	Adult, Aged, Cell Migration Inhibition, Dermatitis, Contact/diagnosis/etiology/immunology, Female, Humans, Leukocyte Count, Leukocytes/immunology, Male, Middle Aged, Nickel/adverse effects, Skin Tests/*methodsAged
Dahl R	Bisgaard H	Dahl R, Bisgaard H	[Bronchial asthma and chromium allergy precipitated by steel welding]	1982	UGESKR L	7101512	0	0	0	0
Bisgaard H	Søndergaard J	Bisgaard H, Kristensen J, Søndergaard J	The effect of leucotriene C4 and D4 on cutaneous blood flow in humans	1982	PROSTAG OTH LIPID M	7122908	0	98	Using a laser-Doppler-flowmeter the microvascular response to LTC4 and LTD4 was measured. Intradermal injection of 1 microgram LTC4 and LTD4 caused an increase in the microvascular cutaneous bloodflow. The increase in flow was equal to that caused by histamine in equimolar amounts. Blocking the triple-response did not change the response. The values measured after injection of histamine and leucotrienes were about 10-15 times the values found in undisturbed skin and represents probably a maximally dilated vascular bed. Injection of the leucotrienes caused a slight sensation of pain.	Adult, Humans, Injections, Intradermal, Lasers, Microcirculation/drug effects, Middle Aged, Regional Blood Flow/drug effects, SRS-A/administration & dosage/pharmacology, Skin/blood supply, Humans
Bisgaard H	Sondergaard J	Bisgaard H, Kristensen J, Sondergaard J	The effect of leukotrienes C4 and D4 on microcirculatory flow in humans	1983	BRIT J DERMATOL	6860580	4,706	5	By quantifying the flare response, leukotrienes LTC4 and LTD4 were shown to increase the microcirculatory flow in a sigmoidal dose-response relation over the dose-range of 6.25-800 pmol. LTD4 was found to be more potent than LTC4 after 5 min, but not after 15 min, as estimated by this method. Laser-Doppler flowmeter studies confirmed that LTD4 is a more potent vasodilator than LTC4.	Blood Flow Velocity, Dose-Response Relationship, Drug, Erythema/chemically induced, Humans, Microcirculation/drug effects, Regional Blood Flow/drug effects, SRS-A/pharmacology, Skin/blood supply, Time Factors, Dose-Response Relationship, Drug
Bisgaard H	Dirksen H	Bisgaard H, Groth S, Dirksen H	Leukotriene D4 induces bronchoconstriction in man	1983	ALLERGY	6625125	7,361	21	The effect of leukotriene D4 (LTD4) on lung function was investigated in a controlled study on four normal subjects. A pronounced decrease in airflow was found after inhalation of less than 0.5 nmol, and was most pronounced in the variables generally accepted as indicators of the function of the small airways. No subjective symptoms were experienced.	Asthma/physiopathology, Bronchi/drug effects, Humans, Pulmonary Ventilation/drug effects, SRS-A/immunology/pharmacology, Bronchi/drug effects
Bisgaard H	Madsen F	Bisgaard H, Groth S, Taudorf E, Madsen F	The possible role of LTD4 in asthma in humans investigated in vivo	1984	BIOMED BIOCHEM ACTA	6393971	0	2	The bronchoconstrictor effect of LTD4 was tested in a double blind design in 9 healthy volunteers who inhaled 10 and 40 nmol synthetic LTD4, 10 and 100 mumol histamine, and placebo on 5 different days. As the nebulized testsolutions were administered via a settling bag, an even deposition on the airways could be expected, and consequently a relative predominans of the changes measuring the airflow in the small airways. Accordingly the PEF values were reduced by less than 5% for both active substances. The function of the small airways was measured by (1) the volume of trapped gas in percentage of the total lung capacity, and (2) maximal expiratory flow rate at 30% of vital capacity above residual volume, determined from partial flow-volume curves. A dose-dependent bronchial obstruction was revealed. LTD4 was 3 to 4 decades more potent than histamine on a log molar scale. Pronounced dyspnoea and systemic side effects were experienced after inhalation of histamine whereas LTD4 did not cause any symptoms. Adrenergic beta 2-agonist (Fenoterol) was in all cases capable of reversing the LTD4 induced bronchospasm. 6 patients with verified exogenous asthma were tested in a similar double blind set-up for their reactivity to LTD4. The asthmatics were hyperreactive to LTD4.	Adolescent, Adult, Asthma/physiopathology, Clinical Trials as Topic, Double-Blind Method, Female, Humans, Male, Middle Aged, Reference Values, Respiratory Function Tests, SRS-A/diagnostic useAdult
Bisgaard H	Taudorf E	Bisgaard H, Ford-Hutchinson AW, Charleson S, Taudorf E	Detection of leukotriene C4-liked immunoreactivity in tear fluid from subjects challenged with specific allergen	1984	PROSTAG OTH LIPID M	6729144	0	46	Tear fluid was obtained from allergic subjects from control eyes and eyes challenged with specific allergen and levels of leukotriene C4 (LTC4)-immunoreactivity determined by radioimmunoassay. Formal identification of the leukotrienes released was not possible but the levels of LTC4-immunoreactive material in allergen-challenged tear fluid (4.9 +/- 2.3 ng/ml, n = 9) were significantly higher (p less than 0.01) than those in control tear fluid (0.07 +/- 0.06 ng/ml, n = 9). These results provide evidence that leukotrienes, which account for the biological activity of slow reacting substance of anaphylaxis, may be released in allergic reactions in vivo in man.	Adult, Aged, Allergens, Cross Reactions, Female, Humans, Immune Sera, Male, Middle Aged, Poaceae, Radioimmunoassay/methods, Rhinitis, Allergic, Seasonal/immunology, SRS-A/analysis, Aged, Tears/*analysis/immunology,
Bisgaard H	Bende M	Bisgaard H, Olsson P, Bende M	Leukotriene D4 increases nasal blood flow in humans	1984	PROSTAG OTH LIPID M	6233637	0	31	The effect of leukotriene D4 on the nasal mucosal blood flow in humans was measured using a laser doppler flow meter. The leukotriene solution was applied topically to the nasal mucosa in 9 healthy subjects, and changes in blood flow were measured non-traumatically by the laser doppler instrument. The response showed a consistent increase in blood flow. A dose-response was found in the range of 0.063 - 4.0 nanomole. These results confirm an earlier study on the human skin, implicating leukotriene D4 as an important vasodilator in humans. No increase in nasal secretion was noted by the subjects tested.	Administration, Topical, Dose-Response Relationship, Drug, Humans, Lasers, Nasal Mucosa/blood supply, Regional Blood Flow/drug effects, Rheology, SRS-A/administration & dosage/pharmacologyDose-Response Relationship, Drug
Lerche A	Søndergaard J	Lerche A, Bisgaard H, Christensen JD, Søndergaard J	Human leukocyte cyclic AMP and cyclic GMP levels during chemotaxis in delayed type hypersensitivity	1984	ALLERGY	6324609	7,361	2	Ten nickel-allergic patients and six healthy control subjects participated in a study of the morphology, kinetics and evolution of the cAMP and cGMP concentrations of migrated leukocytes, using an improved skin chamber technique. Also studied was the effect of nickel exposure in the chamber medium during development of an eczematous reaction in the nickel-allergic patients. Nickel exposure had a specific effect on the morphology, from the 24th hour to the end of the 48 h observation period, with a significant increase in the percentages of basophils, eosinophils and lymphocytes and a decrease of neutrophils. A significantly increased leukocyte migration rate (LMR) was observed from the 27th to 39th hour in six of the allergic patients exposed to nickel. There were no specific permanent changes in cAMP and cGMP concentrations during nickel exposure. The control chambers of the allergic patients and healthy controls had identical leukocyte morphology, LMR and leukocyte concentrations of cAMP and cGMP. However, no correlations were found between LMR, cAMP and cGMP in the eczema patients throughout the observation period.	Adult, Aged, Cell Movement, Chemotaxis, Leukocyte, Cyclic AMP/blood, Cyclic GMP/blood, Dermatitis, Contact/etiology, Female, Humans, Hypersensitivity, Delayed/blood/immunology, Leukocytes/analysis/cytology, Male, Middle Aged, Aged, Nickel/adverse effects, Skin Tests
Bisgaard H	Osterballe O	Bisgaard H, Andersen JB, Bach-Mortensen N, Bertelsen A, Friis B, Koch C, Prahl P, Wichmann R, Osterballe O	A clinical comparison of aerosol and powder administration of beclomethasone dipropionate in childhood asthma	1984	ALLERGY	6380331	7,361	8	Forty children with childhood asthma were conducted through a double-blind cross-over study to compare the effect of 400 micrograms beclomethasone dipropionate administered as aerosol and powder (Rotacaps). Children with severe asthma derived more benefit from the steroid administered as aerosol judged from their peak flow performance in the morning, although neither evening peak flow nor symptom scores revealed any difference. It is concluded that the Rotacaps are an advantageous supplement to available medication for the treatment of asthmatic children, although it should be observed that, using equal amounts of BDP, powder administration seems less effective than aerosol.	Adolescent, Aerosols, Asthma/drug therapy, Beclomethasone/administration & dosage, Child, Clinical Trials as Topic, Double-Blind Method, Humans, Powders, Aerosols
Svenson M	Bendtzen K	Svenson M, Bisgaard H, Bendtzen K	Effects of leukotrienes on neutrophil migration, and on production and action of lymphokines	1984	ALLERGY	6093614	7,361	5	The effect of the leukotrienes LTB4, LTC4 and LTD4 on the production of the lymphokine leukocyte migration inhibitory factor (LIF) from human peripheral blood mononuclear cells was tested. LTC4 and LTD4 failed to influence LIF production by cells stimulated by antigen or the polyclonal T cell activator, phytohemagglutinin (PHA). LTB4, at concentrations 10(-7) to 10(-6) M, showed significant inhibition of antigen-induced LIF production but was without effect when cells were stimulated by PHA. The cell levels of cyclic adenosine monophosphate (cAMP) were unaffected by 2.5 X 10(-7) M LTB4 in the absence or presence of theophylline. These results indicate that LTB4 acts on the early effector stage of the immune response without affecting the cellular cAMP content.	Antibody Formation, Blood Cells/metabolism, Cyclic AMP/biosynthesis, Cyclic GMP/biosynthesis, Granulocytes/metabolism, Humans, Leukocyte Migration-Inhibitory Factors/physiology, Leukotriene B4/pharmacology, Lymphokines/*physiology, Blood Cells/metabolism
Bisgaard H	Bisgaard H	Bisgaard H	Leukotrienes and prostaglandins in asthma	1984	ALLERGY	6208802	7,361	24	Leukotrienes and prostaglandins possess properties which are central in the asthmatic reaction. They are bronchoconstrictors, they inhibit the mucociliary clearance, increase blood flow and permeability and thereby induce edema formation, and they attract and activate leukocytes. They are formed partly by allergic reactions and partly by a large number of other more non-specific reactions. Finally, the concentration of prostanoids has been found increased in the asthmatic reaction in vivo. The leukotrienes have not been traced in vivo in asthmatic attacks so far, but have been found in vivo in man in a specific type I allergic conjunctival reaction. Much evidence suggests that these mediators are relevant in asthmatic diseases, even though prostaglandin inhibitors have no effect in asthma. There still remains the need to investigate the influence on asthmatic diseases by as yet unavailable leukotriene blocking agents. Even though leukotrienes are judged today to be important mediators in asthma, it does not seem reasonable to expect that a single mediator is responsible for asthmatic diseases. Rather, it seems quite likely that asthma is caused by a complex interplay of a large number of mediators, circulating hormones, nervous mechanisms, receptor abnormalities, intracellular metabolic defects, etc. Despite this complexity, investigations in recent years have increased the knowledge of the biochemistry and human physiological effects of leukotrienes and prostaglandins which has created an improved understanding of the asthmatic reaction's pathophysiology, contributed a pharmacological rationale for previously used therapy, and stimulated new perspectives for specific pharmacological research.	Anti-Inflammatory Agents/pharmacology, Arachidonic Acid, Arachidonic Acids/biosynthesis/metabolism, Asthma/complications/physiopathology, Autacoids/metabolism, Bronchial Spasm/chemically induced, Ciliary Motility Disorders/etiology, Cyclooxygenase Inhibitors, Edema/chemically induced, Enzyme Inhibitors, Histamine Release, Humans, Leukotriene B4/physiology, Arachidonic Acid, Leukotrienes, Mast Cells/metabolism, Prostaglandins/physiology,
Bisgaard H	Kristensen JK	Bisgaard H, Kristensen JK	Quantitation of microcirculatory blood flow changes in human cutaneous tissue induced by inflammatory mediators	1984	J INVEST DERMATOL	6470522	6,287	24	The cutaneous microcirculation is a desirable model for pharmacologic and physiologic studies of inflammatory mediators. For exact measurements of the induced blood flow changes, two objective methods are introduced. The laser-Doppler flowmeter and the 133Xe washout technique have formerly been used for measurement of the undisturbed cutaneous blood flow. We have modified these methods to measure changes in the blood flow following intracutaneous deposition of a vasodilator, leukotriene D4. When compared with a metric estimate of the erythemal response, the two new methods were found to be more sensitive than the traditional estimate of cutaneous blood flow changes. Both methods exhibited a good sensitivity and reproducibility when applied simultaneously, although the 133Xe washout technique appeared to be able to separate interindividual differences that could not be recognized by the laser-Doppler technique. Even though the laser-Doppler technique is superior in simplicity of use, the 133Xe washout technique is recommended for exact measurements.	Adult, Blood Flow Velocity, Dose-Response Relationship, Drug, Erythema/chemically induced/physiopathology, Female, Humans, Male, Microcirculation/drug effects, Middle Aged, Regional Blood Flow/drug effects, SRS-A/pharmacology, Skin/*blood supply/drug effects, Skin Tests, Blood Flow Velocity
Bisgaard H	Kristensen JK	Bisgaard H, Kristensen JK	Effects of synthetic leukotriene D-4 on the local regulation of blood flow in human subcutaneous tissue	1985	PROSTAG OTH LIPID M	3856899	0	6	Prostaglandin E-1 and E-2 acts as vasodilators partly through inhibition of sympathetic nerves and partly through a direct action on smooth muscle. To elucidate the mechanisms of LTD-4 induced vasodilation, the vascular smooth muscle dependent auto-regulation of blood flow and the sympathetic reflex mechanism of the "vasoconstrictor reflex" was investigated in humans. Blood flow was measured in subcutaneous tissue after injection of 133-Xenon 1) alone, 2) mixed with lidocaine 20 mg/ml for sympathetic blockade, 3) mixed with PGE-2 0.1 ug/ml and 4) mixed with LTD-4 in concentrations of 5 and 20 microM. Blood flow was kept constant during elevation by 20 cm above heart level (preserved autoregulation) except after injection of PGE-2 and LTD-4 20 microM where a significant decrease was observed (defective smooth muscle function). During lowering by 45 cm, a decrease in blood flow by 50% was observed in experiment 1. This response was blocked by lidocaine and PGE-2, partially blocked by LTD-4 20 microM but unaffected by LTD 5 microM. LTD-4 affects vascular smooth muscle function but does not affect sympathetic reflexes in concentrations which does not have a direct smooth muscle action.	Adult, Aged, Dinoprostone, Humans, Lidocaine/pharmacology, Middle Aged, Prostaglandins E/pharmacology, Regional Blood Flow/drug effects, SRS-A/pharmacology, Skin/blood supplyAged
Bisgaard H	Kristensen JK	Bisgaard H, Lerche A, Kristensen JK	Leukotriene- and histamine-induced increases in vascular permeability and interstitial transport in the skin	1985	J INVEST DERMATOL	3889168	6,287	22	The aim of the present study was to investigate the edema induced by leukotriene D4 (LTD4). Edema is the gross effect of increased blood flow and capillary permeability. Our objective was to elucidate the effect of LTD4 on edema generation without the influence of the concomitantly increased blood flow induced by this potent vasodilator. A new method was outlined measuring the exudation through skin windows of a macromolecular tracer [( 131I]albumin) and a micromolecular tracer [( 99Tc]pertechnetat). Exudation of [131I]albumin is a function of enhanced vascular permeability and interstitial transport and blood flow, whereas that of [99Tc] pertechnetat is mainly a function of blood flow. Thus a ratio of the 2 exudate measurements gives a specific estimate of the changes in vascular permeability and interstitial transport. Histamine was employed to establish the method. A dose-response relation was found for histamine in the dose range of 10(-4) to 10(-7) M. The effect of 10(-5) M LTD4 on vascular permeability and interstitial transport of macromolecules was indistinguishable from that of histamine in the same concentration. This property together with their well-known vasodilatory capabilities indicate that the leukotrienes of the slow-reacting substance of anaphylaxis may play a role in the vascular changes in the allergic-inflammatory reaction.	Adult, Aged, Biological Transport/drug effects, Capillary Permeability/drug effects, Dose-Response Relationship, Drug, Extracellular Space/drug effects, Female, Histamine/pharmacology, Humans, Male, Middle Aged, SRS-A/pharmacology, *Skin Window Technique, Aged
Bisgaard H	Madsen F	Bisgaard H, Groth S, Madsen F	Bronchial hyperreactivity to leucotriene D4 and histamine in exogenous asthma	1985	BRIT MED J	3922535	20,785	87	Reactivity of the small and large airways to inhaled leucotriene D4, one of the leucotrienes that constitute slow reacting substance of anaphylaxis, was studied in eight patients with exogenous asthma and nine healthy subjects with no history of atopy. Non-cumulative dose response relations were constructed for leucotriene D4 in a randomised, double blind set up. Reactivity to the leucotriene was compared with reactivity to histamine in the two groups. Both groups reacted to leucotriene D4 with significant airway obstruction evident in forced expiratory volume in one second (FEV1), peak expiratory flow rate, maximal expiratory flow rate at 30% of forced vital capacity estimated from a partial flow volume curve initiated at 50% of vital capacity (V30), and an increase in volume of trapped gas. The airways of the patients were significantly (p less than 0.01) more reactive to leucotriene D4 than those of the controls. The differences were in order of magnitude, 10(2)-10(3) for FEV1 but only about 15 for V30 (p less than 0.05). The hyperreactivity of the airways of the asthmatic subjects to leucotriene D4 was comparable to that to histamine. Inhalation of leucotriene D4 caused pronounced dyspnoea only among the patients. The findings suggest a role for leucotriene D4 in human bronchial asthma.	Adolescent, Adult, Airway Resistance/drug effects, Asthma/immunology/physiopathology, Bronchi/drug effects, Clinical Trials as Topic, Dose-Response Relationship, Drug, Double-Blind Method, Female, Forced Expiratory Volume, Histamine/pharmacology, Humans, Male, Adult, Peak Expiratory Flow Rate, SRS-A/pharmacology, Vital Capacity,
Bisgaard H	Taudorf E	Bisgaard H, Ford-Hutchinson AW, Charleson S, Taudorf E	Production of leukotrienes in human skin and conjunctival mucosa after specific allergen challenge	1985	ALLERGY	2996379	7,361	61	The production of leukotrienes has been monitored in tear fluids from subjects following a conjunctival provocation test, and skin blister fluids following initiation of a Prausnitz-Kustner reaction. In tear fluids elevated levels of leukotriene C4 (LTC4)-immunoreactive material were measured following allergen challenge as compared to control tear fluid obtained by mechanical or reflex stimulation. Analysis by high performance liquid chromatography indicated the presence of LTC4, LTD4 and LTE4. In the skin, significantly elevated levels of LTC4-immunoreactive material were measured following allergen challenge in the Prausnitz-Kustner reaction. HPLC analysis indicated the presence of both LTC4 and LTD4. LTB4 immunoreactive material was detected both in the tear fluid and the skin tissue fluid. However, no significant increase occurred in either tissue after the allergic reactions. These results indicate that the SRS-A leukotrienes are released in vivo in man following allergen challenge, and indicate these mediators may be important in human allergic diseases.	Adolescent, Adult, Conjunctiva/immunology, Female, Humans, Hypersensitivity/physiopathology, Leukotriene B4/metabolism, Male, Radioimmunoassay, SRS-A/immunology/metabolism, Skin/immunology, Tears/immunologyAdult
Bisgaard H	Kristensen JK	Bisgaard H, Kristensen JK	Leukotriene B4 produces hyperalgesia in humans	1985	PROSTAG OTH LIPID M	3001832	0	49	During inflammation, pain receptors are sensitized by inflammatory mediators causing hyperalgesia. Leukotriene B4 (LTB4) is a potent chemoattractant for polymorphonuclear leukocytes in humans in vivo. In the present study we have demonstrated a reduction of the pain threshold in humans after intracutaneous deposition of LTB4. The pain threshold was quantitated by the "Marstock" method in which the testsubject reversed the direction of the temperature change of a thermostimulator whenever a painful temperature was reached. This enabled a quantitative description of the persons pain sensibility. After intracutaneous infiltration of LTB4 (10 microM) a highly significant decrease in the pain threshold could be detected as compared to control with a maximum effect between 6 and 24 h. The decrease in the pain threshold amounted to less than 15% when compared to control and corresponds with the published kinetics of the influx of polymorphonuclear leukocytes. These results support the hypothesis that LTB4 produces hyperalgesia indirectly through recruitment of polymorphonuclear leukocytes and not via a direct effect on the pain receptors. Inhibition of the lipoxygenase might be an advantageous adjunct to the effect of the Non Steroidal Anti-Inflammatory Drugs.	Humans, Hyperalgesia/chemically induced, Hyperesthesia/chemically induced, Leukotriene B4/pharmacology, Pain/physiopathology, Sensory Thresholds/drug effectsHyperalgesia/chemically induced
Søndergaard J	Thorsen S	Søndergaard J, Bisgaard H, Thorsen S	Eicosanoids in skin UV inflammation	1985	PHOTODERMATOL PHOTO	3912734	2,662	41	Several studies have implicated the eicosanoids as mediator substances in different types of UV inflammation. In human UV erythema, various arachidonic acid metabolites--mainly cyclooxygenase products--have been detected, particularly in skin exudates. The concentration and the sequence of release of the various eicosanoids vary in relation to the time course and the various types of UV-induced erythema. UVB, UVC but not UVA erythema at its maximum was only to some extent inhibited by indomethacin despite almost complete inhibition of the synthesis of prostaglandins E2 and F2 alpha. A major issue cannot, as yet, be answered satisfactorily: are one or a number of eicosanoids per se causing the erythema or are they only passive bystanders released by damage to cellular structures? Until further evidence has been provided, the causative role of E and F prostaglandins in relation to development of UV erythema is doubtful. By contrast, PGI2 is a more likely candidate in this respect, being synthesized and released close to the events occurring in the vessel walls. The lipoxygenase pathway is still too unexplored for proper evaluation with regard to a role in the pathogenesis, but the pharmacological properties of leukotrienes and hydroxy-fatty acids may qualify them as potential candidates alone or in a concert of mediator events occurring during the developments of UV inflammation.	Animals, Anti-Inflammatory Agents/pharmacology, Arachidonic Acids/metabolism/pharmacology, Dermatitis/metabolism, Erythema/metabolism, Humans, Prostaglandins/biosynthesis, Skin/radiation effects, Ultraviolet Rays/adverse effects, Anti-Inflammatory Agents/pharmacology
Kristensen JK	Søndergaard J	Kristensen JK, Karlsmark T, Bisgaard H, Søndergaard J	New parameters for evaluation of blood flow in patients with leg ulcers	1986	ACTA DERM-VENEREOL	2424219	3,653	8	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.	Adult, Aged, Blood Flow Velocity, Blood Pressure, Humans, Leg Ulcer/*physiopathology, Middle Aged, RheologyAged
Bisgaard H	Sondergaard J	Bisgaard H, Kristensen JK, Sondergaard J	A new technique for ranking vascular corticosteroid effects in humans using laser-Doppler velocimetry	1986	J INVEST DERMATOL	2943820	6,287	32	By combining laser-Doppler velocimetry with reactive hyperemia, induced by arterial occlusion of 4-min duration we have established a simple and atraumatic new ranking technique for assessing steroid potency. The experiments were performed in 19 healthy volunteers. Budesonide (Preferid) and placebo (vehicle) were applied under occlusion on the flexor aspect of the forearm for 2, 24, and 48 h. Blood flow was measured with a laser-Doppler flowmeter before and after arterial occlusion with a blood pressure cuff on the upper arm. The induced reactive hyperemia reaction was measured planimetrically on the registered curves. The steroid preparation caused a significant reduction of the hyperemia closely related to the application time. The reduction of the hyperemia was confirmed using the atraumatic 133Xe washout technique. In another group, hydrocortisone, hydrocortisone-butyrate (Locoid), budesonide (Preferid), and klobetasol (Dermovat) applied under occlusion for 1 h were compared. A significant dose-response relation corresponding to the expected rank-order efficacy was revealed. In 10 experiments, pretreatment with 50 mg indomethacin i.v. resulted in a significant reduction of the hyperemia reaction. As a hypothesis we therefore suggest that the reactive hyperemia reaction amplifies the vascular events and unmasks steroid-induced inhibition of the synthesis of arachidonic acid metabolites.	Adrenal Cortex Hormones/pharmacology, Adult, Aged, Dose-Response Relationship, Drug, Female, Humans, Lasers/diagnostic use, Male, Middle Aged, Prostaglandins/biosynthesis, Rheology, Skin/blood supply/drug effectsAdult
Bisgaard H	Bende M	Bisgaard H, Olsson P, Bende M	Effect of leukotriene D4 on nasal mucosal blood flow, nasal airway resistance and nasal secretion in humans	1986	CLIN ALLERGY	2427255	0	156	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 can be accounted for by the release of histamine or other mediators.	Administration, Topical, Adolescent, Adult, Airway Resistance/drug effects, Dose-Response Relationship, Drug, Histamine Release/drug effects, Humans, Middle Aged, Nasal Mucosa/blood supply/drug effects/physiopathology/secretion, Regional Blood Flow/drug effects, Respiratory Hypersensitivity/physiopathology, Rheology, SRS-A/administration & dosage/immunology/*pharmacology, Adolescent, Ultrasonography,
Bisgaard H	Søndergaard J	Bisgaard H, Helqvist S, Boudet L, Venge P, Dahl R, Søndergaard J	Chemotactic activity of LTB4 in man	1986	ALLERGY	3021017	7,361	19	An improved skin window chamber technique has been developed and used for a quantitative study of the chemotactic effect of leukotriene B4 (LTB4). LTB4 (0.5 microM) was exposed to a skin window on the forearm of eight healthy volunteers, while phosphate buffered saline served as control in a skin window on the other forearm. Skin window exudates and samples of blood draining the skin window areas were collected after 1, 2, 4, 8, and 24 h. The samples were quantitated for the different types of leukocytes as well as the intra- and extracellular concentration of the eosinophilic cationic protein and lactoferrin as markers of eosinophil and neutrophil granulocytes. A significantly increased migration of neutrophil granulocytes into the skin window chamber containing LTB4 was found from the 2nd to the 8th hour after the initial LTB4 exposure. The eosinophils reached a significant peak at the 4th hour. The rise in the actual number of eosinophil cells did not reach significance, whereas measurements of the eosinophilic cationic protein in the cellular fraction of the exudate exhibited a significant increase as a reflection of the number of eosinophils. This highlights the potential clinical value of eosinophilic cationic protein measurements to reveal eosinophilia instead of the traditional eosinophil counts. Extracellular eosinophilic cationic protein and lactoferrin did not change significantly in the LTB4-exposed skin window, implying that LTB4 does not activate the eosinophils and neutrophils to exocytosis of their enzymes. The present in vivo results support the concept of LTB4 being a potent chemoattractant to neutrophil and less so to eosinophil granulocytes in humans, a chemoattractant that recruits the leukocytes but does not seem to activate them.	Adult, Blood Proteins/metabolism, Chemotaxis/drug effects, Eosinophil Granule Proteins, Eosinophils/drug effects/immunology/physiology, Female, Granulocytes/drug effects/metabolism, Humans, Lactoferrin/metabolism, Leukocyte Count, Leukotriene B4/immunology/physiology, Lymphocytes/drug effects/immunology/physiology, Male, Blood Proteins/metabolism, Neutrophils/drug effects/metabolism, *Ribonucleases, Skin Window Technique,
Fogh	J K Kristensen	Fogh, H, Bisgaard H, J K Kristensen	The Marstock method. A method for measuring sensitivity and pain thresholds	1986	UGESKR L	3787833	0	0	0	Herpes Zoster/physiopathology, Humans, Methods, Pain/physiopathology, Sensory Thresholds, Thermosensing/physiologyHumans
Bisgaard H	Thorsen S	Bisgaard H, Thorsen S	Leukotrienes In Allergic And Inflammatory Conditions	1986	UGESKR L	3027936	0	1	0	Humans, Hypersensitivity/immunology, Inflammation/immunology, Leukotriene B4/physiology, SRS-A/physiology, Hypersensitivity/*immunology
Bisgaard H	Bisgaard H	Bisgaard H	Vascular effects of leukotriene D4 in human skin	1987	J INVEST DERMATOL	3805752	6,287	30	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.	Adolescent, Adult, Female, Histamine/pharmacology, Histamine Antagonists/pharmacology, Humans, Indomethacin/pharmacology, Male, Middle Aged, Nerve Block, Pressoreceptors/physiology, SRS-A/pharmacology, Skin/blood supply/drug effects/innervation, Adult, Skin Tests, Valsalva Maneuver, Vasodilation/drug effects,
Stafanger G	Koch C	Stafanger G, Bisgaard H, Pedersen M, Mørkassel E, Koch C	Effect of N-acetylcysteine on the human nasal ciliary activity in vitro	1987	EUR J RESPIR DIS	3569447	0	10	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.	Acetylcysteine/pharmacology, Cilia/drug effects, Humans, In Vitro Techniques, Movement/drug effects, Nasal Mucosa/drug effects, Perfusion, Cilia/drug effects
Bisgaard H	Pedersen M	Bisgaard H, Pedersen M	SRS-A leukotrienes decrease the activity of human respiratory cilia	1987	CLIN ALLERGY	3581463	0	56	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)	Chromones/pharmacology, Cilia/drug effects, Depression, Chemical, Humans, In Vitro Techniques, Indomethacin/pharmacology, Respiratory System/cytology/drug effects, SRS-A/antagonists & inhibitors/pharmacologyCilia/drug effects
Bisgaard H	Groth S	Bisgaard H, Groth S	Bronchial effects of leukotriene D4 inhalation in normal human lung	1987	CLIN SCI	2953527	4,936	19	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)	Airway Resistance/drug effects, Bronchi/drug effects, Bronchial Provocation Tests, Dose-Response Relationship, Drug, Histamine/pharmacology, Humans, Ipratropium/pharmacology, SRS-A/pharmacologyBronchi/drug effects
Bisgaard H	Søndergaard I	Bisgaard H, Poulsen L, Søndergaard I	Nebulization and selective deposition of LTD4 in human lungs	1987	ALLERGY	3631461	7,361	4	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.	Adult, Aerosols, Asthma/diagnosis, Bronchial Provocation Tests, Chromatography, High Pressure Liquid, Female, Forced Expiratory Volume, Humans, Lung/metabolism, Male, Nebulizers and Vaporizers, Pulmonary Ventilation, SRS-A/administration & dosage/diagnostic use, Aerosols
Bisgaard H	Mygind N	Bisgaard H, Krogsgaard OW, Mygind N	Measurement of secretion in nasal lavage	1987	CLIN SCI	3652626	4,936	27	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)	Absorption, Adsorption, Adult, Female, Histamine/pharmacology, Humans, Iodine Radioisotopes/diagnostic use, Male, Middle Aged, Nasal Mucosa/drug effects/*secretion, Technetium Tc 99m Aggregated Albumin/diagnostic use, Therapeutic IrrigationAdsorption
Bisgaard H	Nyboe J	Bisgaard H, Dalgaard P, Nyboe J	Risk factors for wheezing during infancy. A study of 5,953 infants	1987	ACTA PAEDIATR SCAND	3661172	0	52	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.	Birth Weight, Child Day Care Centers, Female, Follow-Up Studies, Humans, Infant, Male, Prospective Studies, Respiratory Sounds/*etiology, Risk Factors, Sex Factors, Socioeconomic Factors, Tobacco Smoke Pollution/adverse effects, Child Day Care Centers
Bisgaard H	Bisgaard H	Bisgaard H	Laser Doppler flowmeter	1987	INT J DERMATOL	2960632	1,56	7	0	Blood Flow Velocity, Humans, Rheology/utilization, Skin/*blood supply, Skin Physiological Phenomena, Humans
Lerche A	Søndergaard J	Lerche A, Bisgaard H, Christensen JD, Venge P, Dahl R, Søndergaard J	Lactoferrin, myeloperoxidase, lysozyme and eosinophil cationic protein in exudate in delayed type hypersensitivity	1988	ALLERGY	2834974	7,361	11	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)	Adult, Aged, Biopsy, Blood Proteins/analysis/pharmacokinetics, Cell Cycle/drug effects, Dermatitis, Contact, Eosinophil Granule Proteins, Exudates and Transudates/analysis/cytology, Female, Humans, Hypersensitivity, Delayed/metabolism/physiopathology, Lactoferrin/analysis/pharmacokinetics, Lactoglobulins/analysis, Aged, Male, Middle Aged, Neutrophils/cytology/metabolism/physiopathology, Nickel/pharmacology, Peroxidase/analysis/pharmacokinetics, *Ribonucleases, Skin/cytology, Skin Window Technique
Bisgaard H	Holgate ST	Bisgaard H, Robinson C, Rømeling F, Mygind N, Church M, Holgate ST	Leukotriene C4 and histamine in early allergic reaction in the nose	1988	ALLERGY	3377145	7,361	26	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)	Adult, Female, Histamine/analysis, Humans, Male, Nasal Mucosa/secretion, Respiratory Hypersensitivity/metabolism, SRS-A/analysis, Therapeutic Irrigation, Female
Bisgaard H	Østerballe O	Bisgaard H, Damkjaer Nielsen M, Andersen B, Andersen P, Foged N, Fuglsang G, Høst A, Leth C, Pedersen M, Pelck I, Stafanger G, Østerballe O	Adrenal function in children with bronchial asthma treated with beclomethasone dipropionate or budesonide	1988	J ALLERGY CLIN IMMUN	3288682	13,081	99	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.	Adolescent, Adrenal Cortex Function Tests, Androstenedione/blood, Asthma/drug therapy/physiopathology/urine, Beclomethasone/adverse effects/therapeutic use, Budesonide, Child, Circadian Rhythm/drug effects, Clinical Trials as Topic, Double-Blind Method, Drug Administration Schedule, Female, Humans, Adrenal Cortex Function Tests, Hydrocortisone/blood/urine, Male, Pituitary-Adrenal Function Tests, Pregnenediones/adverse effects/therapeutic use, Prospective Studies, Random Allocation
Lerche A	Søndergaard J	Lerche A, Bisgaard H, Kassis V, Christensen JD, Søndergaard J	Prostaglandin E1 and prostaglandin F2 alpha in exudate in nickel allergy	1989	ACTA DERM-VENEREOL	2566235	3,653	2	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.	Adult, Cell Movement, Dermatitis, Contact/immunology/metabolism, Dinoprost/metabolism, Dinoprostone/metabolism, Exudates and Transudates/metabolism, Female, Humans, Hypersensitivity, Delayed/metabolism, Leukocytes, Male, Middle Aged, Nickel/immunology, Cell Movement
Clementsen P	Norn S	Clementsen P, Bisgaard H, Pedersen M, Permin H, Struve-Christensen E, Milman N, Nüchel-Petersen B, Norn S	Staphylococcus aureus and influenza A virus stimulate human bronchoalveolar cells to release histamine and leukotrienes	1989	AG-AC	2473614	0	24	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.	Adult, Aged, Asthma/etiology/immunology, Female, Histamine Release, Humans, In Vitro Techniques, Influenza A virus/immunology, Leukotriene B4/secretion, Leukotrienes/secretion, Male, Middle Aged, Respiratory System/cytology/immunology/secretion, Aged, Respiratory Tract Infections/complications/immunology, SRS-A/secretion, Staphylococcus aureus/immunology,
Bisgaard H	Bisgaard H	Bisgaard H	Sulphidoleukotrienes in human allergic diseases	1989	DAN MED BULL	2651029	1,086	11	0	Asthma/physiopathology, Humans, Hypersensitivity/physiopathology, Leukotrienes/physiology, Rhinitis/physiopathology, Skin Diseases/physiopathologyHumans
Bisgaard H	Ohlsson S	Bisgaard H, Ohlsson S	PEP-spacer: an adaptation for administration of MDI to infants	1989	ALLERGY	2764262	7,361	5	LETTER	Child, Preschool, Equipment Design, Humans, Infant, Methods, *Nebulizers and VaporizersEquipment Design
Bisgaard H	Venge P	Bisgaard H, Grønborg H, Mygind N, Dahl R, Lindqvist N, Venge P	Allergen-induced increase of eosinophil cationic protein in nasal lavage fluid: effect of the glucocorticoid budesonide	1990	J ALLERGY CLIN IMMUN	2185293	13,081	80	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.	Adult, Blood Proteins/analysis, Budesonide, Clinical Trials as Topic, Double-Blind Method, Eosinophil Granule Proteins, Female, Humans, Male, Nasal Mucosa/secretion, Pregnenediones/pharmacology/therapeutic use, Rhinitis, Allergic, Perennial/drug therapy, Ribonucleases, Blood Proteins/*analysis, Therapeutic Irrigation,
Bisgaard H	Ohlsson SV	Bisgaard H, Munck SL, Nielsen JP, Petersen W, Ohlsson SV	Inhaled budesonide for treatment of recurrent wheezing in early childhood	1990	LANCET	1975851	47,831	132	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.	Administration, Inhalation, Administration, Oral, Aerosols, Budesonide, Child, Preschool, Double-Blind Method, Drug Administration Schedule, Drug Evaluation, Female, Glucocorticoids/administration & dosage/therapeutic use, Humans, Infant, Male, Administration, Oral, Masks, Multicenter Studies as Topic, Pregnenediones/administration & dosage/therapeutic use, Randomized Controlled Trials as Topic, Recurrence, Respiratory Sounds/*drug effects, Time Factors,
Clementsen P	Norn S	Clementsen P, Milman N, Struve-Christensen E, Petersen BN, Pedersen M, Bisgaard H, Permin H, Norn S	Bacteria-induced histamine release from human bronchoalveolar cells and blood leukocytes	1991	ALLERGY	1708212	7,361	11	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.	Adult, Aged, Asthma/immunology/microbiology, Basophils/immunology, Bronchoalveolar Lavage Fluid/cytology/metabolism, Cell Count, Female, Histamine Release, Humans, Leukocytes/immunology, Male, Mast Cells, Middle Aged, Aged, Staphylococcal Infections/immunology, Staphylococcus aureus/physiology, Time Factors,
Bisgaard H	Osterballe O	Bisgaard H, Pedersen S, Damkjaer Nielsen M, Osterballe O	Adrenal function in asthmatic children treated with inhaled budesonide	1991	ACTA PAEDIATR SCAND	2035313	0	25	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: 74%-112%). It is concluded, that budesonide is a topical steroid with a favourable ratio between topical and systemic effects in asthmatic children.	Administration, Inhalation, Adolescent, Adrenal Glands/drug effects, Analysis of Variance, Asthma/drug therapy, Bronchodilator Agents/administration & dosage/pharmacology, Budesonide, Child, Circadian Rhythm, Creatinine/urine, Dose-Response Relationship, Drug, Female, Forced Expiratory Volume/drug effects, Adolescent, Humans, Hydrocortisone/urine, Male, Pregnenediones/administration & dosage/pharmacology, Prospective Studies, Single-Blind Method
Dein T	Norn S	Dein T, Kristensen KS, Bisgaard H, Espersen F, Clementsen P, Permin H, Skov PS, Norn S	Histamine release after nasal challenge with anti-IgE and Staphylococcus aureus in patients with allergic rhinitis	1992	PNEUMO ALERG	1284820	0	0	0	Adult, Histamine Release/physiology, Humans, Immunoglobulin E/diagnostic use, Nasal Provocation Tests, Rhinitis, Allergic, Perennial/diagnosis, Staphylococcus aureus/immunology, Histamine Release/*physiology
Fogh J	Bisgaard H	Fogh J, Poulsen LK, Bisgaard H	A specific assay for leukotriene B4 in human whole blood	1992	J PHARM PHARMACOL	1338371	2,405	4	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.	Chromatography, High Pressure Liquid/methods, Humans, In Vitro Techniques, Leukotriene B4/*blood/isolation & purification, Radioimmunoassay/methods, Reference StandardsHumans
Bisgaard H	Schiøtz PO	Bisgaard H, Schiøtz PO	[Treatment of asthmatic bronchitis in small children with steroid inhalation]	1993	UGESKR L	8421881	0	2	0	Administration, Inhalation, Aerosols, Asthma/drug therapy, Bronchitis/drug therapy, Bronchodilator Agents/administration & dosage, Budesonide, Humans, Infant, Pregnenediones/administration & dosage, Aerosols
Grønborg H	Mygind N	Grønborg H, Bisgaard H, Rømeling F, 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	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.	Administration, Topical, Adolescent, Adult, Airway Resistance, Allergens/immunology, Anti-Inflammatory Agents/therapeutic use, Budesonide, Double-Blind Method, Female, Glucocorticoids, Humans, Hypersensitivity/drug therapy, Male, Adolescent, Nasal Provocation Tests, Nose/drug effects/immunology, Pregnenediones/therapeutic use,
Sprogøe-Jakobsen U	Bisgaard H	Sprogøe-Jakobsen U, Viktrup L, Bisgaard H	[Formoterol--a prolonged-action beta 2 agonist]	1993	UGESKR L	7901931	0	0	0	Adrenergic beta-Agonists/chemistry/pharmacokinetics/pharmacology, Bronchodilator Agents/chemistry/pharmacokinetics/pharmacology, Delayed-Action Preparations, Ethanolamines/chemistry/pharmacokinetics/pharmacology, Humans, Bronchodilator Agents/chemistry/pharmacokinetics/pharmacology
Bisgaard H	Bisgaard H	Bisgaard H	Systemic activity of inhaled topical steroid in toddlers studied by knemometry	1993	ACTA PAEDIATR	8155929	2,043	46	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)	Administration, Inhalation, Administration, Topical, Anthropometry/instrumentation/methods, Anti-Inflammatory Agents/administration & dosage/adverse effects, Budesonide, Child, Preschool, Depression, Chemical, Dose-Response Relationship, Drug, Double-Blind Method, Glucocorticoids, Humans, Infant, Leg/growth & development, Administration, Topical, Pregnenediones/administration & dosage/adverse effects, Recurrence, Respiratory Sounds,
Bisgaard H	Bisgaard H	Bisgaard H	Clinical efficacy of nebulized drugs	1994	J AEROSOL MED	10147079	0	2	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)	Adolescent, Asthma/drug therapy, Bronchodilator Agents/administration & dosage, Child, Child, Preschool, Dose-Response Relationship, Drug, Humans, Infant, Nebulizers and Vaporizers, Treatment OutcomeAsthma/*drug therapy
Bisgaard H	Nikander K	Bisgaard H, Pedersen S, Nikander K	Use of budesonide Turbuhaler in young children suspected of asthma	1994	EUR RESPIR J	8005258	10,569	24	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.	Asthma/drug therapy, Bronchodilator Agents/administration & dosage, Budesonide, Child, Child, Preschool, Humans, Infant, Nebulizers and Vaporizers, Powders, Pregnenediones/administration & dosageBronchodilator Agents/administration & dosage
Bisgaard H	Bisgaard H	Bisgaard H	A metal aerosol holding chamber devised for young children with asthma	1995	EUR RESPIR J	7656962	10,569	72	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.	Administration, Inhalation, Aerosols, Asthma/drug therapy, Bronchodilator Agents/administration & dosage/therapeutic use, Budesonide, Child, Child, Preschool, Cross-Over Studies, Equipment Design, Female, Humans, Infant, Male, Aerosols, Nebulizers and Vaporizers, Pregnenediones/administration & dosage/therapeutic use, Single-Blind Method, *Steel
Bisgaard H	Berg E	Bisgaard H, Anhøj J, Klug B, Berg E	A non-electrostatic spacer for aerosol delivery	1995	ARCH DIS CHILD	7492160	3,265	97	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.	Aerosols/administration & dosage, Asthma/drug therapy, Bronchodilator Agents/administration & dosage, Budesonide, Child, Child, Preschool, Female, Humans, Infant, Male, Nebulizers and Vaporizers, Pregnenediones/administration & dosageAsthma/drug therapy
Bisgaard H	Klug B	Bisgaard H, Klug B	Lung function measurement in awake young children	1995	EUR RESPIR J	8666102	10,569	187	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.	Airway Resistance, Blood Gas Monitoring, Transcutaneous, Bronchial Provocation Tests/methods, Child, Child, Preschool, Evaluation Studies as Topic, Humans, Lung Volume Measurements, Oscillometry, Plethysmography, Whole Body, Respiratory Function Tests/*methods, SpirometryBlood Gas Monitoring, Transcutaneous
Klug B	Bisgaard H	Klug B, Bisgaard H	Assessment of bronchial hyperresponsiveness in preschool children: methodological issues	1996	PEDIAT ALLERG IMM	9156724	3,775	3	0	Bronchial Hyperreactivity/diagnosis/physiopathology, Bronchial Provocation Tests/methods, Bronchoconstrictor Agents/administration & dosage/diagnostic use, Child, Preschool, Evaluation Studies as Topic, Humans, Methacholine Chloride/administration & dosage/diagnostic use, Respiratory Function Tests/methodsBronchial Provocation Tests/*methods
Bisgaard H	Pedersen S	Bisgaard H, Pedersen S	Safety of treatment	1996	EUR RESPIR J	8962615	10,569	7	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.	Age Factors, Anti-Asthmatic Agents/administration & dosage/adverse effects/therapeutic use, Asthma/drug therapy, Child, Preschool, Dose-Response Relationship, Drug, Humans, Risk Factors, Steroids/administration & dosage/adverse effects/therapeutic use, Treatment Outcome, *Anti-Asthmatic Agents/administration & dosage/adverse effects/therapeutic use
Nysom K	Hertz H	Nysom K, Holm K, Hesse B, Ulrik CS, Jacobsen N, Bisgaard H, Hertz H	Lung function after allogeneic bone marrow transplantation for leukaemia or lymphoma	1996	ARCH DIS CHILD	8669960	3,265	37	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.	Adolescent, Bone Marrow Transplantation/adverse effects/physiology, Child, Child, Preschool, Cohort Studies, Female, Follow-Up Studies, Humans, Leukemia/therapy, Lung/physiopathology, Lung Diseases/etiology, Lymphoma, T-Cell/therapy, Male, Bone Marrow Transplantation/adverse effects/physiology, Radiation Injuries/etiology, Survivors, Whole-Body Irradiation/adverse effects,
Klug B	Bisgaard H	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 PULM	8726154	2,758	142	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.	Acute Disease, Airway Resistance/drug effects/physiology, Asthma/diagnosis/drug therapy/physiopathology, Blood Gas Monitoring, Transcutaneous, Bronchial Provocation Tests, Bronchodilator Agents/therapeutic use, Child, Preschool, Dose-Response Relationship, Drug, Humans, Methacholine Chloride/diagnostic use, Oscillometry, Plethysmography, Whole Body, Respiratory Function Tests, Airway Resistance/drug effects/physiology, Terbutaline/therapeutic use,
Daugbjerg P	Bisgaard H	Daugbjerg P, Nielsen KG, Skov M, 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	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.	Administration, Inhalation, Adolescent, Albuterol/therapeutic use, Asthma, Exercise-Induced/prevention & control, Bronchodilator Agents/therapeutic use, Child, Cross-Over Studies, Double-Blind Method, Ethanolamines/therapeutic use, Exercise Test, Female, Forced Expiratory Volume/drug effects, Humans, Adolescent, Male, Nebulizers and Vaporizers, Powders, Time Factors
Bisgaard H	Bisgaard H	Bisgaard H	Drug delivery from inhaler devices	1996	BRIT MED J	8876085	20,785	0	0	Bronchodilator Agents/administration & dosage, Cost-Benefit Analysis, Humans, Lung/metabolism, Nebulizers and Vaporizers, Pharmaceutical Preparations/administration & dosageCost-Benefit Analysis
Bisgaard H	Bisgaard H	Bisgaard H	Delivery options for inhaled therapy in children under the age of 6 years	1997	J AEROSOL MED	10165122	0	5	0	Administration, Inhalation, Aerosols/administration & dosage/therapeutic use, Bronchodilator Agents/administration & dosage/therapeutic use, Child, Preschool, Equipment Design, Humans, Infant, Masks, Nebulizers and Vaporizers, Surface PropertiesAerosols/administration & dosage/*therapeutic use
Bisgaard H	Bisgaard H	Bisgaard H	Delivery of inhaled medication to children	1997	J ASTHMA	9428291	1,746	62	0	Administration, Inhalation, Adolescent, Anti-Asthmatic Agents/administration & dosage/adverse effects/pharmacology, Asthma/drug therapy, Child, Child, Preschool, Humans, *Nebulizers and VaporizersAdolescent
Bisgaard H	Bisgaard H	Bisgaard H	Demands on spacer devices for young children	1997	PEDIATR PULM	9443268	2,758	1	0	Administration, Inhalation, Aerosols/administration & dosage, Child, Child, Preschool, Cost-Benefit Analysis, Dose-Response Relationship, Drug, Drug Delivery Systems/instrumentation, Equipment Design, Equipment Safety, Humans, Infant, Nebulizers and Vaporizers/economics, Patient Compliance, Aerosols/administration & dosage, Respiratory Sounds/drug effects,
Klug B	Bisgaard H	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 PULM	9141113	2,758	24	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.	Aerosols, Asthma/diagnosis, Bronchial Provocation Tests/methods, Bronchoconstrictor Agents/administration & dosage/diagnostic use, Child, Preschool, Female, Humans, Male, Methacholine Chloride/administration & dosage/diagnostic use, Reproducibility of Results, Terbutaline/administration & dosage, Asthma/*diagnosis
Klug B	Bisgaard H	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	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.	Adult, Airway Resistance, Asthma/diagnosis, Child, Child, Preschool, Female, Humans, Male, Patient Compliance, Plethysmography, Whole Body/methods/statistics & numerical data, Reproducibility of Results, *Airway Resistance
Nielsen KG	Bisgaard H	Nielsen KG, Skov M, Klug B, Ifversen M, Bisgaard H	Flow-dependent effect of formoterol dry-powder inhaled from the Aerolizer	1997	EUR RESPIR J	9311511	10,569	54	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.	Administration, Inhalation, Adolescent, Asthma, Exercise-Induced/drug therapy/physiopathology, Bronchodilator Agents/administration & dosage, Child, Child, Preschool, Cross-Over Studies, Double-Blind Method, Ethanolamines/administration & dosage, Female, Forced Expiratory Volume/drug effects, Humans, Male, Adolescent, Nebulizers and Vaporizers, Powders, Pulmonary Ventilation/drug effects,
Bisgaard H	Bisgaard H	Bisgaard H	Use of inhaled corticosteroids in pediatric asthma	1997	PEDIATR PULM	9316099	2,758	21	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.	Administration, Inhalation, Adolescent, Adrenal Cortex Hormones/administration & dosage/adverse effects, Adult, Airway Resistance/drug effects, Anti-Asthmatic Agents/administration & dosage/adverse effects, Asthma/diagnosis/*drug therapy, Body Height/drug effects, Bronchial Hyperreactivity/diagnosis/drug therapy, Child, Child, Preschool, Humans, Infant, Adolescent, Lung Volume Measurements,
Bisgaard H	Koch C	Bisgaard H, Pedersen SS, Nielsen KG, Skov M, Laursen EM, Kronborg G, Reimert CM, Høiby N, Koch C	Controlled trial of inhaled budesonide in patients with cystic fibrosis and chronic bronchopulmonary Pseudomonas aeruginosa infection	1997	AM J RESP CRIT CARE	9351621	13,204	56	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.	Administration, Inhalation, Anti-Bacterial Agents/therapeutic use, Anti-Inflammatory Agents/administration & dosage/adverse effects/therapeutic use, Biological Markers, Bronchial Hyperreactivity/diagnosis/etiology/physiopathology, Bronchial Provocation Tests, Bronchopneumonia/complications/drug therapy/microbiology, Budesonide/administration & dosage/adverse effects/therapeutic use, Child, Chronic Disease, Cystic Fibrosis/complications/drug therapy/metabolism, Double-Blind Method, Follow-Up Studies, Anti-Bacterial Agents/therapeutic use, Forced Expiratory Flow Rates, Histamine/diagnostic use, Humans, Pseudomonas Infections/complications/drug therapy/microbiology, Pseudomonas aeruginosa/isolation & purification, Sputum/metabolism/microbiology, Treatment Outcome,
Ellerman A	Bisgaard H	Ellerman A, Bisgaard H	Longitudinal study of lung function in a cohort of primary ciliary dyskinesia	1997	EUR RESPIR J	9387968	10,569	171	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.	Adolescent, Adult, Age Distribution, Bacterial Infections/diagnosis/epidemiology/physiopathology, Child, Child, Preschool, Ciliary Motility Disorders/diagnosis/epidemiology/physiopathology, Cohort Studies, Denmark/epidemiology, Disease Progression, Female, Follow-Up Studies, Forced Expiratory Volume, Adult, Humans, Longitudinal Studies, Male, Middle Aged, Prognosis, Respiratory Function Tests, Respiratory Tract Infections/diagnosis/physiopathology, Time Factors, Vital Capacity,
Bisgaard H	Schiøtz PO	Bisgaard H, Pedersen SE, Schiøtz PO	Steroid treatment of asthmatic children	1997	UGESKR L	9417698	0	0	0	Administration, Inhalation, Adrenergic beta-Agonists/administration & dosage, Age Factors, Anti-Asthmatic Agents/administration & dosage, Asthma/drug therapy, Bronchodilator Agents/administration & dosage, Child, Preschool, HumansAdrenergic beta-Agonists/*administration & dosage
Bisgaard H	Bisgaard H	Bisgaard H	What dose fraction represents the respirable dose?	1997	RESP MED	9474363	3,217	4	0	Adrenergic beta-Agonists/administration & dosage/therapeutic use, Adult, Asthma/drug therapy, Drug Administration Schedule, Drug Delivery Systems, Humans, Nebulizers and Vaporizers, Particle SizeAdult
Bisgaard H	Bisgaard H	Bisgaard H	Automatic actuation of a dry powder inhaler into a nonelectrostatic spacer	1998	AM J RESP CRIT CARE	9476867	13,204	29	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.	Budesonide/administration & dosage, Child, Preschool, Drug Delivery Systems, Equipment Design, Evaluation Studies as Topic, Half-Life, Humans, Medical Illustration, Nebulizers and Vaporizers, Particle Size, Powders/*administration & dosage, Child, Preschool
Bisgaard H	Munch E	Bisgaard H, Nikander K, Munch E	Comparative study of budesonide as a nebulized suspension vs pressurized metered-dose inhaler in adult asthmatics	1998	RESP MED	9519224	3,217	35	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.	Adult, Anti-Inflammatory Agents/administration & dosage/blood, Asthma/blood/drug therapy, Budesonide/administration & dosage/blood, Cross-Over Studies, Dose-Response Relationship, Drug, Double-Blind Method, Drug Delivery Systems, Female, Humans, Male, Middle Aged, Nebulizers and Vaporizers, Anti-Inflammatory Agents/administration & dosage/blood
Nielsen KG	Bisgaard H	Nielsen KG, Auk IL, Bojsen K, Ifversen M, Klug B, 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	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.	Adolescent, Albuterol/administration & dosage/analogs & derivatives/therapeutic use, Asthma, Exercise-Induced/drug therapy/physiopathology, Bronchoconstriction/drug effects/physiology, Bronchodilator Agents/administration & dosage/therapeutic use, Child, Cross-Over Studies, Double-Blind Method, Exercise, Female, Forced Expiratory Volume/physiology, Humans, Male, Albuterol/administration & dosage/analogs & derivatives/therapeutic use, Nebulizers and Vaporizers, Powders, Pulmonary Ventilation/physiology,
Pedersen W	Mygind N	Pedersen W, Hjuler I, Bisgaard H, Mygind N	Nasal inhalation of budesonide from a spacer in children with perennial rhinitis and asthma	1998	ALLERGY	9574880	7,361	24	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.	Administration, Inhalation, Administration, Intranasal, Adolescent, Anti-Inflammatory Agents/administration & dosage, Asthma/drug therapy, Budesonide/administration & dosage, Child, Cross-Over Studies, Double-Blind Method, Female, Glucocorticoids, Humans, Male, Administration, Intranasal, Rhinitis, Allergic, Perennial/drug therapy,
Klug B	Bisgaard H	Klug B, Bisgaard H	Specific airway resistance, interrupter resistance, and respiratory impedance in healthy children aged 2-7 years	1998	PEDIATR PULM	9635934	2,758	144	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.	Airway Resistance, Child, Child, Preschool, Female, Humans, Male, Reference Values, Respiratory MechanicsChild
Bisgaard H	Burnell PK	Bisgaard H, Klug B, Sumby BS, Burnell PK	Fine particle mass from the Diskus inhaler and Turbuhaler inhaler in children with asthma	1998	EUR RESPIR J	9648964	10,569	77	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.	Androstadienes/administration & dosage/therapeutic use, Anti-Asthmatic Agents/administration & dosage/therapeutic use, Asthma/drug therapy, Bronchodilator Agents/administration & dosage/therapeutic use, Budesonide/administration & dosage/therapeutic use, Child, Child, Preschool, Evaluation Studies as Topic, Humans, Nebulizers and Vaporizers/standards, Particle Size, Powders/administration & dosageAnti-Asthmatic Agents/*administration & dosage/therapeutic use
Berg E	Bisgaard H	Berg E, Madsen J, 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	42	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.	Aerosols, Androstadienes/administration & dosage, Anti-Asthmatic Agents/administration & dosage, Bronchodilator Agents/administration & dosage, Budesonide/administration & dosage, Child, Child, Preschool, Drug Delivery Systems/standards, Equipment Design, Humans, Nebulizers and Vaporizers/*standards, Androstadienes/administration & dosage
Borum S	Mygind N	Borum S, Nielsen K, Bisgaard H, Mygind N	Experimentally induced nasal hypersecretion does not reduce the efficacy of intranasal levocabastine	1998	RHINOLOGY	9923056	2,35	2	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.	Administration, Intranasal, Adult, Analysis of Variance, Double-Blind Method, Female, Histamine/administration & dosage, Histamine H1 Antagonists/administration & dosage/therapeutic use, Humans, Male, Methacholine Chloride/administration & dosage, Nasal Lavage Fluid, Nasal Mucosa/drug effects/secretion, Nasal Provocation Tests, Adult, Piperidines/administration & dosage/therapeutic use, Rhinitis/drug therapy, Sneezing, Statistics, Nonparametric
Bisgaard H	Bisgaard H	Bisgaard H	Towards improved aerosol devices for the young child	1999	PEDIATR PULM	10093104	2,758	1	0	Aerosols/administration & dosage, Child, Humans, Nebulizers and VaporizersChild
Anhøj J	Lipworth BJ	Anhøj J, Bisgaard H, Lipworth BJ	Effect of electrostatic charge in plastic spacers on the lung delivery of HFA-salbutamol in children	1999	BRIT J CLIN PHARMCO	10215759	3,493	34	AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.	Absorption, Administration, Inhalation, Albuterol/administration & dosage/blood/pharmacokinetics, Bronchodilator Agents/administration & dosage/pharmacokinetics, Child, Preschool, Cross-Over Studies, Female, Humans, Hydrocarbons, Fluorinated/administration & dosage/pharmacokinetics, Lung/metabolism, Male, Nebulizers and Vaporizers, Single-Blind Method, Administration, Inhalation, Static Electricity,
Bisgaard H	Maden C	Bisgaard H, Gillies J, Groenewald M, Maden C	The effect of inhaled fluticasone propionate in the treatment of young asthmatic children: a dose comparison study	1999	AM J RESP CRIT CARE	10390389	13,204	134	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.	Administration, Inhalation, Androstadienes/administration & dosage/adverse effects, Anti-Asthmatic Agents/administration & dosage/adverse effects, Anti-Inflammatory Agents/administration & dosage/adverse effects, Asthma/drug therapy, Child, Preschool, Dose-Response Relationship, Drug, Double-Blind Method, Drug Administration Schedule, Female, Humans, Infant, Male, Androstadienes/*administration & dosage/adverse effects
Bisgaard H	Møller H	Bisgaard H, Møller H	Changes in risk of hospital readmission among asthmatic children in Denmark, 1978-93	1999	BRIT MED J	10417085	20,785	21	0	Adolescent, Asthma/therapy, Child, Child, Preschool, Denmark/epidemiology, Humans, Patient Readmission/statistics & numerical data/trends, Risk FactorsAsthma/*therapy
Bisgaard H	Bisgaard H	Bisgaard H	Future options for aerosol delivery to children	1999	ALLERGY	10422756	7,361	13	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.	Aerosols/administration & dosage/pharmacokinetics/therapeutic use, Asthma/drug therapy, Child, Child, Preschool, Drug Delivery Systems/trends, Forecasting, Humans, Lung/metabolism, Nebulizers and Vaporizers/*trends, Asthma/drug therapy
Nikander K	Bisgaard H	Nikander K, Bisgaard H	Impact of constant and breath-synchronized nebulization on inhaled mass of nebulized budesonide in infants and children	1999	PEDIATR PULM	10495335	2,758	16	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.	Administration, Inhalation, Age Factors, Asthma/drug therapy, Bronchodilator Agents/administration & dosage, Budesonide/administration & dosage, Child, Child, Preschool, Cross-Over Studies, Equipment Design, Female, Filtration/instrumentation, Humans, Infant, Age Factors, Male, Nebulizers and Vaporizers, Respiration, Tidal Volume
Bisgaard H	Oj JA	Bisgaard H, Loland L, Oj JA	NO in exhaled air of asthmatic children is reduced by the leukotriene receptor antagonist montelukast	1999	AM J RESP CRIT CARE	10508811	13,204	168	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.	Acetates/therapeutic use, Adolescent, Anti-Asthmatic Agents/therapeutic use, Asthma/diagnosis/drug therapy/physiopathology, Breath Tests, Child, Cross-Over Studies, Double-Blind Method, Forced Expiratory Volume, Glucocorticoids/therapeutic use, Humans, Leukotriene Antagonists/therapeutic use, Maximal Midexpiratory Flow Rate, Adolescent, Nitric Oxide/analysis, Quinolines/*therapeutic use, Spirometry,
Mygind N	Dahl R	Mygind N, Bisgaard H, Dahl R	Simultaneous treatment of rhinitis and asthma by nasal inhalation of corticosteroid from a spacer	1999	ALLERGY	10565489	7,361	4	0	Administration, Inhalation, Adrenal Cortex Hormones/administration & dosage/therapeutic use, Adult, Asthma/drug therapy, Child, Cross-Over Studies, Double-Blind Method, Drug Delivery Systems, Humans, Rhinitis, Allergic, Seasonal/drug therapyAdrenal Cortex Hormones/administration & dosage/therapeutic use
Klug B	Bisgaard H	Klug B, Bisgaard H	Lung function and short-term outcome in young asthmatic children	1999	EUR RESPIR J	10596711	10,569	23	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.	Anti-Asthmatic Agents/administration & dosage, Asthma/diagnosis/drug therapy/physiopathology, Child, Preschool, Cross-Sectional Studies, Female, Follow-Up Studies, Humans, Lung/physiopathology, Male, Respiratory Function Tests, Risk Factors, Time Factors, Treatment Outcome, Asthma/diagnosis/drug therapy/*physiopathology
Zak M	Bisgaard H	Zak M, Madsen J, Berg E, Bülow J, Bisgaard H	A mathematical model of aerosol holding chambers	1999	J AEROSOL MED	10623335	0	14	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, Sodirtalje, 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.	Aerosols/administration & dosage, Anti-Inflammatory Agents/administration & dosage/pharmacokinetics, Budesonide/administration & dosage/pharmacokinetics, Equipment Design, Equipment Safety, Humans, Lung/drug effects, Models, Theoretical, Nebulizers and Vaporizers, Pressure, Reproducibility of Results, Anti-Inflammatory Agents/*administration & dosage/pharmacokinetics
Bisgaard H	Bisgaard H	Bisgaard H	Long-acting beta(2)-agonists in management of childhood asthma: A critical review of the literature	2000	PEDIATR PULM	10686044	2,758	96	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.	Administration, Topical, Adrenergic beta-Agonists/administration & dosage/therapeutic use, Albuterol/administration & dosage/analogs & derivatives/therapeutic use, Anti-Inflammatory Agents/therapeutic use, Asthma/drug therapy, Asthma, Exercise-Induced/drug therapy, Bronchi/drug effects, Bronchial Hyperreactivity/drug therapy, Bronchodilator Agents/administration & dosage/therapeutic use, Child, Double-Blind Method, Drug Combinations, Drug Tolerance, Adrenergic beta-Agonists/administration & dosage/therapeutic use, Ethanolamines/administration & dosage/therapeutic use, Glucocorticoids, Humans, Lung/drug effects, Randomized Controlled Trials as Topic, Status Asthmaticus/drug therapy
Mygind N	Bisgaard H	Mygind N, Dahl R, Bisgaard H	Leukotrienes, leukotriene receptor antagonists, and rhinitis	2000	ALLERGY	10843421	7,361	14	0	Animals, Anti-Asthmatic Agents/therapeutic use, Clinical Trials as Topic, Drug Therapy, Combination, Histamine H1 Antagonists/therapeutic use, Humans, Leukotriene Antagonists/therapeutic use, Leukotrienes/metabolism, Rhinitis/drug therapy, Anti-Asthmatic Agents/*therapeutic use
Nielsen KG	Bisgaard H	Nielsen KG, Bisgaard H	Lung function response to cold air challenge in asthmatic and healthy children of 2-5 years of age	2000	AM J RESP CRIT CARE	10852748	13,204	74	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.	Asthma/diagnosis/drug therapy/physiopathology, Bronchial Hyperreactivity/diagnosis/drug therapy/physiopathology, Bronchial Provocation Tests/methods, Bronchodilator Agents/administration & dosage/adverse effects, Child, Preschool, Feasibility Studies, Female, Humans, Male, Plethysmography, Whole Body, Predictive Value of Tests, Terbutaline/administration & dosage/adverse effectsBronchial Hyperreactivity/diagnosis/drug therapy/physiopathology
Bisgaard H	Nielsen KG	Bisgaard H, Nielsen KG	Bronchoprotection with a leukotriene receptor antagonist in asthmatic preschool children	2000	AM J RESP CRIT CARE	10903240	13,204	80	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.	Acetates/therapeutic use, Asthma/drug therapy, Child, Preschool, Cross-Over Studies, Double-Blind Method, Female, Humans, Leukotriene Antagonists/therapeutic use, Male, Quinolines/therapeutic useAsthma/*drug therapy
Bjermer L	Leff JA	Bjermer L, Bisgaard H, Bousquet J, Fabbri LM, Greening A, Haahtela T, Holgate ST, Picado C, Leff JA	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	RESP MED	10921768	3,217	27	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.	Acetates/administration & dosage, Administration, Inhalation, Adolescent, Adrenal Cortex Hormones/administration & dosage, Adult, Aged, Albuterol/administration & dosage, Androstadienes/therapeutic use, Anti-Asthmatic Agents/administration & dosage, Asthma/drug therapy/physiopathology, Forced Expiratory Volume/drug effects, Humans, Leukotriene Antagonists/administration & dosage, Administration, Inhalation, Middle Aged, Peak Expiratory Flow Rate/drug effects, Quality of Life, Questionnaires, Quinolines/*administration & dosage, Quinolones/administration & dosage
Bisgaard H	Bisgaard H	Bisgaard H	Role of leukotrienes in asthma pathophysiology	2000	PEDIATR PULM	10922142	2,758	36	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.	Adrenal Cortex Hormones/pharmacology, Anti-Inflammatory Agents, Non-Steroidal/therapeutic use, Asthma/drug therapy/physiopathology, Bronchial Hyperreactivity/physiopathology, Cysteine/physiology, Humans, Inflammation Mediators/physiology, Leukotriene Antagonists/therapeutic use, Leukotrienes/physiology, Receptors, Leukotriene/*physiologyAnti-Inflammatory Agents, Non-Steroidal/therapeutic use
Klug B	Bisgaard H	Klug B, Nielsen KG, Bisgaard H	Observer variability of lung function measurements in 2-6-yr-old children	2000	EUR RESPIR J	11028662	10,569	28	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.	Airway Resistance, Child, Child, Preschool, Humans, Observer Variation, Respiratory Function Tests/standardsChild
Nielsen KG	Bisgaard H	Nielsen KG, 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 RESP CRIT CARE	11029368	13,204	106	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.	Administration, Inhalation, Airway Resistance/drug effects, Asthma/diagnosis/drug therapy, Bronchial Provocation Tests, Budesonide/administration & dosage, Child, Preschool, Cold Temperature/diagnostic use, Double-Blind Method, Female, Humans, Male, Methacholine Chloride/diagnostic useAirway Resistance/*drug effects
Onhøj J	Bisgaard H	Onhøj J, Thorsson L, Bisgaard H	Lung deposition of inhaled drugs increases with age	2000	AM J RESP CRIT CARE	11069819	13,204	38	Budesonide plasma concentrations after inhalation of a fixed dose of the drug from a pressurized metered dose inhaler (pMDI) with spacer (Nebuchamber) were compared in young children and adults: 26 patients with mild asthma comprising 8 children 2-3 yr, 8 children 4-6 yr, and 10 adults 20-41 yr. Budesonide 2 x 200 microg was given by pMDI via Nebuchamber with mouthpiece and noseclip. Children of 2-3 yr used a facemask. Plasma was collected regularly for 8 h after drug administration. Budesonide was measured by liquid chromatography plus tandem mass spectrometry. The dose to patient was estimated as the dose of budesonide delivered from the pMDI with adapter minus the amount of budesonide recovered from the spacer, facemask, or mouthpiece, mouth rinse, and facial skin. The systemic exposure was estimated from the plasma concentration and expressed as the area under the curve of plasma concentration versus time (AUC). Terminal half-life (T(1/2)) was evaluated. Dose to patient, AUC, and T(1/2) were similar in the three age groups (p > 0.35). Nebuchamber delivers the same dose of budesonide to young children and adults. Yet the plasma concentration of budesonide was similar in young children and adults. Therefore, lung dose is increased with age. This suggests that from a safety perspective, the prescribed dose of budesonide inhaled from a pMDI with Nebuchamber spacer need not be adjusted for age or use of facemask. Children and adults can use the same nominal dose of budesonide via Nebuchamber as adults without an increased risk of systemic exposure.	0
Bisgaard H	Bisgaard H	Bisgaard H	[Do we follow guidelines for the treatment of asthma in children]	2000	UGESKR L	11107939	0	0	0	Asthma/*drug therapy, Child, Humans, Practice Guidelines as TopicChild
Bisgaard H	Bisgaard H	Bisgaard H	Leukotriene modifiers in pediatric asthma management	2001	PEDIATRICS	11158473	5,705	74	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.	Acetates/therapeutic use, Adrenal Cortex Hormones/pharmacology, Anti-Asthmatic Agents/therapeutic use, Asthma/drug therapy/metabolism/physiopathology, Child, Humans, Hydroxyurea/analogs & derivatives/therapeutic use, Leukotriene Antagonists/therapeutic use, Leukotrienes/biosynthesis/physiology, Membrane Proteins, Quinolines/therapeutic use, *Receptors, Leukotriene, Tosyl Compounds/therapeutic use, Adrenal Cortex Hormones/pharmacology
Buchvald F	Bisgaard H	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 RESP CRIT CARE	11254527	13,204	59	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.	Adolescent, Asthma/metabolism/physiopathology, Child, Child, Preschool, Humans, Nitric Oxide/metabolism, Respiration, Respiratory Sounds/physiopathologyAsthma/metabolism/*physiopathology
Bisgaard H	Bisgaard H	Bisgaard H	Persistent wheezing in very young preschool children reflects lower respiratory inflammation	2001	AM J RESP CRIT CARE	11371382	13,204	16	EDITORIAL	Age Factors, Anti-Inflammatory Agents/therapeutic use, Asthma/diagnosis/drug therapy/etiology, Bronchoalveolar Lavage Fluid/cytology/immunology, Bronchodilator Agents/therapeutic use, Child, Preschool, Chronic Disease, Humans, Inflammation, Leukocyte Count, Recurrence, Respiratory Sounds/diagnosis/etiology, Steroids, Anti-Inflammatory Agents/therapeutic use
Bisgaard H	Bisgaard H	Bisgaard H	Pathophysiology of the cysteinyl leukotrienes and effects of leukotriene receptor antagonists in asthma	2001	ALLERGY	11421935	7,361	52	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.	Anti-Asthmatic Agents/therapeutic use, Asthma/drug therapy/physiopathology, Cysteine/physiology, Humans, Inflammation Mediators/physiology, Leukotriene Antagonists/pharmacology/therapeutic use, Leukotrienes/physiology, Asthma/drug therapy/*physiopathology
Nielsen KG	Bisgaard H	Nielsen KG, Bisgaard H	Bronchodilation and bronchoprotection in asthmatic preschool children from formoterol administered by mechanically actuated dry-powder inhaler and spacer	2001	AM J RESP CRIT CARE	11463597	13,204	24	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.	Administration, Inhalation, Asthma/drug therapy/physiopathology, Bronchi/drug effects/physiopathology, Bronchodilator Agents/administration & dosage, Child, Preschool, Cross-Over Studies, Double-Blind Method, Ethanolamines/administration & dosage, Female, Humans, Male, Nebulizers and Vaporizers, Powders, Asthma/drug therapy/physiopathology
Nielsen KG	Bisgaard H	Nielsen KG, 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 RESP CRIT CARE	11520714	13,204	136	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.	Administration, Inhalation, Age Factors, Airway Resistance, Asthma/diagnosis/physiopathology, Bronchodilator Agents/administration & dosage/diagnostic use, Case-Control Studies, Child, Preschool, Cross-Over Studies, Discriminant Analysis, Double-Blind Method, Female, Humans, Male, Age Factors, Plethysmography, Whole Body/methods/standards, Respiratory Function Tests/methods/standards, Sensitivity and Specificity, Terbutaline/administration & dosage/diagnostic use
Knorr B	Bratton DL	Knorr B, Franchi LM, Bisgaard H, Vermeulen JH, LeSouef P, Santanello N, Michele TM, Reiss TF, Nguyen HH, Bratton DL	Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years	2001	PEDIATRICS	11533366	5,705	195	BACKGROUND: 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. OBJECTIVE: 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. STUDY PARTICIPANTS: 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. RESULTS: 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. CONCLUSIONS: 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.	Acetates/adverse effects/therapeutic use, Administration, Oral, Analysis of Variance, Anti-Asthmatic Agents/adverse effects/therapeutic use, Asthma/blood/classification/drug therapy, Child, Preschool, Double-Blind Method, Drug Administration Schedule, Eosinophils, Female, Humans, Leukocyte Count, Leukotriene Antagonists/adverse effects/therapeutic use, Administration, Oral, Male, Quality of Life, Quinolines/adverse effects/*therapeutic use, Tablets, Treatment Outcome,
Roorda RJ	Maden C	Roorda RJ, Mezei G, Bisgaard H, Maden C	Response of preschool children with asthma symptoms to fluticasone propionate	2001	J ALLERGY CLIN IMMUN	11590379	13,081	64	BACKGROUND: Many uncertainties remain in the diagnosis and treatment of preschool children with asthma symptoms. OBJECTIVE: 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). METHODS: Subgroups of pooled data from 2 similar 12-week multicenter studies were analyzed. RESULTS: 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. CONCLUSIONS: 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.	Administration, Inhalation, Age Factors, Androstadienes/therapeutic use, Anti-Asthmatic Agents/therapeutic use, Asthma/*drug therapy, Child, Preschool, Double-Blind Method, Eczema, Family Characteristics, Female, Humans, Infant, Male, Age Factors, Nebulizers and Vaporizers, Placebos, Respiratory Sounds, Rhinitis
Bisgaard H	Olsen NA	Bisgaard H, Price MJ, Maden C, Olsen NA	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	STUDY OBJECTIVES: To evaluate the cost-effectiveness of inhaled fluticasone propionate (FP) in children aged 12 to 47 months with asthma symptoms. DESIGN: A retrospective economic analysis conducted from the perspective of the Danish health-care system, based on clinical data from a 12-week study. SETTING: Thirty-three outpatient centers in nine countries. PATIENTS: Two hundred thirty-seven children aged 12 to 47 months with documented history of recurrent wheeze or asthma symptoms. INTERVENTIONS: 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. MEASUREMENTS: 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. RESULTS: 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. CONCLUSIONS: 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.	Androstadienes/administration & dosage/adverse effects/economics, Anti-Asthmatic Agents/administration & dosage/adverse effects/economics, Asthma/drug therapy/economics, Child, Preschool, Cost-Benefit Analysis, Denmark, Dose-Response Relationship, Drug, Double-Blind Method, Drug Administration Schedule, Female, Humans, Infant, Male, Anti-Asthmatic Agents/administration & dosage/adverse effects/economics, National Health Programs/economics, Nebulizers and Vaporizers/*economics, Retrospective Studies, Treatment Outcome
Bisgaard H	Schiøtz PO	Bisgaard H, Pedersen SE, Schiøtz PO	[Pediatric pulmonology]	2001	UGESKR L	11816914	0	0	0	Asthma/diagnosis/therapy, Bronchopulmonary Dysplasia/diagnosis/therapy, Child, Ciliary Motility Disorders/diagnosis/therapy, Clinical Competence, Curriculum, Cystic Fibrosis/diagnosis/therapy, Europe, Humans, Infant, Newborn, Lung Diseases/congenital/diagnosis/therapy, Lung Diseases, Interstitial/diagnosis/therapy, Pediatrics/education/organization & administration/standards, Bronchopulmonary Dysplasia/diagnosis/therapy, Pneumonia/diagnosis/microbiology/therapy, *Pulmonary Medicine/education/organization & administration/standards
Anhøj J	Bisgaard H	Anhøj J, Bisgaard AM, Bisgaard H	Systemic activity of inhaled steroids in 1- to 3-year-old children with asthma	2002	PEDIATRICS	11875168	5,705	26	OBJECTIVE: To study the systemic activity of inhaled steroids in young children. METHODS: 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. RESULTS: 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). CONCLUSION: 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.	Administration, Inhalation, Androstadienes/adverse effects/therapeutic use, Asthma/drug therapy/physiopathology, Bronchodilator Agents/adverse effects/therapeutic use, Budesonide/adverse effects/therapeutic use, Child, Preschool, Cross-Over Studies, Double-Blind Method, Growth/drug effects, Humans, Infant, Leg/growth & development, Nebulizers and Vaporizers, Androstadienes/adverse effects/therapeutic use
Benn CS	Melbye M	Benn CS, Thorsen P, Jensen JS, Kjaer BB, Bisgaard H, Andersen M, Rostgaard K, Björkstén B, 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 IMMUN	12110824	13,081	72	BACKGROUND: 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. OBJECTIVE: We sought to study the associations between the composition of the maternal vaginal microflora and the development of wheezing and asthma in childhood. METHODS: 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. RESULTS: 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. CONCLUSION: The composition of the maternal vaginal micro-flora might be associated with wheezing and asthma in the offspring up to 5 years of age.	Anti-Bacterial Agents/therapeutic use, Asthma/drug therapy/etiology, Child, Preschool, Cohort Studies, Female, Gestational Age, Histamine H1 Antagonists/therapeutic use, Hospitalization, Humans, Infant, Infant, Newborn, Maternal Age, Pregnancy, Asthma/drug therapy/etiology, Prenatal Exposure Delayed Effects, Respiratory Sounds/etiology, Staphylococcus/isolation & purification, Ureaplasma urealyticum/isolation & purification, Vagina/microbiology,
Bisgaard H	Bisgaard H	Bisgaard H	Efficacy of steroid treatments in the asthmatic preschool child	2002	ALLERGY	12371911	7,361	4	Asthma represents the most common chronic disease in preschool children. Hospital admission for wheezy disorders is the most common paediatric chronic disease causing hospital admission and more common in young children than later in life.	Asthma/diagnosis/drug therapy, Child Welfare, Child, Preschool, Chronic Disease, Humans, Patient Admission, Respiratory Sounds, Steroids/therapeutic use, Treatment Outcome, Child Welfare
Bisgaard H	Bisgaard H	Bisgaard H [BØNNELYKKE]	A randomized trial of montelukast in respiratory syncytial virus postbronchiolitis	2003	AM J RESP CRIT CARE	12406832	13,204	160	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.	Acetates/therapeutic use, Bronchiolitis, Viral/drug therapy, Double-Blind Method, Female, Humans, Infant, Leukotriene Antagonists/therapeutic use, Male, Quinolines/therapeutic use, Respiratory Syncytial Virus Infections/drug therapyBronchiolitis, Viral/drug therapy
Lipworth BJ	Bisgaard H	Lipworth BJ, Lee DK, Anhøj J, Bisgaard H	Effect of plastic spacer handling on salbutamol lung deposition in asthmatic children	2002	BRIT J CLIN PHARMCO	12445036	3,493	15	AIMS: To study the effects of electrostatics in a plastic spacer on the lung deposition of salbutamol in asthmatic children. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.	Administration, Inhalation, Albuterol/administration & dosage/pharmacokinetics, Asthma/drug therapy, Bronchodilator Agents/administration & dosage/pharmacokinetics, Child, Child, Preschool, Cross-Over Studies, Humans, Lung/chemistry, Metered Dose Inhalers/standards, Nebulizers and Vaporizers, Plastics, Single-Blind Method, Albuterol/administration & dosage/pharmacokinetics
Sampson AP	Bisgaard H	Sampson AP, Pizzichini E, Bisgaard H	Effects of cysteinyl leukotrienes and leukotriene receptor antagonists on markers of inflammation	2003	J ALLERGY CLIN IMMUN	12532086	13,081	29	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.	Anti-Asthmatic Agents/pharmacology/therapeutic use, Anti-Inflammatory Agents/pharmacology/therapeutic use, Asthma/drug therapy/genetics/immunology, Biological Markers/analysis/blood/urine, Bronchoalveolar Lavage Fluid/chemistry, Glutathione Transferase/genetics, Humans, Inflammation/blood/urine, Leukotriene Antagonists/pharmacology/therapeutic use, Nitric Oxide/analysis, SRS-A/physiology, Sputum/chemistryAnti-Inflammatory Agents/pharmacology/therapeutic use
Meyer KA	Bisgaard H	Meyer KA, Arduino JM, Santanello NC, Knorr BA, Bisgaard H	Response to montelukast among subgroups of children aged 2 to 14 years with asthma	2003	J ALLERGY CLIN IMMUN	12704354	13,081	29	BACKGROUND: Determining who responds to asthma therapies, particularly leukotriene modifiers, continues to be explored. OBJECTIVE: We sought to identify patient characteristics predictive of response to montelukast. METHODS: 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. RESULTS: 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. CONCLUSION: The patient characteristics studied do not appear to provide an indication of who will benefit most from treatment with montelukast.	Acetates/therapeutic use, Adolescent, Asthma/drug therapy/physiopathology, Child, Child, Preschool, Double-Blind Method, Female, Forced Expiratory Volume/drug effects, Humans, Leukotriene Antagonists/therapeutic use, Male, Quinolines/therapeutic useAdolescent
Bisgaard H	Bisgaard H	Bisgaard H	Effect of long-acting beta2 agonists on exacerbation rates of asthma in children	2003	PEDIATR PULM	14520721	2,758	88	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.	Administration, Inhalation, Adolescent, Adrenal Cortex Hormones/administration & dosage, Asthma/drug therapy/physiopathology, Child, Child, Preschool, Disease Progression, Drug Therapy, Combination, Hospitalization, Humans, Placebo Effect, Randomized Controlled Trials as Topic, Receptors, Adrenergic, beta-2/*administration & dosage, Adolescent, Risk Assessment, Treatment Outcome
Buchvald F	Bisgaard H	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 ALLERG ASTHMA IM	14533665	3,728	32	BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.	Acetates/therapeutic use, Administration, Inhalation, Adolescent, Albuterol/analogs & derivatives/therapeutic use, Asthma/drug therapy/metabolism, Breath Tests, Bronchodilator Agents/therapeutic use, Budesonide/therapeutic use, Child, Cross-Over Studies, Double-Blind Method, Humans, Nitric Oxide/analysis/metabolism, Administration, Inhalation, Quinolines/therapeutic use,
Bjermer L	Polos PG	Bjermer L, Bisgaard H, Bousquet J, Fabbri LM, Greening AP, Haahtela T, Holgate ST, Picado C, Menten J, Dass SB, Leff JA, Polos PG	Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults: one year, double blind, randomised, comparative trial	2003	BRIT MED J	14563743	20,785	142	OBJECTIVES: 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. PARTICIPANTS: 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. MAIN OUTCOME MEASURES: The primary end point was the percentage of patients with at least one asthma exacerbation. RESULTS: 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. CONCLUSION: The addition of montelukast in patients whose symptoms remain uncontrolled by inhaled fluticasone could provide equivalent clinical control to salmeterol.	Acetates/administration & dosage/adverse effects, Adolescent, Adult, Aged, Albuterol/administration & dosage/adverse effects/analogs & derivatives, Androstadienes/administration & dosage/adverse effects, Anti-Asthmatic Agents/administration & dosage/adverse effects, Asthma/physiopathology/prevention & control, Bronchodilator Agents/administration & dosage/adverse effects, Double-Blind Method, Drug Therapy, Combination, Forced Expiratory Volume/drug effects, Humans, Adolescent, Middle Aged, Quinolines/administration & dosage/adverse effects, Treatment Outcome,
Buchvald F	Bisgaard H	Buchvald F, Eiberg H, Bisgaard H	Heterogeneity of FeNO response to inhaled steroid in asthmatic children	2003	CLIN EXP ALLERGY	14656363	5,264	41	BACKGROUND: 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. OBJECTIVE: The study aimed to describe the independent variables associated with the heterogeneity in the response of exhaled nitric oxide to ICSs. METHODS: 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. RESULTS: 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. CONCLUSION: 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.	Administration, Inhalation, Adolescent, Anti-Inflammatory Agents/administration & dosage/therapeutic use, Asthma/drug therapy/metabolism, Biological Markers/analysis, Breath Tests, Budesonide/administration & dosage/therapeutic use, Case-Control Studies, Child, Cross-Over Studies, Double-Blind Method, Female, Humans, Adolescent, Lung/metabolism, Male, Nebulizers and Vaporizers, Nitric Oxide/*analysis, Regression Analysis,
Bisgaard H	Davies P	Bisgaard H, Allen D, Milanowski J, Kalev I, Willits L, 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	74	OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.	Administration, Inhalation, Androstadienes/adverse effects/pharmacology/therapeutic use, Anti-Asthmatic Agents/pharmacology/therapeutic use, Asthma/drug therapy, Bronchodilator Agents/adverse effects/pharmacology/therapeutic use, Cataract/chemically induced, Child, Preschool, Cromolyn Sodium/pharmacology/therapeutic use, Female, Growth/drug effects, Humans, Hydrocortisone/blood/urine, Infant, Androstadienes/adverse effects/pharmacology/therapeutic use, Male, Respiratory Sounds/drug effects, Treatment Outcome,
Jeganathan D	Mitchison HM	Jeganathan D and Chodhari R, Meeks M, Faeroe O, Smyth D, Nielsen K, Amirav I, Luder AS, Bisgaard H, Gardiner RM, Chung EM, Mitchison HM	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	LETTER	Chromosome Mapping, Chromosomes, Human, Pair 15/genetics, Chromosomes, Human, Pair 16/genetics, Ciliary Motility Disorders/epidemiology/genetics, Consanguinity, Female, Genetic Heterogeneity, Geography, Great Britain/ethnology, Humans, Israel/epidemiology/ethnology, Lod Score, Male, Chromosomes, Human, Pair 15/*genetics, Netherlands/ethnology, Norway/ethnology, Pedigree, Software
Nielsen KG	Bisgaard H	Nielsen KG, Pressler T, Klug B, Koch C, Bisgaard H	Serial lung function and responsiveness in cystic fibrosis during early childhood	2004	AM J RESP CRIT CARE	15028557	13,204	69	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.	Airway Resistance/drug effects/physiology, Bronchial Provocation Tests, Bronchodilator Agents/therapeutic use, Child, Child Welfare, Child, Preschool, Cold Temperature, Cystic Fibrosis/drug therapy/microbiology/physiopathology, Female, Forced Expiratory Volume/drug effects/physiology, Humans, Longitudinal Studies, Lung/physiopathology, Bronchial Provocation Tests, Male, Prospective Studies, Pseudomonas aeruginosa, Reproducibility of Results, Spirometry, Staphylococcus aureus, Statistics as Topic, Treatment Outcome
Kocevar VS	Thomas J 3rd	Kocevar VS, Bisgaard H, Jönsson L, Valovirta E, Kristensen F, Yin DD, Thomas J 3rd	Variations in pediatric asthma hospitalization rates and costs between and within Nordic countries	2004	CHEST	15136376	6,044	41	BACKGROUND: We assessed variations in hospitalization parameters and costs among asthmatic children in four Nordic countries by geographic location and age groups. METHODS: Cross-sectional, county-level aggregate data on asthma-related hospitalizations in 1999, obtained from public national databases for children < 15 years old from Denmark, Sweden, Norway, and Finland, together with country-specific asthma management cost were used to estimate the incidence of first hospital admission (per 1,000), length of hospital stay (LOS), and hospitalization cost. Longitudinal patient-specific data from 1998/1999 were used to calculate the relative hazard of readmission (RHR) using a multivariate Cox proportional hazards model. RESULTS: Nordic incidence of first hospital admission in 1999 was 2.17 per 1,000 children, readmission was noted in 16% of the patients, mean LOS was 2.64 days, and total hospitalization cost was almost 14 million dollars. Hospitalization incidence, RHR, and costs were significantly higher in children < 5 years old compared with school children 6 to 14 years old. Hospital LOS, incidence of first hospital admission, and cost per child were the highest in Denmark, though RHR did not differ significantly from Sweden. CONCLUSIONS: Large variations in all parameters were observed between and within countries. Given the similarities among the four countries studied, these results may, among other reasons, indicate different efficiencies of the various asthma management plans between and within them. The presented measures of hospitalization patterns could prove to be valuable quality-of-care measures to guide further improvements in asthma management.	Adolescent, Asthma/economics/epidemiology, Child, Child, Preschool, Costs and Cost Analysis, Denmark/epidemiology, Finland/epidemiology, Hospitalization/economics/statistics & numerical data, Humans, Infant, Length of Stay, Norway/epidemiology, Patient Readmission, Asthma/economics/epidemiology, Retrospective Studies, Sweden/epidemiology
Holgate ST	Reginster JY	Holgate ST, Bousquet J, Chung KF, Bisgaard H, Pauwels R, Fabbri L, Rabe K, Doherty M, Snell NJ, Cuss F, D'Amato M, Reginster JY	Summary of recommendations for the design of clinical trials and the registration of drugs used in the treatment of asthma	2004	RESP MED	15191031	3,217	13	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.	Acute Disease, Administration, Inhalation, Adult, Aged, Anti-Asthmatic Agents/therapeutic use, Asthma/diagnosis/drug therapy, Child, Clinical Trials as Topic/*methods, Drug Evaluation, Preclinical/methods, Humans, Nebulizers and Vaporizers, Treatment OutcomeAdministration, Inhalation
Heitmann BL	Bisgaard H	Heitmann BL, Anhøj J, Bisgaard AM, Ward L, Bisgaard H	Changes in body water distribution during treatment with inhaled steroid in pre-school children	2004	ANN HUM BIOL	15204348	1,24	5	PRIMARY OBJECTIVE: The study aimed to examine the changes in water distribution in the soft tissue during systemic steroid activity. RESEARCH DESIGN: 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. METHODS AND PROCEDURES: 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. MAIN OUTCOMES AND RESULTS: 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). CONCLUSION: Decreased growth during inhaled steroid treatment seems to partly reflect generalized changes in body water.	Administration, Inhalation, Androstadienes/adverse effects/therapeutic use, Asthma/drug therapy, Body Water/metabolism, Bronchodilator Agents/adverse effects/therapeutic use, Budesonide/adverse effects/therapeutic use, Child, Preschool, Cross-Over Studies, Double-Blind Method, Electric Impedance, Female, Humans, Male, Androstadienes/*adverse effects/therapeutic use, Skin/metabolism/ultrasonography,
O'Byrne PM	Bateman ED	O'Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist M, Zhu Y, Ekström T, Bateman ED	Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma	2005	AM J RESP CRIT CARE	15502112	13,204	398	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.	Adolescent, Adrenergic beta-Agonists/administration & dosage/adverse effects/pharmacology, Adult, Aged, Aged, 80 and over, Anti-Inflammatory Agents/administration & dosage/adverse effects/pharmacology, Asthma/drug therapy, Budesonide/administration & dosage/adverse effects/pharmacology, Child, Child, Preschool, Double-Blind Method, Drug Combinations, Ethanolamines/administration & dosage/adverse effects/pharmacology, Adrenergic beta-Agonists/administration & dosage/adverse effects/pharmacology, Female, Humans, Male, Metered Dose Inhalers, Middle Aged, Peak Expiratory Flow Rate/drug effects, Proportional Hazards Models, Regression Analysis, Safety,
Bisgaard H	Bisgaard H	Bisgaard H	The Copenhagen Prospective Study on Asthma in Childhood (COPSAC): design, rationale, and baseline data from a longitudinal birth cohort study	2004	ANN ALLERG ASTHMA IM	15521375	3,728	101	BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.	Asthma/diagnosis/etiology/genetics, Child, Preschool, Cohort Studies, Dermatitis, Atopic/diagnosis, Environment, Female, Humans, Hypersensitivity/diagnosis, Infant, Infant, Newborn, Life Style, Longitudinal Studies, Male, Child, Preschool, Pregnancy, Prospective Studies, Research Design, Respiratory Function Tests, Rhinitis/diagnosis, Sweden
Bisgaard H	Polos P	Bisgaard H, Zielen S, Garcia-Garcia ML, Johnston SL, Gilles L, Menten J, Tozzi CA, Polos P	Montelukast reduces asthma exacerbations in 2- to 5-year-old children with intermittent asthma	2005	AM J RESP CRIT CARE	15542792	13,204	237	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.	Acetates/administration & dosage/adverse effects/therapeutic use, Adrenal Cortex Hormones/therapeutic use, Adrenergic beta-Agonists/therapeutic use, Anti-Asthmatic Agents/administration & dosage/adverse effects/therapeutic use, Asthma/complications/drug therapy, Child, Preschool, Double-Blind Method, Drug Administration Schedule, Eosinophils/drug effects, Female, Humans, Male, Quinolines/administration & dosage/adverse effects/therapeutic use, Adrenal Cortex Hormones/therapeutic use, Respiratory Tract Infections/complications, Severity of Illness Index, Time Factors, Treatment Outcome
Nielsen KG	Bisgaard H	Nielsen KG, Bisgaard H	Hyperventilation with cold versus dry air in 2- to 5-year-old children with asthma	2005	AM J RESP CRIT CARE	15542794	13,204	16	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. CONCLUSION: 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.	Air, Airway Resistance/physiology, Asthma/diagnosis/physiopathology, Bronchial Hyperreactivity/diagnosis/physiopathology, Bronchial Provocation Tests/methods, Bronchoconstriction/physiology, Child, Preschool, Cold Temperature/diagnostic use, Female, Humans, Hyperventilation/*physiopathology, Male, Plethysmography, Whole Body, Airway Resistance/physiology
Sazonov Kocevar V	Bisgaard H	Sazonov Kocevar V, Thomas J 3rd, Jonsson L, Valovirta E, Kristensen F, Yin DD, Bisgaard H	Association between allergic rhinitis and hospital resource use among asthmatic children in Norway	2005	ALLERGY	15679719	7,361	29	BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: Concomitant allergic rhinitis in asthmatic children was associated with increased likelihood of asthma-related hospital readmissions and greater total hospital days.	Adolescent, Asthma/complications/therapy, Child, Child, Preschool, Cohort Studies, Female, Hospitalization/statistics & numerical data, Humans, Hypersensitivity/complications, Infant, Infant, Newborn, Least-Squares Analysis, Male, Asthma/complications/therapy, Multivariate Analysis, Norway, Patient Admission/statistics & numerical data, Prognosis, Proportional Hazards Models, Retrospective Studies, Rhinitis/*etiology,
Bisgaard H	Szefler SJ	Bisgaard H, Szefler SJ	Understanding mild persistent asthma in children: the next frontier	2005	J ALLERGY CLIN IMMUN	15805988	13,081	23	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.	Adolescent, Adult, Anti-Asthmatic Agents/therapeutic use, Asthma/drug therapy/*epidemiology/physiopathology, Child, Data Collection, Humans, Prevalence, Prognosis, Research DesignAdult
Santanello NC	Bisgaard H	Santanello NC, Norquist JM, Nelsen LM, Williams VS, Hill CD, Bisgaard H	Validation of a pediatric caregiver diary to measure symptoms of postacute respiratory syncytial virus bronchiolitis	2005	PEDIATR PULM	15858804	2,758	9	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.	Bronchiolitis, Viral/complications/diagnosis/therapy, Caregivers, Cough/classification/etiology, Double-Blind Method, Dyspnea/classification/etiology, Female, Humans, Infant, Infant Care/instrumentation/methods, Male, Medical Records, Night Care, Pilot Projects, Caregivers, Psychometrics, Reproducibility of Results, Respiratory Sounds/classification/etiology, Respiratory Syncytial Virus Infections/complications/diagnosis/therapy
Buchvald F	Bisgaard H	Buchvald F, Baraldi E, Carraro S, Gaston B, De Jongste J, Pijnenburg MW, Silkoff PE, Bisgaard H	Measurements of exhaled nitric oxide in healthy subjects age 4 to 17 years	2005	J ALLERGY CLIN IMMUN	15940124	13,081	262	BACKGROUND: Fractional exhaled nitric oxide (FE NO ) is used in monitoring of asthma. OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.	Adolescent, Age Factors, Asthma/diagnosis/ethnology, Breath Tests/instrumentation/methods, Child, Child, Preschool, Conjunctivitis/diagnosis, Ethnic Groups, Europe, Exhalation, Feasibility Studies, Female, Humans, Age Factors, Male, Nitric Oxide/*analysis/standards, Questionnaires, Reference Values, Reproducibility of Results, Rhinitis/diagnosis, Sex Factors, United States
Bisgaard H	Nielsen KG	Bisgaard H, Nielsen KG	Plethysmographic measurements of specific airway resistance in young children	2005	CHEST	16002957	6,044	62	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.	Airway Resistance, Child, Child, Preschool, Humans, Infant, Lung Volume Measurements, Plethysmography, Whole Body/standards, Quality Assurance, Health Care, Reproducibility of Results, Respiratory Function Tests, Safety, Sensitivity and SpecificityChild
Pedersen SE	Schiøtz PO	Pedersen SE, Bisgaard H, Schiøtz PO	[No risk of development of osteoporosis or inhibition of growth in children with asthma treated with inhaled corticosteroids]	2005	UGESKR L	16008003	0	1	0	Administration, Inhalation, Adrenal Cortex Hormones/administration & dosage/adverse effects, Anti-Asthmatic Agents/administration & dosage/adverse effects, Asthma/drug therapy, Bone Density/drug effects, Bronchodilator Agents/administration & dosage/adverse effects, Child, Fractures, Spontaneous/chemically induced, Growth/drug effects, Humans, Osteoporosis/chemically induced, Risk FactorsAdrenal Cortex Hormones/administration & dosage/adverse effects
Buchvald F	Bisgaard H	Buchvald F, Hermansen MN, Nielsen KG, Bisgaard H	Exhaled nitric oxide predicts exercise-induced bronchoconstriction in asthmatic school children	2005	CHEST	16236842	6,044	42	BACKGROUND: 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. OBJECTIVE: The aim of this study was to estimate the value of FeNO as a predictor of EIB in asthmatic children. METHODS: Stable outpatient asthmatic school children performed standard exercise challenge tests and measurement of FeNO. RESULTS: 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. CONCLUSION: 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.	Adolescent, Asthma, Exercise-Induced/physiopathology, Breath Tests, Bronchoconstriction, Child, Exhalation, Female, Humans, Male, Nitric Oxide/analysis, Outpatients, Asthma, Exercise-Induced/physiopathology
Nielsen KG	Bisgaard H	Nielsen KG, Bisgaard H	Cold air challenge and specific airway resistance in preschool children	2005	PAEDIATR RESPIR REV	16298308	2,214	17	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.	Airway Resistance, Asthma/drug therapy/physiopathology, Bronchial Provocation Tests/instrumentation/methods, Child, Preschool, Humans, Plethysmography, Quality Control, Respiratory Tract Diseases/physiopathology, Sensitivity and Specificity, Asthma/drug therapy/physiopathology
Bisgaard H	Szefler S	Bisgaard H, Szefler S	Long-acting beta(2) agonists and paediatric asthma	2006	LANCET	16443026	47,831	45	0	Adolescent, Adrenergic beta-Agonists/therapeutic use, Asthma/drug therapy, Child, Child, Preschool, Humans, Pediatrics, Product Surveillance, PostmarketingAdrenergic beta-Agonists/*therapeutic use
Loland L	Bisgaard H	Loland L, Buchvald FF, Halkjaer LB, Anhøj J, Hall GL, Persson T, Krause TG, Bisgaard H	Sensitivity of bronchial responsiveness measurements in young infants	2006	CHEST	16537866	6,044	22	OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.	Asthma/diagnosis/physiopathology, Blood Gas Monitoring, Transcutaneous, Bronchial Provocation Tests, Bronchoconstrictor Agents/diagnostic use/pharmacology, Dose-Response Relationship, Drug, Female, Forced Expiratory Volume, Humans, Infant, Male, Methacholine Chloride/diagnostic use/pharmacology, Tidal VolumeBlood Gas Monitoring, Transcutaneous
Palmer CN	McLean WH	Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O'Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeant A, Munro CS, El Houate B, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, McLean WH	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	1509	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.	Alleles, Asthma/genetics/immunology, Child, Cohort Studies, Dermatitis, Atopic/genetics/immunology, Female, Genetic Predisposition to Disease, Humans, Intermediate Filament Proteins/genetics/immunology/physiology, Male, Mutation, Pedigree, Skin Physiological Phenomena, Asthma/genetics/immunology
Hermansen MN	Bisgaard H	Hermansen MN, Nielsen KG, Buchvald F, Jespersen JJ, Bengtsson T, Bisgaard H	Acute relief of exercise-induced bronchoconstriction by inhaled formoterol in children with persistent asthma	2006	CHEST	16685010	6,044	17	STUDY OBJECTIVE: 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. DESIGN: 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. PATIENTS: Twenty-four 7- to 15-year-old children with persistent asthma. INTERVENTIONS: 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. RESULTS: 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). CONCLUSION: 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.	Administration, Inhalation, Adolescent, Adrenergic beta-Agonists/administration & dosage/therapeutic use, Asthma/drug therapy/etiology/physiopathology, Bronchoconstriction/drug effects, Child, Cross-Over Studies, Delayed-Action Preparations, Dose-Response Relationship, Drug, Double-Blind Method, Ethanolamines/administration & dosage/therapeutic use, Exercise Test/adverse effects, Female, Adolescent, Follow-Up Studies, Forced Expiratory Volume/drug effects/physiology, Humans, Male, Treatment Outcome,
Bisgaard H	Buchvald F	Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F	Intermittent inhaled corticosteroids in infants with episodic wheezing	2006	NEW ENGL J MED	16687712	72,406	349	BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).	Administration, Inhalation, Asthma/prevention & control, Bronchodilator Agents/administration & dosage, Budesonide/administration & dosage, Disease Progression, Disease-Free Survival, Double-Blind Method, Drug Administration Schedule, Female, Humans, Infant, Male, Prospective Studies, Asthma/prevention & control, Respiratory Sounds/*drug effects, Risk Factors, Treatment Failure,
Halkjaer LB	Bisgaard H	Halkjaer LB, Loland L, Buchvald FF, Agner T, Skov L, Strand M, 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	0	66	OBJECTIVES: 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. DESIGN: 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. SETTING: 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. PARTICIPANTS: A total of 411 infants were enrolled in the cohort; 55 had incomplete follow-up and were excluded from certain analyses. MAIN OUTCOME MEASURES: 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. RESULTS: 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. CONCLUSIONS: 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.	Age Factors, Asthma/complications, Child, Preschool, Cohort Studies, Denmark/epidemiology, Dermatitis, Atopic/complications/*epidemiology/physiopathology, Disease-Free Survival, Female, Humans, Infant, Infant, Newborn, Longitudinal Studies, Male, Asthma/complications, Prevalence, Prospective Studies, Risk Factors, Severity of Illness Index, Sex Factors,
Vahlkvist S	Bisgaard H	Vahlkvist S, Sinding M, Skamstrup K, Bisgaard H	Daily home measurements of exhaled nitric oxide in asthmatic children during natural birch pollen exposure	2006	J ALLERGY CLIN IMMUN	16750986	13,081	62	BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. CLINICAL IMPLICATIONS: This simple handheld device expands the potential use of FENO to a wider group of asthma clinics and even home measurements.	Adolescent, Allergens/adverse effects/immunology, Asthma/diagnosis/immunology/metabolism, Betula/immunology, Biological Markers, Child, Child, Preschool, Feasibility Studies, Female, Home Care Services, Humans, Male, Nitric Oxide/analysis/metabolism, Allergens/adverse effects/immunology, Pollen/adverse effects/immunology, Reproducibility of Results, Self Care, Sensitivity and Specificity
Gammelgaard A	Bisgaard H	Gammelgaard A, Knudsen LE, Bisgaard H	Perceptions of parents on the participation of their infants in clinical research	2006	ARCH DIS CHILD	16820387	3,265	17	OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: It is possible to design and accomplish invasive clinical research on infants and young children in a manner that parents find ethically sound.	Altruism, Asthma/epidemiology, Attitude to Health, Biomedical Research, Child, Preschool, Denmark/epidemiology, Humans, Infant, Infant, Newborn, Mothers/*psychology, Motivation, Perception, Prospective Studies, Asthma/epidemiology
Lauritzen L	Bisgaard H	Lauritzen L, Halkjaer LB, Mikkelsen TB, Olsen SF, Michaelsen KF, Loland L, Bisgaard H	Fatty acid composition of human milk in atopic Danish mothers	2006	AM J CLIN NUTR	16825695	6,926	23	BACKGROUND: Atopic dermatitis has been related to a disturbed metabolism of polyunsaturated fatty acids (PUFAs). OBJECTIVE: 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. DESIGN: 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. RESULTS: 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. CONCLUSION: 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.	Adult, Asthma/metabolism, Cohort Studies, Denmark, Dermatitis, Atopic/metabolism, Diet, Fatty Acids, Omega-3/analysis, Fatty Acids, Omega-6/analysis, Fatty Acids, Unsaturated/analysis/metabolism, Female, Humans, Infant, Newborn, Lactation/metabolism, Asthma/metabolism, Milk, Human/chemistry, Prospective Studies, Questionnaires,
Bisgaard H	Hultquist C	Bisgaard H, Le Roux P, Bjåmer D, Dymek A, Vermeulen JH, Hultquist C	Budesonide/formoterol maintenance plus reliever therapy: a new strategy in pediatric asthma	2006	CHEST	17166990	6,044	121	OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.	Adrenal Cortex Hormones/administration & dosage/adverse effects, Adrenergic beta-Agonists/administration & dosage/adverse effects, Anti-Asthmatic Agents/administration & dosage/adverse effects, Asthma/drug therapy, Budesonide/administration & dosage/adverse effects, Child, Child, Preschool, Delayed-Action Preparations, Dose-Response Relationship, Drug, Double-Blind Method, Drug Administration Schedule, Drug Combinations, Drug Therapy, Combination, Adrenergic beta-Agonists/administration & dosage/adverse effects, Ethanolamines/administration & dosage/adverse effects, Female, Forced Expiratory Volume/drug effects, Glucocorticoids/administration & dosage/adverse effects, Humans, Male, Prospective Studies, Terbutaline/administration & dosage
Bønnelykke K	Bisgaard H	Bønnelykke K, Jespersen JJ, Bisgaard H	Age dependent systemic exposure to inhaled salbutamol	2007	BRIT J CLIN PHARMCO	17335545	3,493	9	AIMS: To determine the effect of age on systemic exposure to inhaled salbutamol in children. METHODS: 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. RESULTS: 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%CI) = 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%CI) = 1.7 (1.3, 2.2)). CONCLUSIONS: 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.	Administration, Inhalation, Adolescent, Age Factors, Albuterol/administration & dosage/pharmacokinetics, Asthma/drug therapy, Bronchodilator Agents/administration & dosage/pharmacokinetics, Child, Child, Preschool, Dose-Response Relationship, Drug, Female, Humans, Lung/metabolism, Male, Adolescent
Bisgaard H	Weiss ST	Bisgaard H, Pedersen S, Anhøj J, Agertoft L, Hedlin G, Gulsvik A, Bjermer L, Carlsen KH, Nordvall L, Lundbäck B, Wennergren G, Werner S, Bønnelykke K, Weiss ST	Determinants of lung function and airway hyperresponsiveness in asthmatic children	2007	RESP MED	17336509	3,217	10	BACKGROUND: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.	Adolescent, Adult, Age Factors, Asthma/drug therapy/genetics/physiopathology, Bronchial Hyperreactivity/genetics/physiopathology, Child, Cross-Sectional Studies, Drug Administration Schedule, Female, Forced Expiratory Volume/drug effects, Glucocorticoids/administration & dosage/therapeutic use, Humans, Male, Adult, Smoking/physiopathology,
Sørensen M	Loft S	Sørensen M, Bisgaard H, Stage M, Loft S	Biomarkers of exposure to environmental tobacco smoke in infants	2007	BIOMARKERS	17438652	2,006	23	Non-invasive biomonitoring of exposure to environmental tobacco smoke (ETS) by means of hair is attractive in children, although systematic evaluation is required in infants. The objective was to compare nicotine and cotinine concentrations in hair and plasma and parentally reported exposure to ETS in a birth cohort of 411 infants. Plasma was collected from 356 six-month-old infants and hair samples were collected from 368 one-year-old infants. Concentrations of nicotine and cotinine were measured by an optimized gas chromatography-mass spectrometry (GC/MS)-based method requiring 4 mg hair or 200 microl plasma. Information was obtained on the number of days with ETS exposure during the first year of life, the smoking habits of the parents, and the number of cigarettes smoked per day in the home. All three parentally reported indices of ETS exposure were significantly associated with the biomarkers, with clear dose response relationships. There was a significant association between days with ETS exposure and nicotine in hair at relatively low exposure levels (10-99 days per year), whereas the other biomarkers only showed significant increases at higher exposure levels. In conclusion, nicotine in hair appears to be the biomarker most strongly associated with parental reports on exposure to ETS in infants.	Biological Markers/analysis/blood, Cotinine/analysis/blood, Environmental Exposure, Gas Chromatography-Mass Spectrometry, Hair/chemistry, Humans, Infant, Nicotine/analysis/blood, Smoke/adverse effects, TobaccoCotinine/*analysis/blood
Beydon N	Wilson NM	Beydon N, Davis SD, Lombardi E, Allen JL, Arets HG, Aurora P, Bisgaard H, Davis GM, Ducharme FM, Eigen H, Gappa M, Gaultier C, Gustafsson PM, Hall GL, Hantos Z, Healy MJ, Jones MH, Klug B, Lødrup Carlsen KC, McKenzie SA, Marchal F, Mayer OH, Merkus PJ, Morris MG, Oostveen E, Pillow JJ, Seddon PC, Silverman M, Sly PD, Stocks J, Tepper RS, Vilozni D, Wilson NM	An official American Thoracic Society/European Respiratory Society statement: pulmonary function testing in preschool children	2007	AM J RESP CRIT CARE	17545458	13,204	563	0	Bronchial Provocation Tests/standards, Child, Preschool, Disease Progression, Functional Residual Capacity, Humans, Lung Diseases/diagnosis, Quality Control, Respiratory Function Tests/methods/standards, Respiratory Sounds/diagnosis, Spirometry/instrumentation/standardsChild, Preschool
Bisgaard H	Szefler S	Bisgaard H, Szefler S	Prevalence of asthma-like symptoms in young children	2007	PEDIATR PULM	17598172	2,758	143	OBJECTIVE: To determine the prevalence, impact, and treatment of asthma-like symptoms in preschool children in USA and Europe. STUDY DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.	Asthma/drug therapy/*epidemiology, Child, Preschool, Cough/epidemiology, Europe/epidemiology, Female, Humans, Infant, Interviews as Topic, Male, Prevalence, Respiratory Sounds, United States/epidemiologyChild, Preschool
Bisgaard H	Bisgaard H	Bisgaard H	What drives prescription patterns in pediatric asthma management?	2007	J ALLERGY CLIN IMMUN	17637472	13,081	9	LETTER	Administration, Inhalation, Adolescent, Adrenergic beta-Agonists/administration & dosage, Asthma/drug therapy, Child, Drug Therapy, Combination, Humans, Physician's Practice Patterns/*statistics & numerical dataAdolescent
Bisgaard H	Pipper CB	Bisgaard H, Hermansen MN, Buchvald F, Loland L, Halkjaer LB, Bønnelykke K, Brasholt M, Heltberg A, Vissing NH, Thorsen SV, Stage M, Pipper CB	Childhood asthma after bacterial colonization of the airway in neonates	2007	NEW ENGL J MED	17928596	72,406	480	BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.	Asthma/drug therapy/immunology/microbiology, Bacterial Infections/complications/immunology, Budesonide/therapeutic use, Child, Preschool, Cohort Studies, Haemophilus influenzae/isolation & purification, Humans, Hypersensitivity/microbiology, Hypopharynx/microbiology, Immunoglobulin E/blood, Infant, Infant, Newborn, Kaplan-Meier Estimate, Bacterial Infections/complications/immunology, Male, Moraxella (Branhamella) catarrhalis/isolation & purification, Neutrophils/physiology, Respiratory Sounds/etiology, Respiratory Tract Infections/complications, Risk Factors, Staphylococcus aureus/isolation & purification, Streptococcus pneumoniae/isolation & purification
Loland L	Bisgaard H	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	BACKGROUND: 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. METHOD: 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. RESULTS: 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. CONCLUSION: 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.	Feasibility Studies, Humans, Infant, Respiratory Function Tests/*methodsHumans
Lerbaek A	Menné T	Lerbaek A, Bisgaard H, Agner T, Ohm Kyvik K, Palmer CN, Menné T	Filaggrin null alleles are not associated with hand eczema or contact allergy	2007	BRIT J DERMATOL	17970802	4,706	42	BACKGROUND: 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. OBJECTIVES: To explore associations between the variant alleles, hand eczema, contact allergy and atopic dermatitis. METHODS: 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. RESULTS: 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. CONCLUSION: There is no association between the variant alleles and hand eczema or contact allergy.	Adult, Cohort Studies, Dermatitis, Contact/genetics, Female, Hand Dermatoses/genetics, Humans, Intermediate Filament Proteins/*genetics, Longitudinal Studies, Male, Prospective Studies, Skin Tests, Twins, MonozygoticCohort Studies
Andersen ZJ	Bisgaard H	Andersen ZJ, Loft S, Ketzel M, Stage M, Scheike T, Hermansen MN, Bisgaard H	Ambient air pollution triggers wheezing symptoms in infants	2008	THORAX	18267985	8,272	63	BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Air pollution related to traffic is significantly associated with triggering of wheezing symptoms in the first 3 years of life.	Air Pollutants/analysis/toxicity, Air Pollution/adverse effects/analysis, Asthma/genetics, Carbon Monoxide/toxicity, Child, Preschool, Denmark, Epidemiologic Methods, Female, Genetic Predisposition to Disease, Humans, Infant, Male, Nitrogen Dioxide/analysis/toxicity, Air Pollution/adverse effects/analysis, Nitrogen Oxides/analysis/toxicity, Particulate Matter/analysis/toxicity, Pedigree, Prospective Studies, Respiratory Sounds/etiology, Time Factors, Vehicle Emissions/analysis/toxicity,
Thomsen SF	Bisgaard H	Thomsen SF, Stensballe LG, Skytthe A, Kyvik KO, Backer V, Bisgaard H	Increased concordance of severe respiratory syncytial virus infection in identical twins	2008	PEDIATRICS	18310197	5,705	49	OBJECTIVE: We estimated differences in the severity of respiratory syncytial virus infection attributable to genetic and environmental factors. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.	Age Distribution, Child, Preschool, Confidence Intervals, Denmark/epidemiology, Enzyme-Linked Immunosorbent Assay, Female, Follow-Up Studies, Genetic Predisposition to Disease/epidemiology, Humans, Incidence, Infant, Male, Probability, Child, Preschool, Proportional Hazards Models, Registries, Respiratory Syncytial Virus Infections/diagnosis/epidemiology/genetics, Retrospective Studies, Risk Factors, Severity of Illness Index, Sex Distribution, Twins, Monozygotic
Bønnelykke K	Bisgaard H	Bønnelykke K, Pipper CB, Bisgaard H	Sensitization does not develop in utero	2008	J ALLERGY CLIN IMMUN	18328892	13,081	53	BACKGROUND: 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. OBJECTIVE: To investigate the relevance of allergen-specific IgE in cord blood to sensitization in early infancy and the origin of such IgE. METHODS: 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. RESULTS: 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. CONCLUSION: 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.	Allergens/immunology, Enzyme-Linked Immunosorbent Assay, Fetal Blood/immunology, Food Hypersensitivity/etiology/immunology, Humans, Hypersensitivity, Immediate/blood/immunology, Immunoglobulin A/blood, Immunoglobulin E/blood, Infant, Infant, Newborn, Inhalation Exposure/adverse effects, Pregnancy, Prenatal Exposure Delayed Effects/blood/immunology, Enzyme-Linked Immunosorbent Assay
Kjaer BB	Bisgaard H	Kjaer BB, Jensen JS, Nielsen KG, Fomsgaard A, Böttiger B, Dohn B, Bisgaard H	Lung function and bronchial responsiveness after Mycoplasma pneumoniae infection in early childhood	2008	PEDIATR PULM	18435477	2,758	15	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.	Airway Resistance, Bronchial Hyperreactivity/diagnosis/microbiology, Bronchial Provocation Tests, Child, Preschool, Cohort Studies, Female, Humans, Infant, Male, Mycoplasma Infections/complications/diagnosis/microbiology, Mycoplasma pneumoniae/isolation & purification, Plethysmography, Whole Body, Polymerase Chain Reaction, Bronchial Hyperreactivity/diagnosis/*microbiology, Retrospective Studies,
Bisgaard H	Custovic A	Bisgaard H, Simpson A, Palmer CN, Bønnelykke K, McLean I, Mukhopadhyay S, Pipper CB, Halkjaer LB, Lipworth B, Hankinson J, Woodcock A, 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	143	BACKGROUND: 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. METHODS AND FINDINGS: 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. CONCLUSIONS: 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.	Age Factors, Age of Onset, Animals, Cats/immunology, Codon, Nonsense/physiology, Cohort Studies, Dermatitis, Atopic/genetics, Dogs, Environment, Environmental Exposure, Gene Expression Regulation, Genetic Predisposition to Disease, Genotype, Age of Onset, Humans, Infant, Infant, Newborn, Intermediate Filament Proteins/genetics/physiology, Parturition, Risk Factors
Bisgaard H	Knorr BA	Bisgaard H, Flores-Nunez A, Goh A, Azimi P, Halkas A, Malice MP, Marchal JL, Dass SB, Reiss TF, Knorr BA	Study of montelukast for the treatment of respiratory symptoms of post-respiratory syncytial virus bronchiolitis in children	2008	AM J RESP CRIT CARE	18583576	13,204	82	RATIONALE: 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. OBJECTIVES: 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. METHODS: 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 (%SFD; day with no daytime cough, wheeze, and shortness of breath, and no nighttime cough). MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: In this study, montelukast did not improve respiratory symptoms of post-RSV bronchiolitis in children.	Acetates/administration & dosage/therapeutic use, Bronchiolitis/diagnosis/drug therapy/virology, Child, Preschool, Dose-Response Relationship, Drug, Double-Blind Method, Female, Follow-Up Studies, Humans, Infant, Leukotriene Antagonists/administration & dosage/therapeutic use, Male, Pilot Projects, Quinolines/administration & dosage/therapeutic use, Bronchiolitis/diagnosis/drug therapy/virology, Respiratory Syncytial Virus Infections/diagnosis/drug therapy/virology, Respiratory Syncytial Viruses/*isolation & purification, Retrospective Studies, Severity of Illness Index, Treatment Outcome,
Bønnelykke K	Bisgaard H	Bønnelykke K, Jespersen JJ, Bisgaard H	Early bioavailability of inhaled salbutamol reflects lung dose in children	2008	BRIT J CLIN PHARMCO	18637892	3,493	1	LETTER	Adolescent, Albuterol/administration & dosage, Biological Availability, Bronchodilator Agents/administration & dosage, Child, Child, Preschool, Female, Humans, Lung/drug effects, MaleAlbuterol/*administration & dosage
Sleiman PM	Hakonarson H	Sleiman PM and Annaiah K, Imielinski M, Bradfield JP, Kim CE, Frackelton EC, Glessner JT, Eckert AW, Otieno FG, Santa E, Thomas K, Smith RM, Glaberson W, Garris M, Gunnlaugsson S, Chiavacci RM, Allen J, Spergel J, Grundmeier R, Grunstein MM, Magnusson M, Bisgaard H, Grant SF, Hakonarson H	ORMDL3 variants associated with asthma susceptibility in North Americans of European ancestry	2008	J ALLERGY CLIN IMMUN	18760456	13,081	71	LETTER	Asthma/epidemiology/genetics/metabolism, Chromosomes, Human, Pair 17/genetics/metabolism, Cohort Studies, European Continental Ancestry Group, Female, Humans, Male, Membrane Proteins/biosynthesis/genetics, *Polymorphism, Single Nucleotide, Quantitative Trait Loci/genetics, United States/epidemiology, Chromosomes, Human, Pair 17/genetics/metabolism
Brand PL	Bush A	Brand PL, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez JA, Custovic A, de Blic J, de Jongste JC, Eber E, Everard ML, Frey U, Gappa M, Garcia-Marcos L, Grigg J, Lenney W, Le Souëf P, McKenzie S, Merkus PJ, Midulla F, Paton JY, Piacentini G, Pohunek P, Rossi GA, Seddon P, Silverman M, Sly PD, Stick S, Valiulis A, van Aalderen WM, Wildhaber JH, Wennergren G, Wilson N, Zivkovic Z, Bush A	Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach	2008	EUR RESPIR J	18827155	10,569	468	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.	Adrenal Cortex Hormones/metabolism, Allergens/metabolism, Child, Child, Preschool, Cohort Studies, Evidence-Based Medicine, Glucocorticoids/metabolism, Humans, Multicenter Studies as Topic, Patient Education as Topic, Phenotype, Randomized Controlled Trials as Topic, Respiratory Sounds/*diagnosis, Allergens/metabolism, Time Factors, Treatment Outcome
Giwercman C	Menné T	Giwercman C, Lerbaek A, Bisgaard H, Menné T	Classification of atopic hand eczema and the filaggrin mutations	2008	CONTACT DERMATITIS	18976374	4,335	10	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.	Dermatitis, Atopic/classification/epidemiology/genetics, Female, Gene Expression Regulation, Genetic Predisposition to Disease/epidemiology, Hand Dermatoses/classification/epidemiology/genetics, Humans, Incidence, Intermediate Filament Proteins/genetics, Male, Mutation, Prognosis, Sensitivity and SpecificityFemale
Bisgaard H	Hakonarsson H	Bisgaard H, Bønnelykke K, Sleiman PM, Brasholt M, Chawes B, Kreiner-Møller E, Stage M, Kim C, Tavendale R, Baty F, Pipper CB, Palmer CN, Hakonarsson H	Chromosome 17q21 gene variants are associated with asthma and exacerbations but not atopy in early childhood	2009	AM J RESP CRIT CARE	19029000	13,204	130	RATIONALE: An asthma predisposition locus on chromosome 17q12-q21 has recently been replicated in different ethnic groups. OBJECTIVES: To characterize the asthma and atopy phenotypes in early childhood that associate with the 17q12-21 locus. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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.	Airway Resistance/physiology, Asthma/epidemiology/genetics/physiopathology, Child, Child, Preschool, Chromosomes, Human, Pair 17/genetics, Denmark/epidemiology, Female, Follow-Up Studies, Forced Expiratory Flow Rates, Genetic Predisposition to Disease, Genetic Variation, Humans, Hypersensitivity, Immediate/epidemiology/genetics/physiopathology, Asthma/epidemiology/genetics/physiopathology, Incidence, Infant, Infant, Newborn, Lung Volume Measurements, Male, Oximetry, Phenotype, Prognosis, Prospective Studies, Recurrence, Time Factors,
Holgate S	Wahn U	Holgate S, Bisgaard H, Bjermer L, Haahtela T, Haughney J, Horne R, McIvor A, Palkonen S, Price DB, Thomas M, Valovirta E, Wahn U	The Brussels Declaration: the need for change in asthma management	2008	EUR RESPIR J	19043008	10,569	76	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.	Adult, Asthma/epidemiology/therapy, Belgium, Child, Clinical Competence, Disease Management, Europe, Humans, Inflammation, Outcome Assessment (Health Care)/standards, Prevalence, Pulmonary Medicine/methods/standards, Registries, Asthma/epidemiology/therapy
Swern AS	Bisgaard H	Swern AS, Tozzi CA, Knorr B, Bisgaard H	Predicting an asthma exacerbation in children 2 to 5 years of age	2008	ANN ALLERG ASTHMA IM	19119707	3,728	16	BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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%. CONCLUSIONS: 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.	Acetates/administration & dosage/therapeutic use, Adrenergic beta-Agonists/administration & dosage/therapeutic use, Anti-Asthmatic Agents/administration & dosage/therapeutic use, Asthma/physiopathology/prevention & control, Child, Preschool, Cough/physiopathology, Drug Administration Schedule, Humans, Multivariate Analysis, Prognosis, Quinolines/administration & dosage/therapeutic use, Remission, Spontaneous, Respiratory Sounds/physiopathology, Adrenergic beta-Agonists/*administration & dosage/therapeutic use, Severity of Illness Index,
Stensballe LG	Bisgaard H	Stensballe LG, Simonsen JB, Thomsen SF, Larsen AM, Lysdal SH, Aaby P, Kyvik KO, Skytthe A, Backer V, Bisgaard H	The causal direction in the association between respiratory syncytial virus hospitalization and asthma	2009	J ALLERGY CLIN IMMUN	19130934	13,081	77	BACKGROUND: 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. OBJECTIVE: The current study examined the causal direction of the associations between RSV hospitalization and asthma in a population-based cohort of twins. METHODS: 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. RESULTS: 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. CONCLUSION: 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.	Asthma/epidemiology/virology, Child, Child, Preschool, Denmark, Environmental Exposure, Female, Genetic Predisposition to Disease, Hospitalization, Humans, Infant, Infant, Newborn, Male, Registries, Child, Respiratory Syncytial Virus Infections/epidemiology, Respiratory Syncytial Viruses, Risk Factors, Time Factors
Bisgaard H	Pipper CB	Bisgaard H, Loland L, Holst KK, Pipper CB	Prenatal determinants of neonatal lung function in high-risk newborns	2009	J ALLERGY CLIN IMMUN	19152964	13,081	43	BACKGROUND: Neonatal lung function is suspected to be associated with wheezy disorders, but little is known about risk factors for the early lung function. OBJECTIVES: To study prenatal determinants of neonatal lung function. METHODS: 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. RESULTS: 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. CONCLUSION: 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.	Body Mass Index, Bronchial Hyperreactivity/epidemiology/physiopathology, Denmark/epidemiology, Female, Forced Expiratory Volume, Humans, Infant, Newborn, Lung/embryology/physiopathology, Male, Maternal-Fetal Exchange, Methacholine Chloride/diagnostic use, Pregnancy, Prenatal Nutritional Physiological Phenomena, Bronchial Hyperreactivity/epidemiology/physiopathology, Prospective Studies, Respiratory Sounds/physiology, Risk Factors, Smoking/adverse effects, Spirometry,
Skov L	Bisgaard H	Skov L, Halkjaer LB, Agner T, Frimodt-Møller N, Jarløv JO, Bisgaard H	Neonatal colonization with Staphylococcus aureus is not associated with development of atopic dermatitis	2009	BRIT J DERMATOL	19239467	4,706	14	BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.	Age Factors, Child, Preschool, Cohort Studies, Denmark/epidemiology, Dermatitis, Atopic/epidemiology/microbiology, Female, Follow-Up Studies, Humans, Infant, Infant, Newborn, Male, Pregnancy, Risk Factors, Child, Preschool, Severity of Illness Index, Staphylococcal Skin Infections/epidemiology, Staphylococcus aureus/*isolation & purification, Statistics as Topic
Thomsen SF	Bisgaard H	Thomsen SF, van der Sluis S, Stensballe LG, Posthuma D, Skytthe A, Kyvik KO, Duffy DL, Backer V, Bisgaard H	Exploring the association between severe respiratory syncytial virus infection and asthma: a registry-based twin study	2009	AM J RESP CRIT CARE	19286626	13,204	109	RATIONALE: Severe respiratory syncytial virus (RSV) infection is associated with asthma but the nature of this association is imperfectly understood. OBJECTIVES: To examine the nature of the association between severe RSV infection and asthma in a population-based sample of twins. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: RSV infection that is severe enough to warrant hospitalization does not cause asthma but is an indicator of the genetic predisposition to asthma.	Antigens, Viral/analysis, Asthma/epidemiology/etiology, Child, Child, Preschool, Denmark/epidemiology, Enzyme-Linked Immunosorbent Assay, Female, Follow-Up Studies, Hospitalization/statistics & numerical data, Humans, Incidence, Male, Models, Theoretical, Asthma/epidemiology/etiology, Prognosis, Registries, Respiratory Syncytial Virus Infections/complications/epidemiology/virology, Respiratory Syncytial Virus, Human/immunology, Retrospective Studies, Risk Factors, Twins/*genetics,
Bisgaard H	Noonan G	Bisgaard H, Skoner D, Boza ML, Tozzi CA, Newcomb K, Reiss TF, Knorr B, Noonan G	Safety and tolerability of montelukast in placebo-controlled pediatric studies and their open-label extensions	2009	PEDIATR PULM	19449366	2,758	52	BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.	Acetates/adverse effects, Adolescent, Anti-Asthmatic Agents/adverse effects, Asthma/drug therapy, Child, Child, Preschool, Humans, Infant, Quinolines/adverse effects, Rhinitis, Allergic, Perennial/*drug therapyAdolescent
Poorisrisak P	Bisgaard H	Poorisrisak P, Vrang C, Henriksen JM, Klug B, Hanel B, Bisgaard H	Accuracy of whole-body plethysmography requires biological calibration	2009	CHEST	19497894	6,044	11	BACKGROUND: 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. METHOD: 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. RESULTS: (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). CONCLUSION: 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.	Airway Resistance/physiology, Child, Preschool, Denmark, Female, Humans, Male, Observer Variation, Plethysmography, Whole Body/methods/*standards, Reference Values, Sensitivity and SpecificityChild, Preschool
Bisgaard H	Strand M	Bisgaard H, Halkjaer LB, Hinge R, Giwercman C, Palmer C, Silveira L, Strand M	Risk analysis of early childhood eczema	2009	J ALLERGY CLIN IMMUN	19501236	13,081	53	BACKGROUND: The increasing prevalence of eczema suggests the role of environmental factors triggering a genetic predisposition. OBJECTIVE: To analyze the effect of environmental exposures in early life and genetic predisposition on the development of eczema before age 3 years. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.	Alleles, Child, Preschool, Denmark/epidemiology, Eczema/drug therapy/*epidemiology/genetics, Female, Follow-Up Studies, Genetic Predisposition to Disease, Genotype, Humans, Hydrocortisone/therapeutic use, Infant, Infant, Newborn, Intermediate Filament Proteins/genetics, Child, Preschool, Logistic Models, Male, Monte Carlo Method, Mutation/genetics, Prevalence, Prospective Studies, Risk Factors,
Flory JH	Hakonarson H	Flory JH, Sleiman PM, Christie JD, Annaiah K, Bradfield J, Kim CE, Glessner J, Imielinski M, Li H, Frackelton EC, 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 SF, Bønnelykke K, Bisgaard 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 IMMUN	19660801	13,081	55	LETTER	Adolescent, Asthma/epidemiology/genetics, Case-Control Studies, Child, Child, Preschool, Chromosomes, Human, Pair 17/genetics, Cohort Studies, European Continental Ancestry Group/genetics, Female, Genetic Predisposition to Disease, Humans, Infant, Infant, Newborn, Asthma/epidemiology/genetics, Male, Membrane Proteins/genetics, Polymorphism, Single Nucleotide, Risk Factors, Smoking/adverse effects, Tobacco/adverse effects
Chawes BL	Bisgaard H	Chawes BL, Kreiner-Møller E, Bisgaard H	Objective assessments of allergic and nonallergic rhinitis in young children	2009	ALLERGY	19663868	7,361	38	BACKGROUND: Allergic and nonallergic rhinitis are common childhood disorders. OBJECTIVE: To study nasal eosinophilia and nasal airway patency in young children with allergic and nonallergic rhinitis to assess the pathology behind such diagnoses. METHODS: 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. RESULTS: 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. CONCLUSION: 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.	Allergens/adverse effects/immunology, Child, Cohort Studies, Eosinophilia/complications, Humans, Nasal Obstruction/complications/pathology, Rhinitis/complications/diagnosis/pathology, Rhinitis, Allergic, Perennial/complications/diagnosis/pathology, *Rhinitis, Allergic, Seasonal/complications/diagnosis/pathology, Rhinometry, AcousticChild
Smyth AR	Merkus PJ	Smyth AR, 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, Merkus PJ	Respiratory medicines for children: current evidence, unlicensed use and research priorities	2010	EUR RESPIR J	19840958	10,569	26	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.	Adrenal Cortex Hormones/pharmacology, Anti-Bacterial Agents/pharmacology, Biomedical Research/trends, Child, Child, Preschool, Clinical Trials as Topic, Drug Therapy/methods, Evidence-Based Medicine, Humans, Immunosuppressive Agents/pharmacology, Infant, Infant, Newborn, Neonatal Screening, Anti-Bacterial Agents/pharmacology, Off-Label Use, Pediatrics/methods, Physician's Practice Patterns, Pulmonary Medicine/methods, Respiration Disorders/*drug therapy,
Kindlund K	Bisgaard H	Kindlund K, Thomsen SF, Stensballe LG, Skytthe A, Kyvik KO, Backer V, Bisgaard H	Birth weight and risk of asthma in 3-9-year-old twins: exploring the fetal origins hypothesis	2010	THORAX	19996338	8,272	47	AIM: To examine the relationship between birth weight and risk of asthma in a population of twins. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.	Anthropometry/methods, Apgar Score, Asthma/embryology/epidemiology, Birth Weight, Child, Child, Preschool, Denmark/epidemiology, Diseases in Twins/*embryology/epidemiology, Epidemiologic Methods, Female, Humans, Infant, Newborn, Male, Apgar Score, Pregnancy, Prenatal Exposure Delayed Effects, Twins, Dizygotic, Twins, Monozygotic
Raaschou-Nielsen O	Bisgaard H	Raaschou-Nielsen O, Hermansen MN, Loland L, Buchvald F, Pipper CB, Sørensen M, Loft S, Bisgaard H	Long-term exposure to indoor air pollution and wheezing symptoms in infants	2010	INDOOR AIR	20028431	4,383	16	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.	Air Pollution, Indoor/adverse effects, Denmark, Humans, Infant, Infant, Newborn, Inhalation Exposure/adverse effects, Nitrogen Oxides/adverse effects/analysis, Prospective Studies, Respiratory Sounds/etiology/*physiopathology, Time FactorsDenmark
Sleiman PM	Hakonarson H	Sleiman PM, Flory J, Imielinski M, Bradfield JP, Annaiah K, Willis-Owen SA, Wang K, Rafaels NM, Michel S, Bønnelykke K, Zhang H, Kim CE, Frackelton EC, Glessner JT, Hou C, Otieno FG, Santa E, Thomas K, Smith RM, Glaberson WR, Garris M, Chiavacci RM, Beaty TH, Ruczinski I, Orange JS, Allen J, Spergel JM, Grundmeier R, Mathias RA, Christie JD, von Mutius E, Cookson WO, Kabesch M, Moffatt MF, Grunstein MM, Barnes KC, Devoto M, Magnusson M, Li H, Grant SF, Bisgaard H, Hakonarson H	Variants of DENND1B associated with asthma in children	2010	NEW ENGL J MED	20032318	72,406	200	BACKGROUND: Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown. METHODS: 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. RESULTS: 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 alpha receptor [corrected]. CONCLUSIONS: We have identified a locus containing DENND1B on chromosome 1q31.3 that is associated with susceptibility to asthma.	African Continental Ancestry Group/genetics, Asthma/genetics, Case-Control Studies, Child, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 17, Death Domain Receptor Signaling Adaptor Proteins/genetics, European Continental Ancestry Group/genetics, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Guanine Nucleotide Exchange Factors/genetics, Humans, Asthma/genetics, Male, Meta-Analysis as Topic, North America, Odds Ratio, *Polymorphism, Single Nucleotide, Receptors, Tumor Necrosis Factor/metabolism
Chawes BLK	Bisgaard H	Chawes BLK, Kreiner-Møller E, Bisgaard H	Upper and lower airway patency are associated in young children	2010	CHEST	20118204	6,044	18	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.	Adrenergic alpha-Agonists/administration & dosage, Adrenergic beta-Agonists/administration & dosage, Airway Obstruction/physiopathology, Anthropometry, Asthma/physiopathology, Biological Markers/analysis, Child, Eosinophilia/diagnosis, Female, Forced Expiratory Volume, Humans, Immunoglobulin E/analysis, Linear Models, Adrenergic beta-Agonists/administration & dosage, Male, Nitric Oxide/analysis, Prospective Studies, Rhinitis, Allergic, Seasonal/*physiopathology, Rhinometry, Acoustic, Spirometry
Giwercman C	Bisgaard H	Giwercman C, Halkjaer LB, Jensen SM, Bønnelykke K, Lauritzen L, 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 IMMUN	20236698	13,081	53	BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.	Breast Feeding/adverse effects, Cohort Studies, Denmark/epidemiology, Eczema/diagnosis/epidemiology/etiology, Fatty Acids/analysis, Female, Humans, Infant, Male, Milk, Human/chemistry, Respiratory Sounds/diagnosis/etiology/physiopathology, Risk Assessment, Risk Factors, Cohort Studies
Chawes BL	Bisgaard H	Chawes BL, Buchvald F, Bischoff AL, Loland L, Hermansen M, Halkjaer LB, Bønnelykke K, Bisgaard H	Elevated exhaled nitric oxide in high-risk neonates precedes transient early but not persistent wheeze	2010	AM J RESP CRIT CARE	20299533	13,204	36	RATIONALE: Elevated fractional exhaled nitric oxide (Fe(NO)) concentration has been suggested to predict early childhood wheeze and sensitization. OBJECTIVES: 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. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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.	Asthma/epidemiology, Breath Tests, Cell Count, Child, Eosinophils/metabolism, Exhalation, Female, Follow-Up Studies, Humans, Immunoglobulin E/blood, Infant, Newborn, Male, Mothers, Breath Tests, Nitric Oxide/metabolism, Prospective Studies, Recurrence, Respiratory Function Tests, *Respiratory Sounds, Tobacco Smoke Pollution
Chawes BL	Hansel TT	Chawes BL, Edwards MJ, Shamji B, Walker C, Nicholson GC, Tan AJ, Følsgaard NV, Bønnelykke K, Bisgaard H, Hansel TT	A novel method for assessing unchallenged levels of mediators in nasal epithelial lining fluid	2010	J ALLERGY CLIN IMMUN	20304470	13,081	38	LETTER	Allergens/immunology, Case-Control Studies, Child, Female, High-Throughput Screening Assays, Humans, Immunity, Mucosal, Immunization, Inflammation Mediators/metabolism, Male, Nasal Lavage Fluid/immunology, Nasal Mucosa/immunology/metabolism, Rhinitis, Allergic, Perennial/diagnosis/immunology, Case-Control Studies, Rhinitis, Allergic, Seasonal/*diagnosis/immunology,
Brasholt M	Bisgaard H	Brasholt M, Baty F, Bisgaard H	Physical activity in young children is reduced with increasing bronchial responsiveness	2010	J ALLERGY CLIN IMMUN	20392480	13,081	23	BACKGROUND: 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. OBJECTIVE: We sought to study an association between physical activity in preschool children and objectively assessed intermediary asthma phenotypes. METHODS: 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. RESULTS: 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. CONCLUSION: 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.	Airway Resistance, Asthma/physiopathology, Bronchial Hyperreactivity/physiopathology, Child, Preschool, Cohort Studies, Exercise/physiology, Female, Humans, Male, Motor Activity, Nitric Oxide/analysis, Principal Component Analysis, Respiratory Function Tests, Asthma/physiopathology
Poorisrisak P	Bisgaard H	Poorisrisak P, Halkjaer LB, Thomsen SF, Stensballe LG, Kyvik KO, Skytthe A, Schioetz PO, Bisgaard H	Causal direction between respiratory syncytial virus bronchiolitis and asthma studied in monozygotic twins	2010	CHEST	20435661	6,044	33	BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.	Asthma/diagnosis/etiology, Bronchiolitis, Viral/complications, Child, Child, Preschool, Diseases in Twins, Female, Humans, Hypersensitivity/diagnosis/etiology, Male, Registries, Respiratory Function Tests, Respiratory Syncytial Virus Infections/complications, Respiratory Syncytial Virus, Human, Bronchiolitis, Viral/*complications, Twins, Monozygotic,
Bønnelykke K	Bisgaard H	Bønnelykke K, Pipper CB, Tavendale R, Palmer CN, Bisgaard H	Filaggrin gene variants and atopic diseases in early childhood assessed longitudinally from birth	2010	PEDIAT ALLERG IMM-UK	20573035	3,775	36	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.	Age Factors, Age of Onset, Asthma/blood/epidemiology/genetics/physiopathology, Child, Preschool, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Immunoglobulin E/blood, Incidence, Infant, Intermediate Filament Proteins/*genetics, Male, Age of Onset, Polymorphism, Genetic, Prevalence
Bisgaard H	Bønnelykke K	Bisgaard H, Bønnelykke K	Long-term studies of the natural history of asthma in childhood	2010	J ALLERGY CLIN IMMUN	20688204	13,081	84	BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.	Adrenal Cortex Hormones/therapeutic use, Adult, Age Factors, *Asthma/genetics/metabolism/pathology/physiopathology/prevention & control, Child, Child, Preschool, Environmental Exposure/adverse effects, Female, Humans, Male, Risk Factors, Severity of Illness Index, Sex Factors, Adult, Time Factors,
Chawes BL	Bisgaard H	Chawes BL, Bønnelykke K, Kreiner-Møller E, Bisgaard H	Children with allergic and nonallergic rhinitis have a similar risk of asthma	2010	J ALLERGY CLIN IMMUN	20816191	13,081	58	BACKGROUND: Both allergic and nonallergic rhinitis have been associated with increased prevalence of asthma. OBJECTIVE: To characterize asthma and intermediary asthma endpoints in young children with allergic and nonallergic rhinitis. METHODS: 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. RESULTS: 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. CONCLUSION: 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.	Allergens/immunology, Asthma/complications/epidemiology, Child, Female, Humans, Intermediate Filament Proteins/genetics, Male, Questionnaires, Rhinitis/complications, Rhinitis, Allergic, Seasonal/complications/genetics, Risk Factors, Asthma/complications/epidemiology
Bønnelykke K	Bisgaard H	Bønnelykke K, Pipper CB, Bisgaard H	Transfer of maternal IgE can be a common cause of increased IgE levels in cord blood	2010	J ALLERGY CLIN IMMUN	20816197	13,081	34	BACKGROUND: 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. OBJECTIVE: We sought to determine to what extent increased levels of total IgE in cord blood is the result of maternofetal transfer of IgE. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.	Female, Fetal Blood/immunology, Histocompatibility, Maternal-Fetal, Humans, Immunoglobulin E/blood, Infant, Newborn, Pregnancy, Prenatal Exposure Delayed EffectsFetal Blood/immunology
Bisgaard H	Johnston SL	Bisgaard H, Hermansen MN, Bønnelykke K, Stokholm J, Baty F, Skytt NL, Aniscenko J, Kebadze T, Johnston SL	Association of bacteria and viruses with wheezy episodes in young children: prospective birth cohort study	2010	BRIT MED J	20921080	20,785	135	OBJECTIVE: To study the association between wheezy symptoms in young children and the presence of bacteria in the airways. DESIGN: Birth cohort study. SETTING: Clinical research unit in Copenhagen. PARTICIPANTS: Children of asthmatic mothers, from age 4 weeks to 3 years, with planned visits and acute admissions to the research clinic. MAIN OUTCOME MEASURE: Frequency of bacteria and virus carriage in airway aspirates during wheezy episodes and at planned visits without respiratory symptoms. RESULTS: 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. CONCLUSION: Acute wheezy episodes in young children were significantly associated with bacterial infections similar to but independent of the association with virus infections.	Acute Disease, Bacteria/isolation & purification, Bacterial Infections/microbiology, Bronchi/microbiology, Bronchial Diseases/microbiology, Child, Preschool, Humans, Infant, Prospective Studies, Respiratory Sounds/etiology, Respiratory Tract Infections/microbiology, Virus Diseases/virology, Viruses/isolation & purification, Bacteria/isolation & purification
Raaschou-Nielsen O	Bisgaard H	Raaschou-Nielsen O, Sørensen M, Hertel O, Chawes BL, Vissing N, Bønnelykke K, Bisgaard H	Predictors of indoor fine particulate matter in infants' bedrooms in Denmark	2011	ENVIRON RES	21059467	3,835	9	BACKGROUND: 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. OBJECTIVE: To identify sources of fine PM in infants' bedrooms. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.	Cohort Studies, Denmark, Housing, Humans, Infant, Linear Models, Particulate Matter/*analysis, Risk Factors, Seasons, Denmark
Bisgaard H	Bønnelykke K	Bisgaard H, Pipper CB, Bønnelykke K	Endotyping early childhood asthma by quantitative symptom assessment	2011	J ALLERGY CLIN IMMUN	21439619	13,081	39	BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.	Age of Onset, Anti-Asthmatic Agents/therapeutic use, Asthma/diagnosis/drug therapy/genetics/physiopathology, Child, Child, Preschool, Cohort Studies, Genetic Variation, Humans, Infant, Infant, Newborn, Longitudinal Studies, Membrane Proteins/*genetics/metabolism, Prospective Studies, Anti-Asthmatic Agents/therapeutic use, Questionnaires, Severity of Illness Index
Thyssen JP	Menné T	Thyssen JP, Carlsen BC, Bisgaard H, Giwercman C, Johansen JD, Linneberg A, Meldgaard M, Szecsi PB, Stender S, 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	21501248	3,528	11	BACKGROUND: 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. OBJECTIVES: The aim of this study was to describe the natural history of individuals with no filaggrin expression. MATERIALS: 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. RESULTS: 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. CONCLUSIONS: 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.	Adolescent, Adult, Aged, Denmark, Dermatitis, Atopic/genetics, Female, Genotype, Homozygote, Humans, Intermediate Filament Proteins/genetics, Longitudinal Studies, Male, Middle Aged, Adult, Mutation, Prospective Studies, Questionnaires, Remission Induction, Risk Factors,
Chawes BL	Bisgaard H	Chawes BL, Bønnelykke 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 RESP CRIT CARE	21680952	13,204	8	RATIONALE: 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. OBJECTIVES: To investigate whether eosinophil protein X, leukotriene-C4/D4/E4, and 11beta-prostaglandin (PG) F2alpha (PGD2 metabolite) assessed in urine from healthy at-risk neonates precede development of atopic disease during the first 6 years of life. METHODS: We measured eosinophil protein X (n = 369), leukotriene-C4/D4/E4 (n = 367), and 11beta-PGF2alpha (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. MEASUREMENTS AND MAIN RESULTS: 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 11beta-PGF2alpha was associated with any of the atopic phenotypes. CONCLUSIONS: 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.	Biological Markers/urine, Child, Child, Preschool, Cohort Studies, Eosinophil-Derived Neurotoxin/urine, Female, Humans, Hypersensitivity, Immediate/urine, Infant, Infant, Newborn, Male, Odds Ratio, Prostaglandins/urine, Child, SRS-A/urine,
Hollegaard MV	Hougaard DM	Hollegaard MV, Grove J, Grauholm J, Kreiner-Møller E, Bønnelykke K, Nørgaard M, Benfield TL, Nørgaard-Pedersen B, Mortensen PB, Mors O, Sørensen HT, Harboe ZB, Børglum AD, Demontis D, Ørntoft TF, Bisgaard H, Hougaard DM	Robustness of genome-wide scanning using archived dried blood spot samples as a DNA source	2011	BMC GENET	21726430	2,266	31	BACKGROUND: 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. RESULTS: 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. CONCLUSION: 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.	Blood Specimen Collection, DNA/analysis/blood, Denmark, Female, Genetic Predisposition to Disease/genetics, Genetic Testing/methods, Genome-Wide Association Study, Humans, Infant, Newborn, Male, Polymorphism, Single Nucleotide, Sequence Analysis, DNA/methods, Specimen Handling, DNA/analysis/*blood
Thyssen JP	Menné T	Thyssen JP, Ross-Hansen K, Johansen JD, Zachariae C, Carlsen BC, Linneberg A, Bisgaard H, Carson CG, Nielsen NH, Meldgaard M, Szecsi PB, Stender S, 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	BRIT J DERMATOL	21777221	4,706	26	BACKGROUND: 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. OBJECTIVES: To investigate whether filaggrin loss-of-function mutations are associated with skin fissures on the hands and/or fingers in the general population. METHODS: Participants in a population-based study were questioned about skin symptoms, genotyped for filaggrin mutation, patch tested for nickel allergy and skin prick tested. RESULTS: 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. CONCLUSIONS: 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.	Adolescent, Adult, Aged, Cross-Sectional Studies, Dermatitis, Atopic/genetics, Female, Genotype, Hand Dermatoses/genetics, Heterozygote, Humans, Intermediate Filament Proteins/genetics, Male, Middle Aged, Adult, Mutation/genetics, Skin Tests, Young Adult,
Bisgaard H	Krogfelt KA	Bisgaard H, Li N, Bønnelykke K, Chawes BL, Skov T, Paludan-Müller G, Stokholm J, Smith B, Krogfelt KA	Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age	2011	J ALLERGY CLIN IMMUN	21782228	13,081	257	BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.	Bacteria/classification/genetics/isolation & purification, Child, Cohort Studies, DNA, Bacterial/analysis, Denaturing Gradient Gel Electrophoresis, Eosinophilia/diagnosis/epidemiology, Feces/microbiology, Humans, Hypersensitivity, Immediate/diagnosis/epidemiology, Immunoglobulin E/blood, Infant, Infant, Newborn, Intestines/microbiology, Child, Metagenome, Polymerase Chain Reaction, RNA, Ribosomal, 16S/genetics, Rhinitis/diagnosis/epidemiology, Risk, Skin Tests
Følsgaard NV	Bisgaard H	Følsgaard NV, Chawes BL, Rasmussen MA, Bischoff AL, Carson CG, Stokholm J, Pedersen L, Hansel TT, Bønnelykke K, Brix S, Bisgaard H	Neonatal cytokine profile in the airway mucosal lining fluid is skewed by maternal atopy	2012	AM J RESP CRIT CARE	22077068	13,204	35	RATIONALE: 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. OBJECTIVES: To study parental atopic imprinting on the cytokines and chemokines in the upper airway mucosal lining fluid of healthy neonates. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: 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). CONCLUSIONS: 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.	Chemokines/genetics/metabolism, Cytokines/genetics/metabolism, Down-Regulation, Female, Genomic Imprinting, Humans, Hypersensitivity, Immediate/genetics/metabolism, Infant, Newborn, Male, Mothers, Nasal Mucosa/metabolism, Principal Component Analysis, Prospective Studies, Cytokines/*genetics/metabolism
Iskandar A	Bisgaard H	Iskandar A, Andersen ZJ, Bønnelykke K, Ellermann T, Andersen KK, 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	68	BACKGROUND: Short-term exposure to air pollution can trigger hospital admissions for asthma in children, but it is not known which components of air pollution are most important. There are no available studies on the particular effect of ultrafine particles (UFPs) on paediatric admissions for asthma. AIM: To study whether short-term exposure to air pollution is associated with hospital admissions for asthma in children. It is hypothesised that (1) the association between asthma admissions and air pollution is stronger with UFPs than with coarse (PM10) and fine (PM2.5) particles, nitrogen oxides (NOx) or nitrogen dioxide (NO2); and (2) infants are more susceptible to the effects of exposure to air pollution than older children. METHOD: Daily counts of admissions for asthma in children aged 0-18 years to hospitals located within a 15 km radius of the central fixed background urban air pollution measurement station in Copenhagen between 2001 and 2008 were extracted from the Danish National Patient Registry. A time-stratified case crossover design was applied and data were analysed using conditional logistic regression to estimate the effect of air pollution on asthma admissions. RESULTS: A significant association was found between hospital admissions for asthma in children aged 0-18 years and NOx (OR 1.11; 95% CI 1.05 to 1.17), NO2 (1.10; 95% CI 1.04 to 1.16), PM10 (1.07; 95% CI 1.03 to 1.12) and PM2.5 (1.09; 95% CI 1.04 to 1.13); there was no association with UFPs. The association was stronger in infants than in older children for all pollutants, but no statistically significant interaction was detected. CONCLUSION: Short-term exposure to air pollution can trigger hospital admission for asthma in children, with infants possibly being most susceptible. These effects seemed to be mediated by larger particles and traffic-related gases, whereas UFPs showed no effect.	Adolescent, Age Factors, Asthma/epidemiology/etiology, Child, Child, Preschool, Cross-Over Studies, Denmark/epidemiology, Environmental Monitoring/methods, Epidemiological Monitoring, Hospitalization/statistics & numerical data, Humans, Infant, Infant, Newborn, Age Factors, Nitrogen Dioxide/adverse effects/analysis, Nitrogen Oxides/adverse effects/analysis, Particle Size, Particulate Matter/adverse effects/analysis, Sex Factors, Urban Health/statistics & numerical data
Paternoster	Weidinger S	Paternoster L and Standl M, Chen CM, Ramasamy A, Bønnelykke K, Duijts L, Ferreira MA, Alves AC, Thyssen JP, Albrecht E, Baurecht H, Feenstra B, Sleiman PM, Hysi P, Warrington NM, Curjuric I, Myhre R, Curtin JA, Groen-Blokhuis MM, Kerkhof M, Sääf A, Franke A, Ellinghaus D, Fölster-Holst R, Dermitzakis E, Montgomery SB, Prokisch H, Heim K, Hartikainen AL, Pouta A, Pekkanen J, Blakemore AI, Buxton JL, Kaakinen M, Duffy DL, Madden PA, Heath AC, Montgomery GW, Thompson PJ, Matheson MC, Le Souëf P; Australian Asthma Genetics Consortium (AAGC), St Pourcain B, Smith GD, Henderson J, Kemp JP, Timpson NJ, Deloukas P, Ring SM, Wichmann HE, Müller-Nurasyid M, Novak N, Klopp N, Rodríguez E, McArdle W, Linneberg A, Menné T, Nohr EA, Hofman A, Uitterlinden AG, van Duijn CM, Rivadeneira F, de Jongste JC, van der Valk RJ, Wjst M, Jogi R, Geller F, Boyd HA, Murray JC, Kim C, Mentch F, March M, Mangino M, Spector TD, Bataille V, Pennell CE, Holt PG, Sly P, Tiesler CM, Thiering E, Illig T, Imboden M, Nystad W, Simpson A, Hottenga JJ, Postma D, Koppelman GH, Smit HA, Söderhäll C, Chawes B, Kreiner-Møller E, Bisgaard H, Melén E, Boomsma DI, Custovic A, Jacobsson B, Probst-Hensch NM, Palmer LJ, Glass D, Hakonarson H, Melbye M, Jarvis DL, Jaddoe VW, Gieger C; Genetics of Overweight Young Adults (GOYA) Consortium, Strachan DP, Martin NG, Jarvelin MR, Heinrich J and Evans DM and Weidinger S	Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis	2011	NAT GENET	22197932	27,959	153	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 x 10(-13)) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 x 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 x 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.	Cell Differentiation/genetics, Chromosomes, Human, Pair 11/genetics, Chromosomes, Human, Pair 20/genetics, Chromosomes, Human, Pair 5, Cytokines/genetics, DNA-Binding Proteins/genetics, Dermatitis, Atopic/genetics/immunology, Epidermis/immunology, Female, Genetic Loci, Genetic Predisposition to Disease, *Genome-Wide Association Study, Humans, Chromosomes, Human, Pair 11/genetics, Intermediate Filament Proteins/genetics, Kinesin/genetics, Male, Polymorphism, Single Nucleotide, Risk, Transcription Factors/genetics
Bisgaard H	Knorr B	Bisgaard H, Swern AS, Knorr B	"To wheeze or not to wheeze": that is not the question--the sequel	2012	J ALLERGY CLIN IMMUN	22365706	13,081	7	LETTER	Asthma/complications/diagnosis/physiopathology, Biological Markers, Caregivers, Child, Preschool, Cough/complications/diagnosis/physiopathology, Dyspnea/complications/diagnosis/physiopathology, Emergency Medical Services, Humans, Medical Records, Respiratory Sounds/diagnosis/physiopathology, Severity of Illness Index, Biological Markers
Sevelsted A	Bisgaard H	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	21	BACKGROUND: We hypothesized that anthropometrics in the newborn is associated with development of asthma later in life. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.	Adult, Age Factors, Asthma/etiology, Birth Weight, Body Mass Index, Child, Dermatitis, Atopic/*etiology, Female, Gestational Age, Humans, Infant, Newborn, Longitudinal Studies, Male, Age Factors, Pregnancy, Prospective Studies, Risk Factors,
Bisgaard H	Bønnelykke K	Bisgaard H, Jensen SM, Bønnelykke K	Interaction between asthma and lung function growth in early life	2012	AM J RESP CRIT CARE	22461370	13,204	119	RATIONALE: 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. OBJECTIVES: To analyze the interaction between lung function development and asthma from birth to 7 years of age. METHODS: 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%). MEASUREMENTS AND MAIN RESULTS: 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). CONCLUSIONS: 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.	Age Factors, Anti-Asthmatic Agents/therapeutic use, Asthma/drug therapy/physiopathology/prevention & control, Breath Tests, Bronchial Hyperreactivity/diagnosis/physiopathology, Child Development/physiology, Child, Preschool, Denmark, Disease Progression, Female, Follow-Up Studies, Humans, Infant, Anti-Asthmatic Agents/therapeutic use, Infant, Newborn, Male, Nitric Oxide/analysis, Prospective Studies, Respiratory Function Tests, Risk Assessment, Severity of Illness Index, Spirometry/methods, Treatment Outcome,
Bradfield JP	Grant SF	Bradfield JP and Taal HR, Timpson NJ, Scherag A, Lecoeur C, Warrington NM, Hypponen E, Holst C, Valcarcel B, Thiering E, Salem RM, Schumacher FR, Cousminer DL, Sleiman PM, Zhao J, Berkowitz RI, Vimaleswaran KS, Jarick I, Pennell CE, Evans DM, St Pourcain B, Berry DJ, Mook-Kanamori DO, Hofman A, Rivadeneira F, Uitterlinden AG, van Duijn CM, van der Valk RJ, de Jongste JC, Postma DS, Boomsma DI, Gauderman WJ, Hassanein MT, Lindgren CM, Mägi R, Boreham CA, Neville CE, Moreno LA, Elliott P, Pouta A, Hartikainen AL, Li M, Raitakari O, Lehtimäki T, Eriksson JG, Palotie A, Dallongeville J, Das S, Deloukas P, McMahon G, Ring SM, Kemp JP, Buxton JL, Blakemore AI, Bustamante M, Guxens M, Hirschhorn JN, Gillman MW, Kreiner-Møller E, Bisgaard H, Gilliland FD, Heinrich J, Wheeler E, Barroso I, O'Rahilly S, Meirhaeghe A, Sørensen TI, Power C, Palmer LJ, Hinney A, Widen E, Farooqi IS, McCarthy MI, Froguel P, Meyre D, Hebebrand J, Jarvelin MR, Jaddoe VW, Smith GD, Hakonarson H, Grant SF	A genome-wide association meta-analysis identifies new childhood obesity loci	2012	NAT GENET	22484627	27,959	182	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 x 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 x 10(-9); odds ratio (OR) = 1.22) and within HOXB5 at 17q21 (rs9299; P = 3.54 x 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).	Adolescent, Adult, Body Mass Index, Case-Control Studies, Genetic Loci, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Obesity/genetics, Polymorphism, Single Nucleotide/*genetics, Young AdultAdult
Taal HR	Jaddoe VW	Taal HR and St Pourcain B and Thiering E and Das S and Mook-Kanamori DO, Warrington NM, Kaakinen M, Kreiner-Møller E, Bradfield JP, Freathy RM, Geller F, Guxens M, Cousminer DL, Kerkhof M, Timpson NJ, Ikram MA, Beilin LJ, Bønnelykke K, Buxton JL, Charoen P, Chawes BL, Eriksson J, Evans DM, Hofman A, Kemp JP, Kim CE, Klopp N, Lahti J, Lye SJ, McMahon G, Mentch FD, Müller-Nurasyid M, O'Reilly PF, Prokopenko I, Rivadeneira F, Steegers EA, Sunyer J, Tiesler C, Yaghootkar H Cohorts for Heart and Aging Research in Genetic Epidemiology Consortium, Breteler MM, Decarli C, Breteler MM, Debette S, Fornage M, Gudnason V, Launer LJ, van der Lugt A, Mosley TH Jr, Seshadri S, Smith AV, Vernooij MW Early Genetics & Lifecourse Epidemiology Consortium, Blakemore AI, Chiavacci RM, Feenstra B, Fernandez-Banet J, Grant SF, Hartikainen AL, van der Heijden AJ, Iñiguez C, Lathrop M, McArdle WL, Mølgaard A, Newnham JP, Palmer LJ, Palotie A, Pouta A, Ring SM, Sovio U, Standl M, Uitterlinden AG, Wichmann HE, Vissing NH, DeCarli C, van Duijn CM, McCarthy MI, Koppelman GH, Estivill X, Hattersley AT, Melbye M, Bisgaard H, Pennell CE, Widen E, Hakonarson H, Smith GD and Heinrich J and Jarvelin MR and Jaddoe VW	Common variants at 12q15 and 12q24 are associated with infant head circumference	2012	NAT GENET	22504419	27,959	59	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 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 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 x 10(-7) for rs7980687 and P = 1.3 x 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 x 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.	Chromosomes, Human, Pair 12/genetics, European Continental Ancestry Group/genetics, Female, Genetic Loci, Genetic Markers, Genome-Wide Association Study, Head/growth & development/pathology, Humans, Infant, Male, Meta-Analysis as Topic, Polymorphism, Single Nucleotide/genetics, Pregnancy, European Continental Ancestry Group/genetics, Pregnancy Complications/etiology/pathology,
Chawes BL	Bisgaard H	Chawes BL and Poorisrisak P, Johnston SL, Bisgaard H	Neonatal bronchial hyperresponsiveness precedes acute severe viral bronchiolitis in infants	2012	J ALLERGY CLIN IMMUN	22713595	13,081	40	BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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 mumol; 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). CONCLUSION: Bronchial hyperresponsiveness in at-risk neonates precedes acute severe bronchiolitis in response to infections with respiratory tract virus.	Acute Disease, Bronchial Hyperreactivity/complications/immunology/virology, Bronchial Provocation Tests, Bronchiolitis, Viral/complications/immunology/virology, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Methacholine Chloride/immunology, Prospective Studies, Respiratory Function Tests, Bronchial Hyperreactivity/complications/immunology/virology, Respiratory Syncytial Virus Infections/complications/immunology/virology, Respiratory Syncytial Viruses/immunology, Severity of Illness Index, Time Factors
Skytt N	Bisgaard H	Skytt N, Bønnelykke K, Bisgaard H	"To wheeze or not to wheeze": that is not the question	2012	J ALLERGY CLIN IMMUN	22766098	13,081	29	BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.	Age of Onset, Ambulatory Care/statistics & numerical data, Asthma/diagnosis/epidemiology/physiopathology, Child, Child, Preschool, Denmark/epidemiology, Female, Humans, Infant, Lung/immunology/physiopathology, Male, Multivariate Analysis, Prognosis, Ambulatory Care/statistics & numerical data, Prospective Studies, Questionnaires, Respiratory Function Tests, Respiratory Sounds/*diagnosis/physiopathology, Risk Factors, Severity of Illness Index
Carson CG	Bisgaard H	Carson CG, Halkjaer LB, Jensen SM, 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	BACKGROUND: 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. OBJECTIVE: To analyze the impact of alcohol intake during pregnancy on the development of atopic dermatitis during the first 7 years of life. METHOD: 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. RESULTS: 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. LIMITATIONS: 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. CONCLUSION: 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.	Child, Child, Preschool, Dermatitis, Atopic/epidemiology/etiology, Female, Humans, Infant, Infant, Newborn, Pregnancy, Prenatal Exposure Delayed Effects, Prospective Studies, Risk Factors, Child, Preschool
Thyssen JP	Linneberg A	Thyssen JP, Thuesen B, Huth C, Standl M, Carson CG, Heinrich J, Krämer U, Kratzsch J, Berg ND, Menné T, Johansen JD, Carlsen BC, Schwab S, Thorand B, Munk M, Wallaschofski H, Heickendorff L, Meldgaard M, Szecsi PB, Stender S, Bønnelykke K, Weidinger S, Bisgaard H, Linneberg A	Skin barrier abnormality caused by filaggrin (FLG) mutations is associated with increased serum 25-hydroxyvitamin D concentrations	2012	J ALLERGY CLIN IMMUN	22921868	13,081	38	LETTER	Adult, Child, Cohort Studies, Denmark, Dermatitis, Atopic/blood, Dietary Supplements, Female, Genetic Association Studies, Germany, Humans, Infant, Intermediate Filament Proteins/genetics, Male, Child, Middle Aged, Mutation/genetics, Skin/immunology/radiation effects, Ultraviolet Rays/adverse effects, Urocanic Acid/analogs & derivatives/metabolism, Vitamin D/analogs & derivatives/blood/metabolism
Chawes BL	Bisgaard H	Chawes BL, Piccinno A, Kreiner-Møller E, Vissing NH, Poorisrisak P, Mortensen L, Nilson E, Bisgaard A, Dossing A, Deleuran M, Skytt NL, Samandari N, Sergio F, Ciurlia G, Poli G, Acerbi D, Bisgaard H	Pharmacokinetic comparison of inhaled fixed combination vs. the free combination of beclomethasone and formoterol pMDIs in asthmatic children	2013	BRIT J CLIN PHARMCO	22978252	3,493	6	AIM: The fixed combination of beclomethasone (BDP) and formoterol pressurized metered dose inhaler (pMDI) (Foster(R), Chiesi Farmaceutici) is being developed in the lower strength (BDP/formoterol: 50/6 mug) 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(R) pMDI 50/6 mug vs. the free combination of BDP and formoterol pMDIs in asthmatic children. METHODS: Children aged 5-11 years old inhaled BDP 200 mug and formoterol 24 mug 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,infinity), 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. RESULTS: 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. CONCLUSION: 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.	Administration, Inhalation, Anti-Asthmatic Agents/administration & dosage/adverse, effects/pharmacokinetics/pharmacology, Asthma/blood/drug therapy/urine, Beclomethasone/administration & dosage/adverse, effects/pharmacokinetics/pharmacology, Biological Availability, Child, Child, Preschool, Drug Combinations, Drug Therapy, Combination, Ethanolamines/administration & dosage/adverse, effects/pharmacokinetics/pharmacology, Anti-Asthmatic Agents/administration & dosage/adverse, Female, Glucose/metabolism, Heart Rate/drug effects, Humans, Hydrocortisone/urine, Male, Metered Dose Inhalers, Peak Expiratory Flow Rate/drug effects, Potassium/blood,
Pedersen L	Bisgaard H	Pedersen L, Lauritzen L, Brasholt M, Buhl T, Bisgaard H	Polyunsaturated fatty acid content of mother's milk is associated with childhood body composition	2012	PEDIATR RES	23007033	2,882	28	BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.	Body Composition, Child, Fatty Acids, Unsaturated/analysis, Female, Humans, Milk, Human/*chemistryChild
Stokholm J	Bisgaard H	Stokholm J, Schjørring S, Pedersen L, Bischoff AL, Følsgaard N, Carson CG, Chawes B, Bønnelykke K, Mølgaard A, Krogfelt KA, Bisgaard H	Living with cat and dog increases vaginal colonization with E. coli in pregnant women	2012	PLOS ONE	23049986	2,806	14	BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.	Animals, Anti-Bacterial Agents/therapeutic use, Cats, Dogs, Escherichia coli/pathogenicity, Female, Humans, Odds Ratio, Pregnancy, Risk Factors, Urinary Tract Infections/drug therapy/epidemiology/microbiology, Vagina/microbiologyAnti-Bacterial Agents/therapeutic use
Vissing NH	Bisgaard H	Vissing NH, Jensen SM, 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	BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.	Adult, Asthma/diagnosis/epidemiology, Bias (Epidemiology), Child, Preschool, Common Cold/diagnosis/epidemiology, Data Collection/standards, Denmark/epidemiology, Dermatitis, Atopic/diagnosis/epidemiology, Environmental Exposure, Family Practice/standards, Female, Humans, Interviews as Topic, Asthma/diagnosis/epidemiology, Life Style, Medical History Taking, Otitis Media/diagnosis/epidemiology, Parents/psychology, Physicians, Family/psychology, Prospective Studies, Rhinitis, Allergic, Rhinitis, Allergic, Perennial/diagnosis/epidemiology, Severity of Illness Index, Socioeconomic Factors
Kreiner-Møller E	Bisgaard H	Kreiner-Møller E and Sevelsted A, Vissing NH, Schoos AM, 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 IMMUN	23102919	13,081	22	LETTER	Acetaminophen/administration & dosage/adverse effects, Asthma/epidemiology, Child, Child, Preschool, Cohort Studies, Denmark, Female, Follow-Up Studies, Humans, Infant, Infant, Newborn, Male, Maternal Exposure/statistics & numerical data, Asthma/epidemiology, Pregnancy, Pregnancy Trimester, Third, Respiratory Tract Infections/drug therapy/*epidemiology, Risk
Følsgaard NV	Bisgaard H	Følsgaard NV, Chawes BL, Bønnelykke K, Jenmalm MC, Bisgaard H	Cord blood Th2-related chemokine CCL22 levels associate with elevated total-IgE during preschool age	2012	CLIN EXP ALLERGY	23106659	5,264	14	BACKGROUND: Early-life immune deviation is suspected in the inception of atopic disease. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION AND CLINICAL RELEVANCE: 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.	Antibody Specificity/immunology, Asthma/blood/immunology, Biological Markers/blood, Chemokine CCL22/blood, Child, Child, Preschool, Dermatitis, Atopic/blood/immunology, Eosinophils, Female, Fetal Blood/immunology, Humans, Immunoglobulin E/blood, Infant, Asthma/blood/immunology, Leukocyte Count, Male, Rhinitis, Allergic, Rhinitis, Allergic, Perennial/blood/immunology, Th2 Cells/immunology/metabolism,
Kreiner-Møller E	Bisgaard H	Kreiner-Møller E, Chawes BL, Caye-Thomasen P, Bønnelykke K, Bisgaard H	Allergic rhinitis is associated with otitis media with effusion: a birth cohort study	2012	CLIN EXP ALLERGY	23106661	5,264	25	BACKGROUND: Childhood otitis media with effusion is a common disease and a link to allergic diseases has been suggested. OBJECTIVE: To investigate the association between atopic disease and otitis media with effusion diagnosed according to strict objective case definitions by age 6 years. METHODS: 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. RESULTS: 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. CONCLUSION: 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.	Asthma/complications, Child, Child, Preschool, Cohort Studies, Denmark, Eczema/complications, Humans, Infant, Infant, Newborn, Morbidity, Otitis Media with Effusion/complications, Prospective Studies, Rhinitis, Allergic, Child, Rhinitis, Allergic, Perennial/complications,
Stensballe LG	Bisgaard H	Stensballe LG, Simonsen J, Jensen SM, Bønnelykke K, Bisgaard H	Use of antibiotics during pregnancy increases the risk of asthma in early childhood	2013	J PEDIATR	23140881	3,874	101	OBJECTIVES: To investigate the hypothesis that mother's use of antibiotics in pregnancy could influence asthma and eczema in early life. STUDY DESIGN: 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. RESULTS: 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. CONCLUSION: 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.	Adrenal Cortex Hormones/therapeutic use, Algorithms, Anti-Bacterial Agents/adverse effects, Asthma/etiology, Child, Preschool, Cohort Studies, Denmark, Eczema/etiology, Female, Hospitalization, Humans, Male, Pregnancy, Algorithms, Pregnancy Complications, Infectious/drug therapy, Prenatal Exposure Delayed Effects, Risk, Treatment Outcome
Carson CG	Bisgaard H	Carson CG, Rasmussen MA, Thyssen JP, Menné T, 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	33	BACKGROUND: 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. METHOD: 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. RESULTS: 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. CONCLUSION: 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.	Child, Child, Preschool, Cohort Studies, Denmark/epidemiology, Dermatitis, Atopic/epidemiology/genetics, European Continental Ancestry Group/genetics, Genotype, Humans, Infant, Intermediate Filament Proteins/*genetics, Mutation/genetics, Polymerase Chain Reaction, Proportional Hazards Models, Child, Preschool, Prospective Studies, Risk Assessment, Statistics, Nonparametric,
Malby Schoos AM	Bisgaard H	Malby Schoos AM, Chawes BL, Bønnelykke K, 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	8	BACKGROUND: Elevated fraction of exhaled nitric oxide (FENO) and bronchial hyperresponsiveness are used as surrogate markers of asthma. These traits may be continuous in the population. The objective of this study was to investigate whether FENO and bronchial responsiveness are associated in both children with and children without a history of asthma symptoms. METHODS: One hundred ninety-six 6-year-old children with no asthma symptoms, intermittent asthma symptoms, and persistent asthma were randomly included from the Copenhagen Prospective Study on Asthma in Childhood prospective clinical birth cohort of mothers with asthma. Bronchial responsiveness was assessed as the relative change in specific airway resistance after cold dry air hyperventilation. FENO measurements were performed prior to the hyperventilation test. The association between FENO and bronchial responsiveness was assessed by generalized linear models. RESULTS: Bronchial responsiveness and FENO exhibited a significant and linear association in the population. A doubling of FENO corresponded to an 8.4% (95% CI, 3.7%-13.1%; P = .0006) increase in airway resistance after challenge testing and remained significant after adjustment for sex, allergic rhinitis, current asthma, inhaled corticosteroid treatment, and upper respiratory tract infections prior to testing. Stratified analyses showed similar associations in children with and without asthma. CONCLUSIONS: FENO and bronchial responsiveness are associated and continuous traits in young children regardless of asthma symptoms, suggesting a continuous subclinical to clinical process underlying asthma. The findings also suggest caution against the use of these surrogate markers for a dichotomized approach to asthma diagnosis.	Air, Asthma/metabolism/physiopathology, Biological Markers/metabolism, Bronchi/metabolism/physiopathology, Child, Cohort Studies, Cold Temperature, Denmark, Exhalation, Female, Humans, Hyperventilation/metabolism/physiopathology, Linear Models, Asthma/metabolism/physiopathology, Male, Nitric Oxide/*metabolism, Severity of Illness Index,
Horikoshi M	Freathy RM	Horikoshi M and Yaghootkar H and Mook-Kanamori DO, Sovio U, Taal HR, Hennig BJ, Bradfield JP, St Pourcain B, Evans DM, Charoen P, Kaakinen M, Cousminer DL, Lehtimäki T, Kreiner-Møller E, Warrington NM, Bustamante M, Feenstra B, Berry DJ, Thiering E, Pfab T, Barton SJ, Shields BM, Kerkhof M, van Leeuwen EM, Fulford AJ, Kutalik Z, Zhao JH, den Hoed M, Mahajan A, Lindi V, Goh LK, Hottenga JJ, Wu Y, Raitakari OT, Harder MN, Meirhaeghe A, Ntalla I, Salem RM, Jameson KA, Zhou K, Monies DM, Lagou V, Kirin M, Heikkinen J, Adair LS, Alkuraya FS, Al-Odaib A, Amouyel P, Andersson EA, Bennett AJ, Blakemore AI, Buxton JL, Dallongeville J, Das S, de Geus EJ, Estivill X, Flexeder C, Froguel P, Geller F, Godfrey KM, Gottrand F, Groves CJ, Hansen T, Hirschhorn JN, Hofman A, Hollegaard MV, Hougaard DM, Hyppönen E, Inskip HM, Isaacs A, Jørgensen T, Kanaka-Gantenbein C, Kemp JP, Kiess W, Kilpeläinen TO, Klopp N, Knight BA, Kuzawa CW, McMahon G, Newnham JP, Niinikoski H, Oostra BA, Pedersen L, Postma DS, Ring SM, Rivadeneira F, Robertson NR, Sebert S, Simell O, Slowinski T, Tiesler CM, Tönjes A, Vaag A, Viikari JS, Vink JM, Vissing NH, Wareham NJ, Willemsen G, Witte DR, Zhang H, Zhao J, Wilson JF, Stumvoll M, Prentice AM, Meyer BF, Pearson ER, Boreham CA, Cooper C, Gillman MW, Dedoussis GV, Moreno LA, Pedersen O, Saarinen M, Mohlke KL, Boomsma DI, Saw SM, Lakka TA, Körner A, Loos RJ, Ong KK, Vollenweider P, van Duijn CM, Koppelman GH, Hattersley AT, Holloway JW, Hocher B, Heinrich J, Power C, Melbye M, Guxens M, Pennell CE, Bønnelykke K, Bisgaard H, Eriksson JG, Widén E, Hakonarson H, Uitterlinden AG, Pouta A, Lawlor DA, Smith GD, Frayling TM, McCarthy MI and Grant SF and Jaddoe VW and Jarvelin MR and Timpson NJ and Prokopenko I and Freathy RM	New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism	2013	NAT GENET	23202124	27,959	136	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.	Adult, Birth Weight/genetics, Blood Pressure/genetics, Body Height/genetics, Diabetes Mellitus, Type 2/genetics, Female, Fetal Development/genetics, Genetic Linkage, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Infant, Newborn, Male, Birth Weight/genetics, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Quantitative Trait Loci,
Følsgaard NV	Bisgaard H	Følsgaard NV, Schjørring S, Chawes BL, Rasmussen MA, Krogfelt KA, Brix S, Bisgaard H	Pathogenic bacteria colonizing the airways in asymptomatic neonates stimulates topical inflammatory mediator release	2013	AM J RESP CRIT CARE	23370914	13,204	56	RATIONALE: 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. OBJECTIVES: To study a possible association between colonization with pathogenic bacterial strains and the immune signature of the upper airways in healthy neonates. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: Colonization with M. catarrhalis and H. influenzae induced a mixed T helper cell (Th) type 1/Th2/Th17 response with high levels of IL-1beta (M. catarrhalis, P = 2.2 x 10(-12); H. influenzae, P = 7.1 x 10(-10)), TNF-alpha (M. catarrhalis, P = 1.5 x 10(-9); H. influenzae, P = 5.9 x 10(-7)), and macrophage inflammatory protein-1beta (M. catarrhalis, P = 1.6 x 10(-11); H. influenzae, P = 2.7 x 10(-7)). S. aureus colonization demonstrated a Th17-promoting profile with elevated IL-17 levels (P = 1.6 x 10(-24)). S. pneumoniae colonization was not significantly associated with any of the mediators. CONCLUSIONS: 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.	Asthma/immunology/microbiology, Bronchi/immunology/microbiology, Colony Count, Microbial, Haemophilus influenzae/isolation & purification, Humans, Hypopharynx/microbiology, Infant, Newborn, Inflammation Mediators/metabolism, Moraxella (Branhamella) catarrhalis/isolation & purification, Mucous Membrane/immunology, Streptococcus pneumoniae/isolation & purification, T-Lymphocytes/immunologyBronchi/immunology/*microbiology
Cousminer DL	Ripatti S	Cousminer DL, Berry DJ, Timpson NJ, Ang W, Thiering E, Byrne EM, Taal HR, Huikari V, Bradfield JP, Kerkhof M, Groen-Blokhuis MM, Kreiner-Møller E, Marinelli M, Holst C, Leinonen JT, Perry JR, Surakka I, Pietiläinen O, Kettunen J, Anttila V, Kaakinen M, Sovio U, Pouta A, Das S, Lagou V, Power C, Prokopenko I, Evans DM, Kemp JP, St Pourcain B, Ring S, Palotie A, Kajantie E, Osmond C, Lehtimäki T, Viikari JS, Kähönen M, Warrington NM, Lye SJ, Palmer LJ, Tiesler CM, Flexeder C, Montgomery GW, Medland SE, Hofman A, Hakonarson H, Guxens M, Bartels M, Salomaa V; ReproGen Consortium, Murabito JM, Kaprio J, Sørensen TI, Ballester F, Bisgaard H, Boomsma DI, Koppelman GH, Grant SF, Jaddoe VW, Martin NG, Heinrich J, Pennell CE, Raitakari OT, Eriksson JG, Smith GD, Hyppönen E, Järvelin MR, McCarthy MI, Ripatti S	Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity	2013	HUM MOL GENET	23449627	5,34	59	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 x 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.	Adiposity/genetics, Adolescent, Age Factors, Body Height/genetics, Body Mass Index, Child, Female, Follow-Up Studies, Gene Expression, Genetic Linkage, Genome-Wide Association Study, Humans, Male, Adolescent, Menarche, Mitogen-Activated Protein Kinase 3/genetics/metabolism, Neoplasms/genetics/metabolism, Phenotype, Puberty/genetics, *Quantitative Trait Loci, Signal Transduction, Transforming Growth Factor beta/metabolism, Young Adult,
Calışkan M	Ober C	Calışkan M, Bochkov YA, Kreiner-Møller E, Bønnelykke K, Stein MM, Du G, Bisgaard H, Jackson DJ, Gern JE, Lemanske RF Jr, Nicolae DL, Ober C	Rhinovirus wheezing illness and genetic risk of childhood-onset asthma	2013	NEW ENGL J MED	23534543	72,406	180	BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.).	Asthma/genetics/virology, Child, Chromosomes, Human, Pair 17, Common Cold/complications, DNA/isolation & purification, Gene Expression, Genetic Predisposition to Disease, Genotype, Humans, Leukocytes, Mononuclear, Polymorphism, Single Nucleotide, RNA/isolation & purification, Respiratory Sounds/genetics, Child, Respiratory Syncytial Virus Infections/complications, Respiratory Syncytial Viruses, Rhinovirus, Risk
Bønnelykke K	Bisgaard H	Bønnelykke K, Chawes BL, Vindfeld S, Moore AC, Bisgaard H	Aerosol particle size does not predict pharmacokinetic determined lung dose in children	2013	J CLIN PHARMACOL	23553595	2,812	1	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(R)) 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(R) 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.	Administration, Inhalation, Adolescent, Aerosols, Androstadienes/administration & dosage/blood/pharmacokinetics, Anti-Asthmatic Agents/administration & dosage/blood/pharmacokinetics, Area Under Curve, Asthma/metabolism, Child, Child, Preschool, Female, Humans, Lung/metabolism, Male, Adolescent, Nebulizers and Vaporizers, Particle Size
Bischoff AL	Bisgaard H	Bischoff AL, Følsgaard NV, Carson CG, Stokholm J, Pedersen L, Holmberg M, Bisgaard A, Birch S, Tsai TF, Bisgaard H	Altered response to A(H1N1)pnd09 vaccination in pregnant women: a single blinded randomized controlled trial	2013	PLOS ONE	23637733	2,806	25	BACKGROUND: 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(R)-adjuvanted vaccine (Focetria(R)) in H1N1pnd09-naive pregnant and non-pregnant women. The secondary aims were to compare influences of dose and adjuvant on the immune response. METHODS: 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 [1ratio1ratio1] controlled clinical trial in pregnant women after gestational week 20: (1) 7.5 microg H1N1pnd09 antigen with MF59-adjuvant (Pa7.5 microg); (2) 3.75 microg antigen half MF59-adjuvanted (Pa3.75 microg); (3) 15 microg antigen unadjuvanted (P15 microg); and in non-pregnant women receiving (4) 7.5 microg antigen full adjuvanted (NPa7.5 microg). Blood samples were collected at baseline, 3 weeks, 3 and 10 months after vaccination, adverse events were recorded prospectively. RESULTS: 58 pregnant women were allocated to Pa7.5 microg and 149 non-pregnant women were recruited to NPa7.5 microg. The sero-conversion rate was significantly increased in non-pregnant (NPa7.5 microg) compared with pregnant (Pa7.5 microg) 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 microg) and non-pregnant (NPa7.5 microg) groups (OR = 0.49 [0.13-1.85], p = 0.29). CONCLUSION: Our study suggests the immune response to the 7.5 microg MF59-adjuvanted Focetria(R) H1N1pnd09 vaccine in pregnant women may be diminished compared with non-pregnant women. TRIAL REGISTRATION: ClinicalTrials.gov NCT01012557.	Adjuvants, Immunologic, Adult, Female, Humans, Influenza A Virus, H1N1 Subtype/immunology, Influenza Vaccines/administration & dosage/adverse effects/immunology, Influenza, Human/prevention & control, Polysorbates, Pregnancy, Pregnancy Complications, Infectious/prevention & control, Prospective Studies, Seroepidemiologic Studies, Squalene, Adult, Vaccination,
Carlsen K	Bisgaard H	Carlsen K, Pedersen L, Bønnelykke K, Stark KD, Lauritzen L, 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	BACKGROUND/OBJECTIVES: 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. SUBJECTS/METHODS: 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. RESULTS: 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). CONCLUSION: 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.	Birth Weight/drug effects, Body Height/drug effects, Body Mass Index, Fatty Acids, Omega-3/blood, Fatty Acids, Omega-6/blood, Female, Femur/drug effects/growth & development, Fetal Weight/*drug effects, Gestational Age, Humans, Linear Models, Pregnancy, Prospective Studies, Body Height/drug effects, Weight Gain/drug effects,
Brasholt M	Bisgaard H	Brasholt M, Chawes B, Kreiner-Møller E, Vahlkvist S, Sinding M, Bisgaard H	Objective assessment of levels and patterns of physical activity in preschool children	2013	PEDIATR RES	23770920	2,882	19	BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.	Accelerometry, Body Mass Index, Child, Preschool, Denmark, Female, Fourier Analysis, Humans, Male, Motor Activity/physiology, Sex Factors, Time Factors, *Body Mass Index
Bønnelykke K	Henderson AJ	Bønnelykke K and Matheson MC and Pers TH, Granell R, Strachan DP, Alves AC, Linneberg A, Curtin JA, Warrington NM, Standl M, Kerkhof M, Jonsdottir I, Bukvic BK, 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 EH, Tiesler CM, Duffy DL, Jones G, Ring SM, McArdle WL, Price L, Robertson CF, Pekkanen J, Tang CS, Thiering E, Montgomery GW, Hartikainen AL, Dharmage SC, Husemoen LL, Herder C, Kemp JP, Elliot P, James A, Waldenberger M, Abramson MJ, Fairfax BP, Knight JC, Gupta R, Thompson PJ, Holt P, Sly P, Hirschhorn JN, Blekic M, Weidinger S, Hakonarsson H, Stefansson K, Heinrich J, Postma DS, Custovic A, Pennell CE, Jarvelin MR, Koppelman GH, Timpson N, Ferreira MA and Bisgaard H and Henderson AJ	Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization	2013	NAT GENET	23817571	27,959	116	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.	Alleles, Computational Biology, Gene Regulatory Networks, Genetic Loci, Genome-Wide Association Study, Genomics, Humans, Hypersensitivity/*genetics/metabolism, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Signal TransductionComputational Biology
Vissing NH and Sevelsted A	Bisgaard H	Vissing NH and Sevelsted A, 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	BACKGROUND: 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. METHODS: The study compared annual hospitalization rates for childhood infections from 2005 to 2011. RESULTS: Admission rates for infections were higher during the year of the pandemic compared to the rest of the period. CONCLUSION: There were no indications of a preventive effect by the hygiene campaign on incidence of severe common childhood infections.	Child, Child, Preschool, Communicable Disease Control/methods/statistics & numerical data, Denmark/epidemiology, Hospitalization, Humans, Hygiene, Incidence, Infant, Infant, Newborn, Influenza A Virus, H1N1 Subtype, Influenza, Human/epidemiology/*prevention & control, Pandemics, Child, Preschool, Patient Admission, Registries, Seasons,
Bønnelykke K	Bisgaard H	Bønnelykke K, Pedersen S, Rubak SL, Schiøtz O, Bisgaard H	[Childhood asthma: Danish guidelines for diagnosis and treatment]	2013	UGESKR L	23937873	0	1	0	NA
Mortensen LJ	Bisgaard H	Mortensen LJ, Kreiner-Møller E, Hakonarson H, Bønnelykke K, Bisgaard H	The PCDH1 gene and asthma in early childhood	2014	EUR RESPIR J	23988763	10,569	8	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.	Alleles, Asthma/genetics, Cadherins/genetics/metabolism, Cell Adhesion, Child, Child, Preschool, Dermatitis, Atopic/genetics, Genotype, Humans, Infant, Kaplan-Meier Estimate, Longitudinal Studies, Phenotype, Asthma/*genetics, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors,
Vissing NH	Bisgaard H	Vissing NH, Chawes BL, Bisgaard H	Increased risk of pneumonia and bronchiolitis after bacterial colonization of the airways as neonates	2013	AM J RESP CRIT CARE	24090102	13,204	55	RATIONALE: 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. OBJECTIVES: To investigate the relation between neonatal airway colonization and pneumonia and bronchiolitis during the first 3 years of life. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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.	Asthma/diagnosis/epidemiology/microbiology, Bronchiolitis/diagnosis/epidemiology/microbiology, Child, Preschool, Denmark/epidemiology, Female, Follow-Up Studies, Haemophilus influenzae/isolation & purification, Humans, Hypopharynx/microbiology, Incidence, Infant, Infant, Newborn, Kaplan-Meier Estimate, Bronchiolitis/diagnosis/epidemiology/microbiology, Male, Microbiota, Moraxella (Branhamella) catarrhalis/isolation & purification, Pneumonia/diagnosis/epidemiology/*microbiology, Proportional Hazards Models, Prospective Studies, Risk Factors, Staphylococcus aureus/isolation & purification, Streptococcus pneumoniae/isolation & purification,
Bisgaard H	Bønnelykke K	Bisgaard H, Vissing NH, Carson CG, Bischoff AL, Følsgaard NV, Kreiner-Møller E, Chawes BL, Stokholm J, Pedersen L, Bjarnadóttir E, Thysen AH, Nilsson E, Mortensen LJ, Olsen SF, Schjørring S, Krogfelt KA, Lauritzen L, Brix S, Bønnelykke K	Deep phenotyping of the unselected COPSAC2010 birth cohort study	2013	CLIN EXP ALLERGY	24118234	5,264	28	BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.	Adult, Asthma/etiology, Child, Child, Preschool, Cohort Studies, Denmark, Dietary Supplements, Eczema/etiology/prevention & control, Female, Fish Oils/administration & dosage, Humans, Hypersensitivity/etiology/prevention & control, Infant, Asthma/etiology, Infant, Newborn, Influenza Vaccines/administration & dosage/immunology, Longitudinal Studies, Male, Maternal Exposure, *Phenotype, Pregnancy, Prenatal Exposure Delayed Effects, Questionnaires, Risk Factors
Stokholm J	Bisgaard H	Stokholm J, Schjørring S, Eskildsen CE, Pedersen L, Bischoff AL, Følsgaard N, Carson CG, Chawes BL, Bønnelykke K, Mølgaard A, Jacobsson B, Krogfelt KA, Bisgaard H	Antibiotic use during pregnancy alters the commensal vaginal microbiota	2014	CLIN MICROBIOL INFECT	24118384	5,292	33	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.	Administration, Oral, Adult, Anti-Bacterial Agents/therapeutic use, Biota/drug effects, Denmark, Female, Humans, Pregnancy, Respiratory Tract Infections/drug therapy, Urinary Tract Infections/drug therapy, Vagina/*microbiology, OTO - NOTNLM, Bacteria, Adult, Escherichia coli, Staphylococcus, infections, microbiome, pregnancy,
von Linstow ML	Bisgaard H	von Linstow ML, Schønning K, Hoegh AM, Sevelsted A, Vissing NH, Bisgaard H	Neonatal airway colonization is associated with troublesome lung symptoms in infants	2013	AM J RESP CRIT CARE	24127810	13,204	10	LETTER	Asymptomatic Infections/epidemiology, Child, Preschool, Cough/etiology, Haemophilus Infections/complications/epidemiology, Haemophilus influenzae, Humans, Infant, Infant, Newborn, Kaplan-Meier Estimate, Moraxella (Branhamella) catarrhalis, Moraxellaceae Infections/complications/epidemiology, Nasopharynx/microbiology, Pneumococcal Infections/complications/epidemiology, Child, Preschool, Proportional Hazards Models, Real-Time Polymerase Chain Reaction, Respiratory Sounds/etiology, Streptococcus pneumoniae
Kreiner-Møller E	Bønnelykke K	Kreiner-Møller E, Chawes BL, Vissing NH, Koppelman GH, Postma DS, Madsen JS, Olsen DA, Baty F, Vonk JM, Kerkhof M, Sleiman P, Hakonarsson H, Mortensen LJ, Poorisrisak P, Bisgaard H, Bønnelykke K	VEGFA variants are associated with pre-school lung function, but not neonatal lung function	2013	CLIN EXP ALLERGY	24152156	5,264	10	BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS AND CLINICAL RELEVANCE: 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.	Age Factors, Asthma/genetics/physiopathology, Bronchial Hyperreactivity/genetics/physiopathology, Child, Preschool, Female, Genetic Variation, Humans, Infant, Newborn, Linkage Disequilibrium, Male, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Prospective Studies, Asthma/genetics/physiopathology, Respiratory Function Tests, Risk Factors, Vascular Endothelial Growth Factor A/genetics,
Bønnelykke K	Bisgaard H	Bønnelykke K and Sleiman P and Nielsen K, Kreiner-Møller E, Mercader JM, Belgrave D, den Dekker HT, Husby A, Sevelsted A, Faura-Tellez G, Mortensen LJ, Paternoster L, Flaaten R, Mølgaard A, Smart DE, Thomsen PF, Rasmussen MA, Bonàs-Guarch S, Holst C, Nohr EA, Yadav R, March ME, Blicher T, Lackie PM, Jaddoe VW, Simpson A, Holloway JW, Duijts L, Custovic A, Davies DE, Torrents D, Gupta R, Hollegaard MV, Hougaard DM, Hakonarson H and 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	158	Asthma exacerbations are among the most frequent causes of hospitalization during childhood, but the underlying mechanisms are poorly understood. We performed a genome-wide association study of a specific asthma phenotype characterized by recurrent, severe exacerbations occurring between 2 and 6 years of age in a total of 1,173 cases and 2,522 controls. Cases were identified from national health registries of hospitalization, and DNA was obtained from the Danish Neonatal Screening Biobank. We identified five loci with genome-wide significant association. Four of these, GSDMB, IL33, RAD50 and IL1RL1, were previously reported as asthma susceptibility loci, but the effect sizes for these loci in our cohort were considerably larger than in the previous genome-wide association studies of asthma. We also obtained strong evidence for a new susceptibility gene, CDHR3 (encoding cadherin-related family member 3), which is highly expressed in airway epithelium. These results demonstrate the strength of applying specific phenotyping in the search for asthma susceptibility genes.	Asthma/etiology/genetics, Cadherins/chemistry/genetics/metabolism, Case-Control Studies, Child, Child, Preschool, Chromosomes, Human, Pair 17, DNA Repair Enzymes/genetics, DNA-Binding Proteins/genetics, Denmark, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Cadherins/chemistry/genetics/metabolism, Interleukins/genetics, Male, Membrane Proteins/chemistry/*genetics/metabolism, Models, Molecular, Neoplasm Proteins/genetics, Polymorphism, Single Nucleotide, Protein Conformation, Receptors, Cell Surface/genetics
van der Valk RJ	de Jongste JC	van der Valk RJ and Duijts L and Timpson NJ, Salam MT, Standl M, Curtin JA, Genuneit J, Kerhof M, Kreiner-Møller E, Cáceres A, Gref A, Liang LL, Taal HR, Bouzigon E, Demenais F, Nadif R, Ober C, Thompson EE, Estrada K, Hofman A, Uitterlinden AG, van Duijn C, Rivadeneira F, Li X, Eckel SP, Berhane K, Gauderman WJ, Granell R, Evans DM, St Pourcain B, McArdle W, Kemp JP, Smith GD, Tiesler CM, Flexeder C, Simpson A, Murray CS, Fuchs O, Postma DS, Bønnelykke K, Torrent M, Andersson M, Sleiman P, Hakonarson H, Cookson WO, Moffatt MF, Paternoster L, Melén E, Sunyer J, Bisgaard H, Koppelman GH, Ege M, Custovic A, Heinrich J, Gilliland FD, Henderson AJ and Jaddoe VW and de Jongste JC	Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants	2014	J ALLERGY CLIN IMMUN	24315451	13,081	19	BACKGROUND: 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. OBJECTIVE: We sought to identify the genetic variants associated with childhood Feno values and their relation with asthma. METHODS: 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). RESULTS: We identified 3 SNPs associated with Feno values: rs3751972 in LYR motif containing 9 (LYRM9; P = 1.97 x 10(-10)) and rs944722 in inducible nitric oxide synthase 2 (NOS2; P = 1.28 x 10(-9)), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB; P = 1.88 x 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. CONCLUSION: 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.	Adolescent, Asthma/genetics/metabolism/pathology, Biological Markers/metabolism, Breath Tests, Child, Child, Preschool, Chromosomes, Human, Pair 17, Exhalation, Female, Genome-Wide Association Study, Haplotypes, Humans, Linkage Disequilibrium, Asthma/genetics/metabolism/pathology, Male, Molecular Chaperones/genetics/metabolism, Neoplasm Proteins/genetics/metabolism, Nitric Oxide/biosynthesis, Nitric Oxide Synthase Type II/genetics/metabolism, *Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk
Stokholm J	Bisgaard H	Stokholm J, Schjørring S, Pedersen L, Bischoff AL, Følsgaard N, Carson CG, Chawes BL, Bønnelykke K, Mølgaard A, Krogfelt KA, Bisgaard H	Prevalence and predictors of antibiotic administration during pregnancy and birth	2013	PLOS ONE	24340068	2,806	18	BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.	Administration, Oral, Adult, Anti-Bacterial Agents/administration & dosage, Cohort Studies, Denmark, Drug Therapy/utilization, Female, Humans, Life Style, Maternal Age, Odds Ratio, *Parturition, Pregnancy, Adult, Pregnancy Complications, Infectious/drug therapy/epidemiology, Prevalence, Risk Factors,
Chawes BL	Bisgaard H	Chawes BL and Bischoff AL, Kreiner-Møller E, Buchvald F, Hakonarson H, Bisgaard H	DENND1B gene variants associate with elevated exhaled nitric oxide in healthy high-risk neonates	2015	PEDIATR PULM	24347560	2,758	5	RATIONALE OF THE STUDY: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.	asthma, genetics, infant, nitric oxidegenetics
Nilsson E	Bisgaard H	Nilsson E, Chawes BL, Bønnelykke K, Vindfeld S, Moore AC, Bisgaard H	Effect of delivery device on systemic exposure to inhaled fluticasone propionate in children with asthma	2014	BRIT J CLIN PHARMCO	24527946	3,493	1	LETTER	Administration, Inhalation, Adolescent, Androstadienes/administration & dosage/blood/therapeutic use, Anti-Inflammatory Agents/administration & dosage/blood/therapeutic use, Asthma/drug therapy, Child, Drug Delivery Systems/instrumentation, Dry Powder Inhalers, Female, Humans, Male, Metered Dose InhalersAdolescent
Sonnenschein-van der Voort AM	Duijts L	Sonnenschein-van der Voort AM, Arends LR, de Jongste JC, Annesi-Maesano I, Arshad SH, Barros H, Basterrechea M, Bisgaard H, Chatzi L, Corpeleijn E, Correia S, Craig LC, Devereux G, Dogaru C, Dostal M, Duchen K, Eggesbø M, van der Ent CK, Fantini MP, Forastiere F, Frey U, Gehring U, Gori D, van der Gugten AC, Hanke W, Henderson AJ, Heude B, Iñiguez C, Inskip HM, Keil T, Kelleher CC, Kogevinas M, Kreiner-Møller E, Kuehni CE, Küpers LK, Lancz K, Larsen PS, Lau S, Ludvigsson J, Mommers M, Nybo Andersen AM, Palkovicova L, Pike KC, Pizzi C, Polanska K, Porta D, Richiardi L, Roberts G, Schmidt A, Sram RJ, Sunyer J, Thijs C, Torrent M, Viljoen K, Wijga AH, Vrijheid M, Jaddoe VW, Duijts L	Preterm birth, infant weight gain, and childhood asthma risk: a meta-analysis of 147,000 European children	2014	J ALLERGY CLIN IMMUN	24529685	13,081	41	BACKGROUND: 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. OBJECTIVES: 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). METHODS: 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. RESULTS: 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). CONCLUSION: 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.	Asthma/epidemiology/pathology/physiopathology, Birth Weight, Europe/epidemiology, Female, Gestational Age, Humans, Infant, Infant, Newborn, Male, Premature Birth/epidemiology/pathology/physiopathology, Risk Factors, Weight Gain, PMC - PMC4024198, Birth Weight, OID - NLM: PMC4024198, OTO - NOTNLM, Gestational age, asthma, children, cohort studies, epidemiology, infant growth, low birth weight, wheezing
Bisgaard H	Stokholm J	Bisgaard H, Bønnelykke K, Stokholm J	Immune-mediated diseases and microbial exposure in early life	2014	CLIN EXP ALLERGY	24533884	5,264	16	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.	Age Factors, Host-Pathogen Interactions, Humans, Immune System Diseases/etiology/microbiology/virology*Host-Pathogen Interactions
Larsen JM	Bisgaard H	Larsen JM, Brix S, Thysen AH, Birch S, Rasmussen MA, Bisgaard H	Children with asthma by school age display aberrant immune responses to pathogenic airway bacteria as infants	2014	J ALLERGY CLIN IMMUN	24612682	13,081	25	BACKGROUND: 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. OBJECTIVE: We aimed to assess the bacterial immune response in asymptomatic infants and the association with later development of asthma by age 7 years. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.	Asthma/diagnosis/immunology/microbiology, Bacteria/immunology, Bacterial Infections/immunology/microbiology, Child, Child, Preschool, Cytokines/biosynthesis, Female, Humans, Infant, Lymphocyte Activation/immunology, Male, Phenotype, Prospective Studies, Bacteria/immunology, Respiratory Tract Infections/immunology/microbiology, T-Lymphocyte Subsets/immunology/metabolism, OTO - NOTNLM, Childhood asthma, bacteria, birth cohort, immune response,
Govoni M	Bisgaard H	Govoni M, Piccinno A, Lucci G, Poli G, Acerbi D, Baronio R, Singh D, Kuna P, Chawes BL, 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	3	BACKGROUND: 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. METHODS: 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 mug/24 mug, adolescents and adults: 400 mug/24 mug) via pMDI with AeroChamber Plus. RESULTS: 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. CONCLUSIONS: 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.	Adolescents, Adults, Asthma, Beclometasone, Children, FormoterolAdults
Chawes B	Bisgaard H	Chawes B, Govoni M, Piccinno A, Kreiner-Møller E, Vissing N, Mortensen L, Nilsson E, Bisgaard A, Deleuran M, Skytt N, Samandari N, Acerbi D, 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	BRIT J CLIN PHARMCO	24830339	3,493	2	LETTER	0
Kreiner-Møller E	Bønnelykke K	Kreiner-Møller E, Bisgaard H, Bønnelykke K	Prenatal and postnatal genetic influence on lung function development	2014	J ALLERGY CLIN IMMUN	24857373	13,081	7	BACKGROUND: It is unknown to what extent adult lung function genes affect lung function development from birth to childhood. OBJECTIVE: Our aim was to study the association of candidate genetic variants with neonatal lung function and lung function development until age 7 years. METHODS: 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). RESULTS: 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). CONCLUSION: 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.	Adult, Age Factors, Bronchoconstrictor Agents/administration & dosage, Case-Control Studies, Child, Child, Preschool, Female, Forced Expiratory Volume/drug effects/genetics, Humans, Infant, Infant, Newborn, Lung/growth & development/physiopathology, Lung Volume Measurements/methods, Age Factors, Male, Methacholine Chloride/administration & dosage, Polymorphism, Single Nucleotide, Pregnancy, Prenatal Exposure Delayed Effects/genetics/physiopathology, Prospective Studies, Spirometry/methods, OTO - NOTNLM, Child, asthma, respiratory function tests,
Chawes BL	Bisgaard H	Chawes BL, Bønnelykke K, Jensen PF, Schoos AM, Heickendorff 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	43	BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.	0
Chawes BL	Bisgaard H	Chawes BL, Govoni M, Kreiner-Møller E, Vissing NH, Poorisrisak P, Mortensen L, Nilsson E, Bisgaard A, Dossing A, Deleuran M, Skytt NL, Samandari N, Piccinno A, Sergio F, Ciurlia G, Poli G, Acerbi D, Singh D, Bisgaard H	Systemic exposure to inhaled beclometasone/formoterol DPI is age and body size dependent	2014	RESP MED	24993817	3,217	5	AIM: 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. METHODS: 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 mug/24 mug, adolescents and adults: 400 mug/24 mug) via DPI. RESULTS: 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	Administration, Inhalation, Adolescent, Adult, Age Factors, Aged, Analysis of Variance, Anti-Asthmatic Agents/administration & dosage/pharmacokinetics, Asthma/drug therapy/physiopathology, Beclomethasone/administration & dosage/pharmacokinetics, Body Size/physiology, Child, Cross-Over Studies, Ethanolamines/administration & dosage/pharmacokinetics, Adolescent, Forced Expiratory Volume/drug effects, Half-Life, Humans, Metered Dose Inhalers, Middle Aged, Young Adult, Adolescents, Asthma, Beclometasone-dipropionate, Children, Formoterol,
Stokholm J	Bisgaard H	Stokholm J and Sevelsted A, Bønnelykke K, Bisgaard H	Maternal propensity for infections and risk of childhood asthma: a registry-based cohort study	2014	LANCET RESP MED	25066330	19,287	28	BACKGROUND: 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. METHODS: 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). FINDINGS: 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. INTERPRETATION: 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. FUNDING: The Danish Council for Strategic Research, The Lundbeck Foundation, The Pharmacy Foundation of 1991, the Danish Medical Research Council, and National Finance Act.	0
Schoos AM	Bisgaard H	Schoos AM, Chawes BL, Følsgaard N, Samandari N, Bønnelykke K, Bisgaard H	Disagreement Between Skin Prick Test and Specific IgE in Young Children	2015	ALLERGY	25224528	7,361	26	BACKGROUND: 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. METHODS: SPT and sIgE levels were assessed simultaneously for 16 common inhalant and food allergens at age (1/2), 1(1/2), 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. RESULTS: 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 kappa-coefficients	Agreement, Children, Sensitization, Skin prick test, Specific IgE, Children
Bischoff AL	Bisgaard H	Bischoff AL and Følsgaard NV, Vissing NH, Birch S, Brix S, 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	BACKGROUND: It is recommended to vaccinate pregnant women against influenza. A possible impact on the immune expression of the fetus has never been studied. We aim to study the immune signature in the upper airways and the incidence of infections in neonates born to mothers receiving Influenza A(H1N1)pnd09 vaccination during pregnancy. METHODS: One hundred and fifty-six women from the unselected Copenhagen Prospective Study on Asthma in Childhood (COPSAC2010) received Influenza A(H1N1)pnd09-vaccination during the 2009 pandemic. Fifty-one mothers received the vaccine during pregnancy and 105 after pregnancy; 332 neonates of nonvaccinated mothers were included as secondary controls. Nasal mucosal lining fluid was sampled in 488 neonates and assessed for interleukin (IL)-12p70, IP-10, interferon-gamma (IFN)-gamma, tumor necrosis factor-alpha (TNF)-alpha, MIP-1beta, MCP-1, MCP-4, IL-4, IL-5, IL-13, eotaxin-1, eotaxin-3, TARC, MDC, IL-17, IL-1beta, IL-8, transforming growth factor beta (TGF)-beta1, IL-10 and IL-2. Infections were monitored the first year of life by daily diary cards and clinical controls. RESULTS: Neonates of mothers vaccinated during pregnancy had significant up-regulation of TGF-beta1 [ratio = 1.52 (1.22-1.90), P = 0.0002], and corresponding down-regulation (P < 0.05) of IL-12p70, IFN-gamma, IL-5, eotaxin-1, TARC, MDC, IL-8 in comparison to those vaccinated after pregnancy. The lag-time from vaccination during pregnancy to assessment of the immune signature showed significant and positive association to up-regulation of TGF-beta1 levels (P = 0.0003) and significant negative association to other mediators. The study was not powered to study differences in the incidence of infections in early infancy which did not differ between the study groups. CONCLUSION: Influenza A(H1N1)pnd09 vaccination during pregnancy up-regulates TGF-beta1 and down-regulates key mediators of the protective immunity.	0
van der Valk RJ	Jaddoe VW	van der Valk RJ and Kreiner-Møller E and Kooijman MN and Guxens M and Stergiakouli E, Sääf A, Bradfield JP, Geller F, Hayes MG, Cousminer DL, Körner A, Thiering E, Curtin JA, Myhre R, Huikari V, Joro R, Kerkhof M, Warrington NM, Pitkänen N, Ntalla I, Horikoshi M, Veijola R, Freathy RM, Teo YY, Barton SJ, Evans DM, Kemp JP, St Pourcain B, Ring SM, Davey Smith G, Bergström A, Kull I, Hakonarson H, Mentch FD, Bisgaard H, Chawes B, Stokholm J, Waage J, Eriksen P, Sevelsted A, Melbye M; Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium, van Duijn CM, Medina-Gomez C, Hofman A, de Jongste JC, Taal HR, Uitterlinden AG; Genetic Investigation of ANthropometric Traits (GIANT) Consortium, Armstrong LL, Eriksson J, Palotie A, Bustamante M, Estivill X, Gonzalez JR, Llop S, Kiess W, Mahajan A, Flexeder C, Tiesler CM, Murray CS, Simpson A, Magnus P, Sengpiel V, Hartikainen AL, Keinanen-Kiukaanniemi S, Lewin A, Da Silva Couto Alves A, Blakemore AI, Buxton JL, Kaakinen M, Rodriguez A, Sebert S, Vaarasmaki M, Lakka T, Lindi V, Gehring U, Postma DS, Ang W, Newnham JP, Lyytikäinen LP, Pahkala K, Raitakari OT, Panoutsopoulou K, Zeggini E, Boomsma DI, Groen-Blokhuis M, Ilonen J, Franke L, Hirschhorn JN, Pers TH, Liang L, Huang J, Hocher B, Knip M, Saw SM, Holloway JW, Melén E, Grant SF, Feenstra B, Lowe WL, Widén E, Sergeyev E, Grallert H, Custovic A, Jacobsson B, Jarvelin MR, Atalay M, Koppelman GH, Pennell CE, Niinikoski H, Dedoussis GV, Mccarthy MI, Frayling TM, Sunyer J and Timpson NJ and Rivadeneira F and Bønnelykke K and Jaddoe VW	A novel common variant in DCST2 is associated with length in early life and height in adulthood	2015	HUM MOL GENET	25281659	5,34	20	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.	0
Kreiner-Møller E	Bønnelykke K	Kreiner-Møller E, Strachan DP, Linneberg A, Husemoen LL, Bisgaard H, Bønnelykke K	17q21 gene variation is not associated with asthma in adulthood	2015	ALLERGY	25331618	7,361	5	BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.	adults, asthma, genetic association studies, respiratory function testsasthma
Brix S	Bisgaard H	Brix S, Eriksen C, Madura Larsen J, Bisgaard H	Metagenomic heterogeneity explains dual immune effects of endotoxins	2015	J ALLERGY CLIN IMMUN	25445821	13,081	12	LETTER	Asthma/microbiology, Bacteria/classification/genetics/metabolism, Endotoxins/genetics/immunology/metabolism, Genomics, Humans, Lung/microbiologyBacteria/classification/genetics/metabolism
Sevelsted A	Bisgaard H	Sevelsted A, Stokholm J, Bønnelykke K and Bisgaard H	Cesarean Section and chronic immune disorders	2015	J PEDIATR	25452656	3,874	96	OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.	Adolescent, Cesarean Section/statistics & numerical data, Child, Child, Preschool, Chronic Disease, Female, Humans, Immune System Diseases/epidemiology, Infant, Infant, Newborn, Male, asthma, cesarean section, Cesarean Section/*statistics & numerical data, inflammatory disease, origins, prenatal, programming
Bønnelykke K	Andersen ZJ	Bønnelykke K, Raaschou-Nielsen O, Tjønneland A, Ulrik CS, Bisgaard H, Andersen ZJ	Postmenopausal hormone therapy and asthma-related hospital admission	2015	J ALLERGY CLIN IMMUN	25579482	13,081	4	LETTER	Asthma/etiology/immunology/metabolism/physiopathology, Denmark, Estrogen Replacement Therapy/adverse effects, Estrogens/administration & dosage, Female, Health Surveys, Hospitalization/statistics & numerical data, Humans, Incidence, Middle Aged, Postmenopause/*drug effects/metabolism, Proportional Hazards Models, Risk, Denmark, Smoking/physiopathology,
Chawes BL	Bisgaard H	Chawes BL, Stokholm J, Bønnelykke K, Brix S, Bisgaard H	Neonates with reduced neonatal lung function have systemic low-grade inflammation	2015	J ALLERGY CLIN IMMUN	25579483	13,081	10	BACKGROUND: 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. OBJECTIVE: We sought to investigate the possible association between neonatal lung function and biomarkers of systemic inflammation. METHODS: Plasma levels of high-sensitivity C-reactive protein (hs-CRP), IL-1beta, IL-6, TNF-alpha, 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. RESULTS: The neonatal forced expiratory volume at 0.5 seconds was inversely associated with hs-CRP (beta-coefficient, -0.12; 95% CI, -0.21 to -0.04; P < .01) and IL-6 (beta-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-alpha, 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. CONCLUSION: Diminished neonatal lung function is associated with upregulated systemic inflammatory markers, such as hs-CRP.	Asthma, Children, High sensitivity C-reactive protein, Proteininflammatory cytokines, Spirometry, Children
Jelding-Dannemand E	Bisgaard H	Jelding-Dannemand E, Malby Schoos AM, 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 IMMUN	25843315	13,081	17	BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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 (1/2) year, 1(1/2) 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. RESULTS: 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]: (1/2) year, 1.10 [95% CI, 0.90-1.36]; 1(1/2) 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. CONCLUSION: Exclusive breast-feeding does not affect sensitization in early childhood or associated diseases at 7 years of age in at-risk children.	Breast-Feeding, Sensitization, Asthma, Eczema, Skin prick test, Specific IgE, Children, Sensitization
Bønnelykke K	Bisgaard H	Bønnelykke K, Vissing NH, Sevelsted A, Johnston SL, Bisgaard H	Association between respiratory infections in early life and later asthma is independent of virus type	2015	J ALLERGY CLIN IMMUN	25910716	13,081	46	BACKGROUND: 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. OBJECTIVE: We sought to study the association between specific infections in early life and development of asthma later in childhood. METHODS: 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. RESULTS: 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. CONCLUSION: 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.	Child, Asthma, Bacteria, Respiratory tract infection, virus, Asthma
Thysen AH	Brix S	Thysen AH, Larsen JM, Rasmussen MA, Stokholm J, Bønnelykke K, Bisgaard H, Brix S	Prelabor cesarean section bypasses natural immune cell maturation	2015	J ALLERGY CLIN IMMUN	26094084	13,081	5	LETTER	0
Carlsson CJ	Bisgaard H	Carlsson CJ, Vissing NH, Sevelsted A, Johnston SL, Bønnelykke K, Bisgaard H	Duration of wheezy episodes in early childhood is independent of the microbial trigger	2015	J ALLERGY CLIN IMMUN	26100088	13,081	11	BACKGROUND: 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. OBJECTIVE: We sought to investigate whether the duration of wheezy episodes in young children depends on the microbial trigger. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.	Respiratory tract infections, pediatrics, wheezy episodes, pediatrics
Joshi PK	Wilson JF	Joshi PK, Esko T, Mattsson H, Eklund N, Gandin I, Nutile T, Jackson AU, Schurmann C, Smith AV, Zhang W, Okada Y, Stančáková A, Faul JD, Zhao W, Bartz TM, Concas MP, Franceschini N, Enroth S, Vitart V, Trompet S, Guo X, Chasman DI, O'Connel JR, Corre T, Nongmaithem SS, Chen Y, Mangino M, Ruggiero D, Traglia M, Farmaki AE, Kacprowski T, Bjonnes A, van der Spek A, Wu Y, Giri AK, Yanek LR, Wang L, Hofer E, Rietveld CA, McLeod O, Cornelis MC, Pattaro C, Verweij N, Baumbach C, Abdellaoui A, Warren HR, Vuckovic D, Mei H, Bouchard C, Perry JR, Cappellani S, Mirza SS, Benton MC, Broeckel U, Medland SE, Lind PA, Malerba G, Drong A, Yengo L, Bielak LF, Zhi D, van der Most PJ, Shriner D, Mägi R, Hemani G, Karaderi T, Wang Z, Liu T, Demuth I, Zhao JH, Meng W, Lataniotis L, van der Laan SW, Bradfield JP, Wood AR, Bonnefond A, Ahluwalia TS, Hall LM, Salvi E, Yazar S, Carstensen L, de Haan HG, Abney M, Afzal U, Allison MA, Amin N, Asselbergs FW, Bakker SJ, Barr RG, Baumeister SE, Benjamin DJ, Bergmann S, Boerwinkle E, Bottinger EP, Campbell A, Chakravarti A, Chan Y, Chanock SJ, Chen C, Chen YI, Collins FS, Connell J, Correa A, Cupples LA, Smith GD, Davies G, Dörr M, Ehret G, Ellis SB, Feenstra B, Feitosa MF, Ford I, Fox CS, Frayling TM, Friedrich N, Geller F, Scotland G, Gillham-Nasenya I, Gottesman O, Graff M, Grodstein F, Gu C, Haley C, Hammond CJ, Harris SE, Harris TB, Hastie ND, Heard-Costa NL, Heikkilä K, Hocking LJ, Homuth G, Hottenga JJ, Huang J, Huffman JE, Hysi PG, Ikram MA, Ingelsson E, Joensuu A, Johansson Å, Jousilahti P, Jukema JW, Kähönen M, Kamatani Y, Kanoni S, Kerr SM, Khan NM, Koellinger P, Koistinen HA, Kooner MK, Kubo M, Kuusisto J, Lahti J, Launer LJ, Lea RA, Lehne B, Lehtimäki T, Liewald DC, Lind L, Loh M, Lokki ML, London SJ, Loomis SJ, Loukola A, Lu Y, Lumley T, Lundqvist A, Männistö S, Marques-Vidal P, Masciullo C, Matchan A, Mathias RA, Matsuda K, Meigs JB, Meisinger C, Meitinger T, Menni C, Mentch FD, Mihailov E, Milani L, Montasser ME, Montgomery GW, Morrison A, Myers RH, Nadukuru R, Navarro P, Nelis M, Nieminen MS, Nolte IM, O'Connor GT, Ogunniyi A, Padmanabhan S, Palmas WR, Pankow JS, Patarcic I, Pavani F, Peyser PA, Pietilainen K, Poulter N, Prokopenko I, Ralhan S, Redmond P, Rich SS, Rissanen H, Robino A, Rose LM, Rose R, Sala C, Salako B, Salomaa V, Sarin AP, Saxena R, Schmidt H, Scott LJ, Scott WR, Sennblad B, Seshadri S, Sever P, Shrestha S, Smith BH, Smith JA, Soranzo N, Sotoodehnia N, Southam L, Stanton AV, Stathopoulou MG, Strauch K, Strawbridge RJ, Suderman MJ, Tandon N, Tang ST, Taylor KD, Tayo BO, Töglhofer AM, Tomaszewski M, Tšernikova N, Tuomilehto J, Uitterlinden AG, Vaidya D, van Hylckama Vlieg A, van Setten J, Vasankari T, Vedantam S, Vlachopoulou E, Vozzi D, Vuoksimaa E, Waldenberger M, Ware EB, Wentworth-Shields W, Whitfield JB, Wild S, Willemsen G, Yajnik CS, Yao J, Zaza G, Zhu X; BioBank Japan Project, Salem RM, Melbye M, Bisgaard H, Samani NJ, Cusi D, Mackey DA, Cooper RS, Froguel P, Pasterkamp G, Grant SF, Hakonarson H, Ferrucci L, Scott RA, Morris AD, Palmer CN, Dedoussis G, Deloukas P, Bertram L, Lindenberger U, Berndt SI, Lindgren CM, Timpson NJ, Tönjes A, Munroe PB, Sørensen TI, Rotimi CN, Arnett DK, Oldehinkel AJ, Kardia SL, Balkau B, Gambaro G, Morris AP, Eriksson JG, Wright MJ, Martin NG, Hunt SC, Starr JM, Deary IJ, Griffiths LR, Tiemeier H, Pirastu N, Kaprio J, Wareham NJ, Pérusse L, Wilson JG, Girotto G, Caulfield MJ, Raitakari O, Boomsma DI, Gieger C, van der Harst P, Hicks AA, Kraft P, Sinisalo J, Knekt P, Johannesson M, Magnusson PK, Hamsten A, Schmidt R, Borecki IB, Vartiainen E, Becker DM, Bharadwaj D, Mohlke KL, Boehnke M, van Duijn CM, Sanghera DK, Teumer A, Zeggini E, Metspalu A, Gasparini P, Ulivi S, Ober C, Toniolo D, Rudan I, Porteous DJ, Ciullo M, Spector TD, Hayward C, Dupuis J, Loos RJ, Wright AF, Chandak GR, Vollenweider P, Shuldiner AR, Ridker PM, Rotter JI, Sattar N, Gyllensten U, North KE, Pirastu M, Psaty BM, Weir DR, Laakso M, Gudnason V, Takahashi A, Chambers JC, Kooner JS, Strachan DP, Campbell H, Hirschhorn JN, Perola M, Polašek O, Wilson JF	Directional dominance on stature and cognition in diverse human populations	2015	NATURE	26131930	40,137	46	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.	0
Vinding RK	Bisgaard H	Vinding RK, Stokholm J, Chawes B, Bisgaard H	Blood lipid levels associate with childhood asthma, airway obstruction, bronchial hyperresponsiveness, and aeroallergen sensitization	2016	J ALLERGY CLIN IMMUN	26148797	13,081	10	BACKGROUND: Studies of children's blood lipid profiles in relation to asthma are few, and the results are ambiguous. OBJECTIVE: We sought to examine whether the lipid profile is associated with concurrent asthma, altered lung function, and allergic sensitization in children. METHODS: 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. RESULTS: 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). CONCLUSION: 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.	Blood lipids, asthma, child, inflammation, respiratory function tests, asthma
Sevelsted A	Bisgaard H	Sevelsted A, Pipper CB, Bisgaard H	Stable admission rate for acute asthma in Danish children since 1977	2016	EUR J EPI	26266768	7,226	3	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.	0
Muc M	Lauritzen L	Muc M, Kreiner-Møller E, Larsen JM, Birch S, Brix S, Bisgaard H, Lauritzen L	Maternal fatty acid desaturase genotype correlates with infant immune responses at 6 months	2015	BRIT J NUTR	26283408	3,706	3	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.	0
Shaw DE	Chung KF	Shaw DE, Sousa AR, Fowler SJ, Fleming LJ, Roberts G, Corfield J, Pandis I, Bansal AT, Bel EH, Auffray C, Compton CH, Bisgaard H, Bucchioni E, Caruso M, Chanez P, Dahlén B, Dahlen SE, Dyson K, Frey U, Geiser T, Gerhardsson de Verdier M, Gibeon D, Guo YK, Hashimoto S, Hedlin G, Jeyasingham E, Hekking PW, Higenbottam T, Horváth I, Knox AJ, Krug N, Erpenbeck VJ, Larsson LX, Lazarinis N, Matthews JG, 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 IM, Wagers S, Rowe A, Howarth P, Wagener AH, Djukanovic R, Sterk PJ, Chung KF	Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort	2015	EUR RESPIR J	26357963	10,569	88	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.	0
Loisel DA	Ober C	Loisel DA, Du G, Ahluwalia TS, Tisler CJ, Evans MD, Myers RA, Gangnon RE, Møller EK, Bønnelykke K, Bisgaard H, Jackson DJ, Lemanske RF Jr, Nicolae DL, Gern JE, Ober C	Genetic associations with viral respiratory illnesses and asthma control in children	2016	CLIN EXP ALLERGY	26399222	5,264	7	BACKGROUND: Viral respiratory infections can cause acute wheezing illnesses in children and exacerbations of asthma. OBJECTIVE: 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. METHODS: 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 2,128 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 birth cohort study (COAST). RESULTS: 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. CONCLUSIONS: 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.	0
Fleming L	Roberts G	Fleming L, Murray C, Bansal AT, Hashimoto S, Bisgaard H, Bush A, Frey U, Hedlin G, Singer F, van Aalderen WM, Vissing NH, Zolkipli Z, Selby A, Fowler S, Shaw D, Chung KF, Sousa AR, Wagers S, Corfield J, Pandis I, Rowe A, Formaggio E, Sterk PJ, 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	39	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.	0
Paternoster L	Weidinger S	Paternoster L and Standl M, Waage J, Baurecht H, Hotze M, Strachan DP, Curtin JA, Bønnelykke K, Tian C, Takahashi A, Esparza-Gordillo J, Alves AC, Thyssen JP, den Dekker HT, Ferreira MA, Altmaier E, Sleiman PM, Xiao FL, Gonzalez JR, Marenholz I, Kalb B, Pino-Yanes M, Xu CJ, Carstensen L, Groen-Blokhuis MM, Venturini C, Pennell CE, Barton SJ, Levin AM, Curjuric I, Bustamante M, Kreiner-Møller E, Lockett GA, Bacelis J, Bunyavanich S, Myers RA, Matanovic A, Kumar A, Tung JY, Hirota T, Kubo M, McArdle WL, Henderson AJ, Kemp JP, Zheng J, Smith GD, Rüschendorf F, Bauerfeind A, Lee-Kirsch MA, Arnold A, Homuth G, Schmidt CO, Mangold E, Cichon S, Keil T, Rodríguez E, Peters A, Franke A, Lieb W, Novak N, Fölster-Holst R, Horikoshi M, Pekkanen J, Sebert S, Husemoen LL, Grarup N, de Jongste JC, Rivadeneira F, Hofman A, Jaddoe VW, Pasmans SG, Elbert NJ, Uitterlinden AG, Marks GB, Thompson PJ, Matheson MC, Robertson CF, Aagc AA, Ried JS, Li J, Zuo XB, Zheng XD, Yin XY, Sun LD, McAleer MA, O'Regan GM, Fahy CM, Campbell LE, Macek M, Kurek M, Hu D, Eng C, Postma DS, Feenstra B, Geller F, Hottenga JJ, Middeldorp CM, Hysi P, Bataille V, Spector T, Tiesler CM, Thiering E, Pahukasahasram B, Yang JJ, Imboden M, Huntsman S, Vilor-Tejedor N, Relton CL, Myhre R, Nystad W, Custovic A, Weiss ST, Meyers DA, Söderhäll C, Melén E, Ober C, Raby BA, Simpson A, Jacobsson B, Holloway JW, Bisgaard H, Sunyer J, Probst-Hensch NM, Williams LK, Godfrey KM, Wang CA, Boomsma DI, Melbye M, Koppelman GH, Jarvis D, McLean WH, Irvine AD, Zhang XJ, Hakonarson H, Gieger C, Burchard EG, Martin NG, Duijts L, Linneberg A, Jarvelin MR, Nöthen MM, Lau S, Hübner N, Lee YA, Tamari M, Hinds DA, Glass D, Brown SJ, Heinrich J, Evans DM, 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	77	Genetic association studies have identified 21 loci associated with atopic dermatitis (AD) 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 10 novel risk loci, bringing the total number of known AD risk loci to 31 (with novel secondary signals at 4 of these). Notably, the new loci include candidate genes with roles in regulation of innate host defenses and T-cell function, underscoring the important contribution of (auto-)immune mechanisms to AD pathogenesis.	0
Kragh M	Brix S	Kragh M, Larsen JM, Thysen AH, Rasmussen MA, Wolsk HM, Bisgaard H, 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	5	BACKGROUND: First-born children are at higher risk for development of 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. OBJECTIVE: We studied the association between birth-order and the functional response of stimulated cord blood T cells. METHOD: Purified cord blood T cells were polyclonally activated with anti-CD3/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 supernatants. RESULTS: IL-10 secretion (P = 0.007) and CD25 expression on CD4+ helper T cells (P = 0.0003) in activated cord blood T cells were selectively reduced in first-born children, while the percentage of CD4+ CD25+ cord blood T cells was independent of birth-order. CONCLUSION: First-born infants display a reduced anti-inflammatory profile in T cells at birth. This possible in utero 'birth-order' T cell programing may contribute to later development of immune-mediated diseases by increasing overall immune reactivity in first-born children as compared to younger siblings. This article is protected by copyright. All rights reserved.	0
den Dekker HT	Duijts L	den Dekker HT, Sonnenschein-van der Voort AM, de Jongste JC, Anessi-Maesano I, Arshad SH, Barros H, Beardsmore CS, Bisgaard H, Phar SC, Craig L, Devereux G, van der Ent CK, Esplugues A, Fantini MP, Flexeder C, Frey U, Forastiere F, Gehring U, Gori D, van der Gugten AC,Henderson AJ, Heude B, Ibarluzea J, Inskip HM, Keil T, Kogevinas M, Kreiner-Møller E, Kuehni CE, Lau S, Mélen E, Mommers M, Morales E, Penders J, Pike KC, Porta D, Reiss IK, Roberts G, Schmidt A, Schultz ES, Schulz H, Sunyer J, Torrent M, Vassilaki M, Wijga AH,Zabaleta C, Jaddoe VW, 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 IMMUN	26548843	13,081	29	BACKGROUND: Children born preterm or with a small size for gestational age are at increased risk for childhood asthma. OBJECTIVE: We sought to assess the hypothesis that these associations are explained by reduced airway patency. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.	0
Thysen AH	Brix S	Thysen AH, Rasmussen MA, Kreiner-Møller M, Larsen JM, Følsgaard NV, Bønnelykke K, Stokholm J, Bisgaard H, Brix S	Season of birth shapes neonatal immune function	2016	J ALLERGY CLIN IMMUN	26581916	13,081	6	BACKGROUND: 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. OBJECTIVE: We sought to investigate the influence of season of birth on cord blood immune cell subsets and inflammatory mediators in neonatal airways. METHODS: 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. RESULTS: 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. CONCLUSION: 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.	0
Schoos AM	Bisgaard H	Schoos AM, Chawes BLk, Arendt M, Bloch J, Bønnelykke K, Bisgaard H	Atopic Endotype in Childhood	2016	J ALLERGY CLIN IMMUN	26597163	13,081	7	Background: 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. Methods: Allergic sensitization against 28 inhalant and food allergens was assessed at 1⁄2, 11⁄2, 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. Results: 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 1⁄2, 11⁄2, 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 5 .07) but not at 13 years of age (OR, 1.57 [95% CI, 0.78-3.16]; P 5 .21). We identified 4 latent patterns of disease development that were either dominated by sensitization (37%), eczema (26%), asthma (14%), or healthy status (24%). Conclusion: 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	0
Felix JF	Jaddoe VW	Felix JF, Bradfield JP, Monnereau C, van der Valk RJ, 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 MM, Cousminer DL, Marsh JA, Lehtimäki T, Curtin JA, Vioque J, Ahluwalia TS, Myhre R, Price TS, Vilor-Tejedor N, Yengo L, Grarup N, Ntalla I, Ang W, Atalay M, Bisgaard H, Blakemore AI, Bonnefond A, Carstensen L, Eriksson J, Flexeder C, Franke L, Geller F, Geserick M, Hartikainen AL, Haworth CM, Hirschhorn JN, Hofman A, Holm JC, Horikoshi M, Hottenga JJ, Huang J, Kadarmideen HN, Kähönen M, Kiess W, Lakka HM, Lakka TA, Lewin AM, Liang L, Lyytikäinen LP, Ma B, Magnus P, McCormack SE, McMahon G, Mentch FD, Middeldorp CM, Murray CS, Pahkala K, Pers TH, Pfäffle R, Postma DS, Power C, Simpson A, Sengpiel V, Tiesler CM, Torrent M, Uitterlinden AG, van Meurs JB, Vinding R, Waage J, Wardle J, Zeggini E, Zemel BS, Dedoussis GV, Pedersen O, Froguel P, Sunyer J, Plomin R, Jacobsson B, Hansen T, Gonzalez JR, Custovic A, Raitakari OT, Pennell CE, Widén E, Boomsma DI, Koppelman GH, Sebert S, Järvelin MR, Hyppönen E, McCarthy MI, Lindi V, Harri N, Körner A, Bønnelykke K, Heinrich J, Melbye M, Rivadeneira F, Hakonarson H, Ring SM, Smith GD, Sørensen TI, Timpson NJ, Grant SF, Jaddoe VW	Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index	2016	HUM MOL GENET	26604143	5,34	45	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 genomewide 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-widesignificance (P-value < 5 x 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 x 10-10) increase in childhood body mass index in a population of 1,955 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.	0
Wolsk HM	Bisgaard H	Wolsk HM, Følsgaard NV, Birch S, Brix S, Hansel TT, Johnston SL, Kebadze T, Chawes BL, Bønnelykke K, Bisgaard H	Picornavirus-induced Airway Mucosa Immune Profile in Asymptomatic Neonates	2016	J INFECT DIS	26655299	6,273	6	BACKGROUND: Bacterial airway colonization is known to alter the airway mucosa immune response in neonates whereas the impact of viruses is unknown. The objective was to examine the effect of respiratory viruses on the immune signature in the airways of asymptomatic neonates. METHODS: Nasal aspirates from 571 asymptomatic one-month-old neonates from the COPSAC2010 birth-cohort were investigated for respiratory viruses. Simultaneously, unstimulated airway mucosal lining fluid was obtained and quantified for 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 (PLS-DA). RESULTS: Picornaviruses were detected in 58 (10.2%) and other viruses in 10 (1.8%) neonates. A general up-regulation of immune mediators was found in the neonates with picornavirus (PLS-DA: p<0.0001). 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 upregulating effect. CONCLUSION: Asymptomatic presence of picornavirus in the neonatal airway is a potent activator of the topical immune response. This is of relevance in relation to understanding the immune potentiating effect of early life exposure to viruses. BACKGROUND: Bacterial airway colonization is known to alter the airway mucosa immune response in neonates whereas the impact of viruses is unknown. The objective was to examine the effect of respiratory viruses on the immune signature in the airways of asymptomatic neonates. METHODS: Nasal aspirates from 571 asymptomatic one-month-old neonates from the COPSAC2010 birth-cohort were investigated for respiratory viruses. Simultaneously, unstimulated airway mucosal lining fluid was obtained and quantified for 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 (PLS-DA). RESULTS: Picornaviruses were detected in 58 (10.2%) and other viruses in 10 (1.8%) neonates. A general up-regulation of immune mediators was found in the neonates with picornavirus (PLS-DA: p<0.0001). 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 upregulating effect. CONCLUSION: Asymptomatic presence of picornavirus in the neonatal airway is a potent activator of the topical immune response. This is of relevance in relation to understanding the immune potentiating effect of early life exposure to viruses. BACKGROUND: Bacterial airway colonization is known to alter the airway mucosa immune response in neonates whereas the impact of viruses is unknown. The objective was to examine the effect of respiratory viruses on the immune signature in the airways of asymptomatic neonates. METHODS: Nasal aspirates from 571 asymptomatic one-month-old neonates from the COPSAC2010 birth-cohort were investigated for respiratory viruses. Simultaneously, unstimulated airway mucosal lining fluid was obtained and quantified for 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 (PLS-DA). RESULTS: Picornaviruses were detected in 58 (10.2%) and other viruses in 10 (1.8%) neonates. A general up-regulation of immune mediators was found in the neonates with picornavirus (PLS-DA: p<0.0001). 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 upregulating effect. CONCLUSION: Asymptomatic presence of picornavirus in the neonatal airway is a potent activator of the topical immune response. This is of relevance in relation to understanding the immune potentiating effect of early life exposure to viruses. BACKGROUND: Bacterial airway colonization is known to alter the airway mucosa immune response in neonates whereas the impact of viruses is unknown. The objective was to examine the effect of respiratory viruses on the immune signature in the airways of asymptomatic neonates. METHODS: Nasal aspirates from 571 asymptomatic one-month-old neonates from the COPSAC2010 birth-cohort were investigated for respiratory viruses. Simultaneously, unstimulated airway mucosal lining fluid was obtained and quantified for 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 (PLS-DA). RESULTS: Picornaviruses were detected in 58 (10.2%) and other viruses in 10 (1.8%) neonates. A general up-regulation of immune mediators was found in the neonates with picornavirus (PLS-DA: p<0.0001). 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 upregulating effect. CONCLUSION: Asymptomatic presence of picornavirus in the neonatal airway is a potent activator of the topical immune response. This is of relevance in relation to understanding the immune potentiating effect of early life exposure to viruses.	0
Stokholm J	Bisgaard H	Stokholm J, Chawes BL, Vissing NH, Bjarnadóttir E, Pedersen TM, Vinding RK, Schoos AM, Wolsk HM, Thorsteinsdóttir S, Hallas HW, Arianto L, Schjørring S, Krogfelt KA, Fischer TK, Pipper CB, Bønnelykke K, 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 RESP MED	26704020	19,287	40	BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Lundbeck Foundation, Danish Ministry of Health, Danish Council for Strategic Research, Capital Region Research Foundation.	0
Wolsk HM	Bisgaard H	Wolsk HM, L Chawes B, Følsgaard NV, Rasmussen MA, Brix S, Bisgaard H	Siblings Promote a Type 1/Type 17-oriented immune response in the airways of asymptomatic neonates	2016	ALLERGY	26808998	7,361	2	BACKGROUND: Siblings have been shown to reduce the risk of later 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. We hypothesized that siblings exert immune modulatory effects on neonates mirrored in the airway mucosa. METHODS: 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 analyses (PCA). RESULTS: Neonates with siblings had an up-regulated 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. CONCLUSIONS: 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 presence of unidentified microbes, but further studies are needed to confirm our findings.	0
Chawes BL	Bisgaard H	Chawes BL, Bønnelykke K, Stokholm J, Vissing NH, Bjarndottir E, Schoos AMM, Wolsk HM, Pedersen TM, Vinding RK, Thorsteindottir S, Arianto L, Hallas HW, Heikcendorff L, Brix S, Rasmussen MA, 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	65	IMPORTANCE: 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. OBJECTIVE: To determine whether supplementation of vitamin D3 during the third trimester of pregnancy reduces the risk of persistent wheeze in the offspring. DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTIONS: 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. MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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]. CONCLUSIONS AND RELEVANCE: 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. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00856947.	0
Sevelsted A	Bisgaard H	Sevelsted A, Stokholm J, Bisgaard H	Risk of Asthma from Cesarean Delivery Depends on Membrane Rupture	2016	J PEDIATR	26825289	3,874	7	OBJECTIVE: 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. STUDY DESIGN: 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). RESULTS: 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]). CONCLUSIONS: 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.	0
Schoos AM	Bisgaard H	Schoos AM, Chawes BL, Jelding-Dannemand E, Elfman LB, 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	5	RATIONALE: 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. OBJECTIVES: To investigate the association between perinatal aeroallergen exposure and sensitization and rhinitis to such allergens. METHODS: 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). RESULTS: 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. CONCLUSION: 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. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.	0
Vissing NH	Bisgaard H	Vissing NH, Larsen JM, Rasmussen MA, Chawes BLK, Thysen AH, Bønnelykke K, Brix S, 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	BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Children at risk of future LRI present a perturbed systemic immune response upon exposure to common airway pathogens in early life.	0
Tyrrell J	Freathy RM	Tyrrell J, Richmond RC, Palmer TM, Feenstra B, Rangarajan J, Metrustry S, Cavadino A, Paternoster L, Armstrong LL, De Silva NM, Wood AR, Horikoshi M, Geller F, Myhre R, Bradfield JP, Kreiner-Møller E, Huikari V, Painter JN, Hottenga JJ, Allard C, Berry DJ, Bouchard L, Das S, Evans DM, Hakonarson H, Hayes MG, Heikkinen J, Hofman A, Knight B, Lind PA, McCarthy MI, McMahon G, Medland SE, Melbye M, Morris AP, Nodzenski M, Reichetzeder C, Ring SM, Sebert S, Sengpiel V, Sørensen TI, Willemsen G, de Geus EJ, Martin NG, Spector TD, Power C, Järvelin MR, Bisgaard H, Grant SF, Nohr EA, Jaddoe VW, Jacobsson B, Murray JC, Hocher B, Hattersley AT, Scholtens DM, Davey Smith G, Hivert MF, Felix JF, Hyppönen E, Lowe WL Jr, Frayling TM, Lawlor DA, Freathy RM	Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight	2016	JAMA	26978208	44,405	49	IMPORTANCE: 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. OBJECTIVE: To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight. DESIGN, SETTING, AND PARTICIPANTS: 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. EXPOSURES: 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. MAIN OUTCOME AND MEASURE: Offspring birth weight from 18 studies. RESULTS: 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. CONCLUSIONS AND RELEVANCE: 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.	0
Grønbæk J	Bisgaard H	Grønbæk J, Hallas HW, Arianto L, Pedersen K, Thomsen A, Chawes BL, Bisgaard H	New time-saving predictor algorithm for multiple breath washout in adolescents	2016	PEDIATR RES	27002983	2,882	3	BACKGROUND: Multiple breath washout (MBW) is an informative but time-consuming test. This study evaluates the uncertainty of a time-saving predictor algorithm in adolescents. METHODS: 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%). RESULTS: 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%. CONCLUSION: 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.	0
Stokholm J	Bisgaard H	Stokholm J, Thorsen J, Chawes BL, Schjørring S, Krogfelt KA, Bønnelykke K, Bisgaard H	Cesarean section changes neonatal gut colonization	2016	J ALLERGY CLIN IMMUN	27045582	13,081	20	BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.	0
Okbay A	Benjamin DJ	Okbay A, Beauchamp JP, Fontana MA, Lee JJ, Pers TH, Rietveld CA, Turley P, Chen GB, Emilsson V, Meddens SF, Oskarsson S, Pickrell JK, Thom K, Timshel P, de Vlaming R, Abdellaoui A, Ahluwalia TS, Bacelis J, Baumbach C, Bjornsdottir G, Brandsma JH, Pina Concas M, Derringer J, Furlotte NA, Galesloot TE, Girotto G, Gupta R, Hall LM, Harris SE, Hofer E, Horikoshi M, Huffman JE, Kaasik K, Kalafati IP, Karlsson R, Kong A, Lahti J, van der Lee SJ, deLeeuw C, Lind PA, Lindgren KO, Liu T, Mangino M, Marten J, Mihailov E, Miller MB, van der Most PJ, Oldmeadow C, Payton A, Pervjakova N, Peyrot WJ, Qian Y, Raitakari O, Rueedi R, Salvi E, Schmidt B, Schraut KE, Shi J, Smith AV, Poot RA, St Pourcain B, Teumer A, Thorleifsson G, Verweij N, Vuckovic D, Wellmann J, Westra HJ, Yang J, Zhao W, Zhu Z, Alizadeh BZ, Amin N, Bakshi A, Baumeister SE, Biino G, Bønnelykke K, Boyle PA, Campbell H, Cappuccio FP, Davies G, De Neve JE, Deloukas P, Demuth I, Ding J, Eibich P, Eisele L, Eklund N, Evans DM, Faul JD, Feitosa MF, Forstner AJ, Gandin I, Gunnarsson B, Halldórsson BV, Harris TB, Heath AC, Hocking LJ, Holliday EG, Homuth G, Horan MA, Hottenga JJ, de Jager PL, Joshi PK, Jugessur A, Kaakinen MA, Kähönen M, Kanoni S, Keltigangas-Järvinen L, Kiemeney LA, Kolcic I, Koskinen S, Kraja AT, Kroh M, Kutalik Z, Latvala A, Launer LJ, Lebreton MP, Levinson DF, Lichtenstein P, Lichtner P, Liewald DC; LifeLines Cohort Study, Loukola A, Madden PA, Mägi R, Mäki-Opas T, Marioni RE, Marques-Vidal P, Meddens GA, McMahon G, Meisinger C, Meitinger T, Milaneschi Y, Milani L, Montgomery GW, Myhre R, Nelson CP, Nyholt DR, Ollier WE, Palotie A, Paternoster L, Pedersen NL, Petrovic KE, Porteous DJ, Räikkönen K, Ring SM, Robino A, Rostapshova O, Rudan I, Rustichini A, Salomaa V, Sanders AR, Sarin AP, Schmidt H, Scott RJ, Smith BH, Smith JA, Staessen JA, Steinhagen-Thiessen E, Strauch K, Terracciano A, Tobin MD, Ulivi S, Vaccargiu S, Quaye L, van Rooij FJ, Venturini C, Vinkhuyzen AA, Völker U, Völzke H, Vonk JM, Vozzi D, Waage J, Ware EB, Willemsen G, Attia JR, Bennett DA, Berger K, Bertram L, Bisgaard H, Boomsma DI, Borecki IB, Bültmann U, Chabris CF, Cucca F, Cusi D, Deary IJ, Dedoussis GV, van Duijn CM, Eriksson JG, Franke B, Franke L, Gasparini P, Gejman PV, Gieger C, Grabe HJ, Gratten J, Groenen PJ, Gudnason V, van der Harst P, Hayward C, Hinds DA, Hoffmann W, Hyppönen E, Iacono WG, Jacobsson B, Järvelin MR, Jöckel KH, Kaprio J, Kardia SL, Lehtimäki T, Lehrer SF, Magnusson PK, Martin NG, McGue M, Metspalu A, Pendleton N, Penninx BW, Perola M, Pirastu N, Pirastu M, Polasek O, Posthuma D, Power C, Province MA, Samani NJ, Schlessinger D, Schmidt R, Sørensen TI, Spector TD, Stefansson K, Thorsteinsdottir U, Thurik AR, Timpson NJ, Tiemeier H, Tung JY, Uitterlinden AG, Vitart V, Vollenweider P, Weir DR, Wilson JF, Wright AF, Conley DC, Krueger RF, Davey Smith G, Hofman A, Laibson DI, Medland SE, Meyer MN, Yang J, Johannesson M, Visscher PM, Esko T, Koellinger PD, Cesarini D, Benjamin DJ	Genome-wide association study identifies 74 loci associated with educational attainment	2016	NATURE	27225129	40,137	143	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.	0
Jepsen A	Bisgaard H	Jepsen A, Chawes B, Carson C, Schoos AM, Thysen A, Waage J, Pedersen SB, Bisgaard H	High breast milk IL-1β level is associated with reduced risk of childhood eczema	2016	CLIN EXP ALLERGY	27251401	5,264	3	BACKGROUND: 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. OBJECTIVE: To investigate the possible association between cytokine and chemokine levels in breast milk and development of eczema and recurrent wheeze during early childhood. METHODS: Levels of 19 pro-inflammatory and immune-regulatory cytokines and chemokines were measured in 223 breast milk samples from mothers in the Copenhagen Prospective Study on Asthma in Childhood2000 high-risk birth cohort. Eczema and recurrent wheeze at age 0-3 years were prospectively diagnosed by COPSAC pediatricians adherent to predefined validated algorithms. Association analyses were performed by Cox regression adjusting for potential confounding factors and by multivariable principle component analysis. RESULTS: 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 principle component analysis confirmed that a mediator pattern dominated by high IL-1β, IL-17A, and CCL17 and low 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. CONCLUSIONS AND CLINICAL RELEVANCE: Elevated maternal breast milk IL-1β associated with decreased risk of early childhood eczema suggesting IL-1β as a proxy for a healthy maternal immune system protecting high-risk offspring from eczema, or through a direct effect on the infant. This article is protected by copyright. All rights reserved.	breastfeeding
Garn H	Renz H	Garn H, Bahn S, Baune BT, Binder EB, Bisgaard H, Chatila TA, Chavakis T, Culmsee C, Dannlowski U, Gay S, Gern J, Haahtela T, Kircher T, Müller-Ladner U, Neurath MF, Preissner KT, Reinhardt C, Rook G, Russell S, Schmeck B, Stappenbeck T, Steinhoff U, van Os J, Weiss S, Zemlin M, Renz H	Current concepts in chronic inflammatory diseases: Interactions between microbes, cellular metabolism, and inflammation	2016	J ALLERGY CLIN IMMUN	27373325	13,081	2	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.	0
Thorsteinsdottir S	Bisgaard H	Thorsteinsdottir S, Thyssen JP, Stokholm J, Vissing NH, Waage J, Bisgaard H	Domestic Dog Exposure at birth reduces the Incidence of Atopic Dermatitis	2016	ALLERGY	27385647	7,361	5	BACKGROUND: 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. OBJECTIVE: We investigated whether domestic dog exposure affected the risk of atopic dermatitis in children during the first 3 years of life. METHODS: 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 COPSAC2000, maternal specific serum IgE against 8 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. RESULTS: In 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 COPSAC2010 . The protective effect was restricted to children born by mothers with atopic disease in the unselected COPSAC2010 cohort; (adjusted HR =0.39 [0.19-0.82], p=0.01), since no effect was observed in children born by 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. CONCLUSION: 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 whether in utero exposures may affect the risk of atopic dermatitis and emphasize the importance of the early environment for disease trajectory. This article is protected by copyright. All rights reserved.	0
Bustamante M	Sunyer J	Bustamante M, Standl M, Bassat Q, Vilor-Tejedor N, Medina-Gomez C, Bonilla C, Ahluwalia TS, Bacelis J, Bradfield JP, Tiesler CM, Rivadeneira F, Ring S, Vissing NH, Fink NR, Jugessur A, Mentch FD, Ballester F, Kriebel J, Kiefte-de Jong JC, Wolsk HM, Llop S, Thiering E, Beth SA, Timpson NJ, Andersen J, Schulz H, Jaddoe VW, Evans DM, Waage J, Hakonarson H, Grant SF, Jacobsson B, Bønnelykke K, Bisgaard H, Smith GD, Moll HA, Heinrich J, Estivill X, 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	5,34	3	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 one year of age and around two 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=5,758) followed by replication (N=3,784) identified a genome-wide significant association between rs8111874 and diarrhoea at age one 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, 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.	0
Stokholm J	Bisgaard H	Stokholm J, Sevelsted A, Anderson UD, Bisgaard H	Preeclampsia Associates with Asthma, Allergy, and Eczema in Childhood	2017	AM J RESP CRIT CARE	27626972	13,204	8	Introduction 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. Methods COPSAC2000 is a high-risk birth cohort of 411 Danish children. Asthma, allergy and eczema were diagnosed prospectively, and lung function measured at age 1mo and 7yrs. Sensitization was evaluated at age 6mo, 18mo, 4yrs and 6yrs by skin prick tests and IgE measurements. The register-based cohort included 1.7 million children from Danish national registries. Children born to mothers with preeclampsia were analyzed regarding risk of asthma, allergy and eczema in the 35-year-period 1977-2012. Results COPSAC2000: 5.6% (23) was diagnosed with preeclampsia. Preeclampsia was associated with increased risk of treatment with inhaled corticosteroids at age 7yrs; adjusted Odds Ratio (aOR) 4.01 (1.11 to 14.43), p=0.0337, increased bronchial responsiveness to methacholine; adjusted β-Coefficient log-µmol -0.80 (-1.55 to -0.06), p=0.0348, and allergic rhinitis; aOR 4.83 (1.58 to 14.78), p=0.0057 in the 7-year-old children. Furthermore, the children had an increased risk of sensitization to both aero- and food-allergens, and increased amount of total-IgE during childhood. Registry-based cohort: 3.7% (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. Maternal asthma increased the risk of preeclampsia. Conclusions Preeclampsia is a shared prenatal risk factor for asthma, eczema and allergy in childhood pointing towards in-utero immune programming of the child.	0
Feng H	He K	Feng H, Xun P, Pike K, Wills AK, Chawes BL, Bisgaard H, Cai W, Wan Y, 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 IMMUN	27639938	13,081	9	BACKGROUND: Studies of the associations between in utero 25-hydroxyvitamin D [25(OH) D] exposure and childhood asthma risk, wheeze and respiratory tract infections are inconsistent and inconclusive. OBJECTIVES: To assess the associations between 25(OH) D levels in cord blood or maternal venous blood and risk of offspring's asthma, wheeze and respiratory tract infections. METHODS: Data were derived from PubMed, EMBASE, Google Scholar, references from relevant articles, and de novo results from published studies until December, 2015. Random-effects meta-analysis was conducted among 16 birth cohort studies. RESULTS: Comparing the highest to the lowest category of 25 (OH) D levels, the pooled ORs were 0.84 (95% CI, 0.70 to 1.01; P = 0.064) for asthma, 0.77 (0.58 to 1.03; P = 0.083) for wheeze, and 0.85 (0.66 to 1.09; P = 0.187) 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, 0.29 to 0.62; P < 0.001). CONCLUSIONS: 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 two recently published randomized clinical trials of vitamin D supplementation during pregnancy.	0
Horikoshi M	Freathy RM	Horikoshi M, Beaumont RN, Day FR, Warrington NM, Kooijman MN, Fernandez-Tajes J, Feenstra B, van Zuydam NR, Gaulton KJ, Grarup N, Bradfield JP, Strachan DP, Li-Gao R, Ahluwalia TS, Kreiner E, Rueedi R, Lyytikäinen LP, Cousminer DL, Wu Y, Thiering E, Wang CA, Have CT, Hottenga JJ, Vilor-Tejedor N, Joshi PK, Boh ET, Ntalla I, Pitkänen N, Mahajan A, van Leeuwen EM, Joro R, Lagou V, Nodzenski M, Diver LA, Zondervan KT, Bustamante M, Marques-Vidal P, Mercader JM, Bennett AJ, Rahmioglu N, Nyholt DR, Ma RC, Tam CH, Tam WH; CHARGE Consortium Hematology Working Group., Ganesh SK, van Rooij FJ, Jones SE, Loh PR, Ruth KS, Tuke MA, Tyrrell J, Wood AR, Yaghootkar H, Scholtens DM, Paternoster L, Prokopenko I, Kovacs P, Atalay M, Willems SM, Panoutsopoulou K, Wang X, Carstensen L, Geller F, Schraut KE, Murcia M, van Beijsterveldt CE, Willemsen G, Appel EV, Fonvig CE, Trier C, Tiesler CM, Standl M, Kutalik Z, Bonàs-Guarch S, Hougaard DM, Sánchez F, Torrents D, Waage J, Hollegaard MV, de Haan HG, Rosendaal FR, Medina-Gomez C, Ring SM, Hemani G, McMahon G, Robertson NR, Groves CJ, Langenberg C, Luan J, Scott RA, Zhao JH, Mentch FD, MacKenzie SM, Reynolds RM; Early Growth Genetics (EGG) Consortium., Lowe WL, Tönjes A, Stumvoll M, Lindi V, Lakka TA, van Duijn CM, Kiess W, Körner A, Sørensen TI, Niinikoski H, Pahkala K, Raitakari OT, Zeggini E, Dedoussis GV, Teo YY, Saw SM, Melbye M, Campbell H, Wilson JF, Vrijheid M, de Geus EJ, Boomsma DI, Kadarmideen HN, Holm JC, Hansen T, Sebert S, Hattersley AT, Beilin LJ, Newnham JP, Pennell CE, Heinrich J, Adair LS, Borja JB, Mohlke KL, Eriksson JG, Widén E, Kähönen M, Viikari JS, Lehtimäki T, Vollenweider P, Bønnelykke K, Bisgaard H, Mook-Kanamori DO, Hofman A, Rivadeneira F, Uitterlinden AG, Pisinger C, Pedersen O, Power C, Hyppönen E, Wareham NJ, Hakonarson H, Davies E, Walker BR, Jaddoe VW, Järvelin MR, Grant SF, Vaag AA, Lawlor DA, Frayling TM, Smith GD, Morris AP, Ong KK, Felix JF, Timpson NJ, Perry JR, Evans DM, McCarthy MI, Freathy RM	Genome-wide associations for birth weight and correlations with adult disease	2016	NATURE	27680694	40,137	39	Birth weight (BW) is influenced by both foetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease1. These lifecourse associations have often been attributed to the impact of an adverse early life environment. We performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where foetal genotype was associated with BW (P<5x10-8). Overall, ~15% of variance in BW could be captured by assays of foetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (rg=-0.22, P=5.5x10-13), T2D (rg=-0.27, P=1.1x10-6) and coronary artery disease (rg=-0.30, P=6.5x10-9) and, in large cohort data sets, 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=1.9x10-4). We have 15 demonstrated that lifecourse associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and have highlighted some of the pathways through which these causal genetic effects are mediated.	0
Bisgaard H	Bønnelykke K	Bisgaard H, Stokholm J, Chawes BL, Vissing NH, Bjarnadóttir E, Schoos AM, Wolsk HM, Pedersen TM, Vinding Bisgaard H, Stokholm J, Chawes BL, Vissing NH, Bjarnadóttir E, Schoos AM, Wolsk HM, Pedersen TM, Vinding RK, Thorsteinsdóttir S, Følsgaard NV, Fink NR, Thorsen J, Pedersen AG, Waage J, Rasmussen MA, Stark KD, Olsen SF, Bønnelykke K.RK, Thorsteinsdóttir S, Følsgaard N, Fink NR, Thorsen J, Pedersen AG, Waage J, Rasmussen MA, Stark KD, Olsen SF, Bønnelykke K	Fish Oil-Derived Fatty Acids in Pregnancy and Wheeze and Asthma in Offspring	2016	NEW ENGL J MED	28029926	72,406	41	Background 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. Methods 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. Results 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. Conclusions 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 .).	0
Pedersen TM	Stokholm J	Pedersen TM, Mora-Jensen AC, Waage J, Bisgaard H, Stokholm J	Incidence and Determinants of Ventilation Tubes in Denmark	2016	PLOS ONE	27875554	2,806	3	BACKGROUND AND OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.	0
Chawes B	Bisgaard H	Chawes B, Nilsson E, Nørgaard S, Dossing A, Mortensen L, 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 IMMUN	28012663	13,081	1	BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.	0
Barban N	Mills MC	Barban N, Jansen R, de Vlaming R, Vaez A, Mandemakers JJ, Tropf FC, Shen X, Wilson JF, Chasman DI, Nolte IM, Tragante V, van der Laan SW, Perry JR, Kong A; BIOS Consortium, Ahluwalia TS, Albrecht E, Yerges-Armstrong L, Atzmon G, Auro K, Ayers K, Bakshi A, Ben-Avraham D, Berger K, Bergman A, Bertram L, Bielak LF, Bjornsdottir G, Bonder MJ, Broer L, Bui M, Barbieri C, Cavadino A, Chavarro JE, Turman C, Concas MP, Cordell HJ, Davies G, Eibich P, Eriksson N, Esko T, Eriksson J, Falahi F, Felix JF, Fontana MA, Franke L, Gandin I, Gaskins AJ, Gieger C, Gunderson EP, Guo X, Hayward C, He C, Hofer E, Huang H, Joshi PK, Kanoni S, Karlsson R, Kiechl S, Kifley A, Kluttig A, Kraft P, Lagou V, Lecoeur C, Lahti J, Li-Gao R, Lind PA, Liu T, Makalic E, Mamasoula C, Matteson L, Mbarek H, McArdle PF, McMahon G, Meddens SF, Mihailov E, Miller M, Missmer SA, Monnereau C, van der Most PJ, Myhre R, Nalls MA, Nutile T, Kalafati IP, Porcu E, Prokopenko I, Rajan KB, Rich-Edwards J, Rietveld CA, Robino A, Rose LM, Rueedi R, Ryan KA, Saba Y, Schmidt D, Smith JA, Stolk L, Streeten E, Tönjes A, Thorleifsson G, Ulivi S, Wedenoja J, Wellmann J, Willeit P, Yao J, Yengo L, Zhao JH, Zhao W, Zhernakova DV, Amin N, Andrews H, Balkau B, Barzilai N, Bergmann S, Biino G, Bisgaard H, Bønnelykke K, Boomsma DI, Buring JE, Campbell H, Cappellani S, Ciullo M, Cox SR, Cucca F, Toniolo D, Davey-Smith G, Deary IJ, Dedoussis G, Deloukas P, van Duijn CM, de Geus EJ, Eriksson JG, Evans DA, Faul JD, Sala CF, Froguel P, Gasparini P, Girotto G, Grabe HJ, Greiser KH, Groenen PJ, de Haan HG, Haerting J, Harris TB, Heath AC, Heikkilä K, Hofman A, Homuth G, Holliday EG, Hopper J, Hyppönen E, Jacobsson B, Jaddoe VW, Johannesson M, Jugessur A, Kähönen M, Kajantie E, Kardia SL, Keavney B, Kolcic I, Koponen P, Kovacs P, Kronenberg F, Kutalik Z, La Bianca M, Lachance G, Iacono WG, Lai S, Lehtimäki T, Liewald DC; LifeLines Cohort Study, Lindgren CM, Liu Y, Luben R, Lucht M, Luoto R, Magnus P, Magnusson PK, Martin NG, McGue M, McQuillan R, Medland SE, Meisinger C, Mellström D, Metspalu A, Traglia M, Milani L, Mitchell P, Montgomery GW, Mook-Kanamori D, de Mutsert R, Nohr EA, Ohlsson C, Olsen J, Ong KK, Paternoster L, Pattie A, Penninx BW, Perola M, Peyser PA, Pirastu M, Polasek O, Power C, Kaprio J, Raffel LJ, Räikkönen K, Raitakari O, Ridker PM, Ring SM, Roll K, Rudan I, Ruggiero D, Rujescu D, Salomaa V, Schlessinger D, Schmidt H, Schmidt R, Schupf N, Smit J, Sorice R, Spector TD, Starr JM, Stöckl D, Strauch K, Stumvoll M, Swertz MA, Thorsteinsdottir U, Thurik AR, Timpson NJ, Tung JY, Uitterlinden AG, Vaccargiu S, Viikari J, Vitart V, Völzke H, Vollenweider P, Vuckovic D, Waage J, Wagner GG, Wang JJ, Wareham NJ, Weir DR, Willemsen G, Willeit J, Wright AF, Zondervan KT, Stefansson K, Krueger RF, Lee JJ, Benjamin DJ, Cesarini D, Koellinger PD, den Hoed M, Snieder H, Mills MC	Genome-wide analysis identifies 12 loci influencing human reproductive behavior	2016	NAT GENET	27798627	27,959	17	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.	0
Thorsen J	Waage J	Thorsen J, Brejnrod A, Mortensen M, Rasmussen MA, Stokholm J, Al-Soud WA, Sørensen S, Bisgaard H, 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	13	BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.	0
Pedersen TM	Bisgaard H	Pedersen TM, Stokholm J, Thorsen J, Mora-Jensen AC, Bisgaard H	Antibiotics in Pregnancy Increase Children's Risk of Otitis Media and Ventilation Tubes	2017	J PEDIATR	28088397	3,874	2	OBJECTIVES: 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. STUDY DESIGN: 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. RESULTS: 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. CONCLUSION: 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.	0
Chawes BL	Bisgaard H	Chawes BL, Stokholm J, Schoos AM, Rahman N, Brix S, Bisgaard H	Allergic Sensitization at School Age is a Systemic Low-grade Inflammatory Disorder	2017	ALLERGY	27992959	7,361	2	BACKGROUND: 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. METHODS: 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 6mo (N=214) and 7yrs (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 age ½, 1½, 4 and 6yrs by specific-IgE assessments and skin prick tests. Associations between inflammatory biomarkers and sensitization phenotypes were tested with logistic regression and principle component analyses (PCA). RESULTS: Adjusted for gender, recent infections and a CRP genetic risk-score, hs-CRP at 7yrs 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 univariantly associated with sensitization, but multi-parametric PCA suggested a specific inflammatory response among sensitized children. Inflammatory markers at age 6mo were not associated with subsequent development of sensitization phenotypes. CONCLUSIONS: 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. This article is protected by copyright. All rights reserved.	0
Wolsk HM	Bønnelykke K	Wolsk HM, Andersen MR, Bisgaard H, Bønnelykke K	No evidence of intrauterine sensitization against inhalant allergens	2017	J ALLERGY CLIN IMMUN	28040416	13,081	0	Specific IgE against inhalant allergens in cord blood was a very rare finding when the risk of transfer from the mother was minimized; hence, findings of such IgE should be interpreted with caution.	Atopy
Mortensen MS	Sørensen SJ	Mortensen MS, Brejnrod AD, Roggenbuck M, Abu Al-Soud W, Balle C, Krogfelt KA, Stokholm J, Thorsen J, Waage J, Rasmussen MA, Bisgaard H, Sørensen SJ	The developing hypopharyngeal microbiota in early life	2016	MICROBIOME	28038686	8,496	4	BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.	0
Kreiner E	Bønnelykke K	Kreiner E, Waage J, Standl M, Brix S, Pers TH, Couto Alves A, Warrington NM, Tiesler CM, Fuertes E, Franke L, Hirschhorn JN, James A, Simpson A, Tung JY, Koppelman GH, Postma DS, Pennell CE, Jarvelin MR, Custovic A, Timpson N, Ferreira MA, Strachan DP, Henderson J, Hinds D, Bisgaard H, Bønnelykke K	Shared genetic variants suggest common pathways in allergy and autoimmune diseases	2017	J ALLERGY CLIN IMMUN	28188724	13,081	0	BACKGROUND: The relationship between allergy and autoimmune disorders is complex and poorly understood. OBJECTIVE: To investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms. METHODS: We meta-analyzed two GWAS on self-reported allergy and sensitization comprising a total of 62,330 individuals. These results were used to calculate enrichment for SNPs previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites, and characterized commonalities in the 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 DHS data, and compared the allergy data with all known diseases. RESULTS: 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<0.05. Such enrichment seemed to be a general characteristic for all 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 autoimmune diseases, but not in other diseases. CONCLUSION: We identified shared susceptibility loci and commonalities in pathways between allergy and autoimmune diseases, suggesting shared diseases mechanisms. Further studies of these shared genetic mechanisms might help understanding the complex relationship between these diseases, including the parallel increase in disease prevalence.	0
Smith D	Stefansson K	Smith D, Helgason H, Sulem P, Bjornsdottir US, Lim AC, Sveinbjornsson G, Hasegawa H, Brown M, Ketchem RR, Gavala M, Garrett L, Jonasdottir A, Jonasdottir A, Sigurdsson A, Magnusson OT, Eyjolfsson GI, Olafsson I, Onundarson PT, Sigurdardottir O, Gislason D, Gislason T, Ludviksson BR, Ludviksottir D, Boezen HM, Heinzmann A, Krueger M, Porsbjerg C, Ahluwalia TS, Waage J, Backer V, Deichmann KA, Koppelman GH, Bønnelykke K, Bisgaard H, Masson G, Thorsteinsdottir U, Gudbjartsson DF, Johnston JA, Jonsdottir I, Stefansson K	A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma	2017	PLOS GENET	28273074	6,1	8	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%CI: 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.	0
Schoos AM	Rasmussen MA	Schoos AM, Chawes BL, Melén E, Bergström A, Kull I, Wickman M, Bønnelykke K, Bisgaard H, Rasmussen MA	Sensitization trajectories in childhood revealed by using a cluster analysis	2017	J ALLERGY CLIN IMMUN	28347735	13,081	1	BACKGROUND: Assessment of sensitization at an isolated 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. OBJECTIVE: To explore latent patterns of sensitization during the first 6 years of life and investigate whether such patterns associate to development of asthma, rhinitis, and eczema. METHODS: We investigated 398 children from the at-risk Copenhagen Prospective Studies on Asthma in Childhood 2000 birth cohort (COPSAC2000) with specific-IgE against 13 common food and inhalant allergens at ages ½, 1½, 4, and 6yrs. An unsupervised cluster analysis for three-dimensional data (NNS-PARAFAC) 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 8yrs. RESULTS: The NNS-PARAFAC analysis indicated a complex latent structure involving seven age- and allergen-specific patterns in the COPSAC2000 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 (OR=3.3 [1.5-7.2]), rhinitis with patterns 1-4 and 6 (ORs=2.2-4.3) and eczema with patterns 1-3 and 5-7 (ORs=1.6-2.5). All seven patterns were verified in the independent BAMSE cohort (R2>0.89). CONCLUSION: This study suggests the presence of specific sensitization patterns in early childhood differentially associated to development of clinical outcomes. Using such patterns in future research might provide more robust and clinically relevant results.	0
Schoos AM	Kristensen B	Schoos AM, Bønnelykke K, Chawes BL, Stokholm J, Bisgaard H, Kristensen B	Precision allergy: Separate allergies to male and female dogs	2017	J ALLERGY CLIN IMMUN PRACT	28499775	5,317	1	0	0
Skaaby T	Linneberg A	Skaaby T, Taylor AE, Jacobsen RK, Paternoster L, Thuesen BH, Ahluwalia TS, Larsen SC, Zhou A, Wong A, Gabrielsen ME, Bjørngaard JH, Flexeder C, Männistö S, Hardy R, Kuh D, Barry SJ, Tang Møllehave L, Cerqueira C, Friedrich N, Bonten TN, Noordam R, Mook-Kanamori DO, Taube C, Jessen LE, McConnachie A, Sattar N, Upton MN, McSharry C, Bønnelykke K, Bisgaard H, Schulz H, Strauch K, Meitinger T, Peters A, Grallert H, Nohr EA, 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 PR, Skorpen F, Kaprio J, R Munafò M, 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	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.	0
Medina-Gomez C	Rivadeneira F	Medina-Gomez C, Kemp JP, Dimou NL, Kreiner E, Chesi A, Zemel BS, Bønnelykke K, Boer CG, Ahluwalia TS, Bisgaard H, Evangelou E, Heppe DHM, Bonewald LF, Gorski JP, Ghanbari M, Demissie S, Duque G, Maurano MT, Kiel DP, Hsu YH, C J van der Eerden B, Ackert-Bicknell C, Reppe S, Gautvik KM, Raastad T, Karasik D, van de Peppel J, Jaddoe VWV, Uitterlinden AG, Tobias JH, Grant SFA, Bagos PG, Evans DM, Rivadeneira F	Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus	2017	NAT CUMMUN	28743860	12,124	2	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.	0
Farzan N	Maitland-van der Zee AH	Farzan N, Vijverberg SJ, Andiappan AK, Arianto L, Berce V, Blanca-López N, Bisgaard H, Bønnelykke K, Burchard EG, Campo P, Canino G, Carleton B, Celedón JC, Chew FT, Chiang WC, Cloutier MM, Daley D, Den Dekker HT, Dijk NF, Duijts L, Flores C, Forno E, Hawcutt DB, Hernandez-Pacheco N, de Jongste JC, Kabesch M, Koppelman GH, Manolopoulos VG, Melén E, Mukhopadhyay S, Nilsson S, Palmer CN, Pino-Yanes M, Pirmohamed M, Potočnki U, Raaijmakers JA, Repnik K, Schieck M, Sio YY, Smyth RL, Szalai C, Tantisira KG, Turner S, van der Schee MP, Verhamme KM, Maitland-van der Zee AH	Rationale and design of the multiethnic Pharmacogenomics in Childhood Asthma consortium	2017	PHARMACOGENOMICS	28639505	2,35	1	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. MATERIALS & METHODS: Investigators of each study participating in PiCA provided data on the study characteristics by answering an online questionnaire. RESULTS: 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. CONCLUSION: PiCA is a valuable platform to perform pharmacogenetics studies within a multiethnic pediatric asthma population.	asthma; children; consortium; genetics; pharmacogenomics; treatment
Husby A	Bønnelykke K	Husby A, Pasanen A, Waage J, Sevelsted A, Hodemaekers H, Janssen R, Karjalainen MK, Stokholm J, Chawes BL, Korppi M, Wennergren G, Heinzmann A, Bont L, Bisgaard H, Bønnelykke K	CDHR3 gene variation and childhood bronchiolitis	2017	J ALLERGY CLIN IMMUN	28782631	13,081	2	This genetic study combining data from five countries shows that the CDHR3 rs6967330 polymorphism is not associated to bronchiolitis triggered by RSV but might increase risk of bronchiolitis triggered by other infectious agents.	0
Wolsk HM	Bisgaard H	Wolsk HM, Chawes BL, Thorsen J, Stokholm J, Bønnelykke K, Brix S, Bisgaard H	Noninvasive Sampling of Mucosal Lining Fluid for the Quantification of In Vivo Upper Airway Immune-mediator Levels	2017	JOVE-J VIS EXP	28809842	1,232	0	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.	0
Vinding RK	Stokholm J	Vinding RK, Sejersen TS, Chawes BL, Bønnelykke K, Buhl T, Bisgaard H, Stokholm J	Cesarean Delivery and Body Mass Index at 6 Months and Into Childhood	2017	PEDIATRICS	28814549	5,705	0	BACKGROUND AND OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.	0
Chinnaswamy S	Kowalski ML	Chinnaswamy S, Wardzynska A, Pawelczyk M, Makowska J, Skaaby T, Mercader JM, Ahluwalia TS, Grarup N, Guindo-Martinez M, Bisgaard H, Torrents D, Linneberg A, Bønnelykke K, Kowalski ML	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	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.	0
Wolsk HM	Weiss ST	Wolsk HM, Chawes BL, Litonjua AA, Hollis BW, Waage J, Stokholm J, Bønnelykke K, Bisgaard H, Weiss ST	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	5	BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.	0
Stokholm J	Bisgaard H	Stokholm J, Chawes BL, Vissing N, Bønnelykke K, Bisgaard H	Cat exposure in early life decreases asthma risk from the 17q21 high-risk variant	2017	J ALLERGY CLIN IMMUN	29102067	13,081	0	BACKGROUND: Early-life exposure to cats and dogs has shown diverging associations with childhood asthma risk, and gene-environment interaction is one possible explanation. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.	0
Bønnelykke K	Bisgaard H	Bønnelykke K, Coleman AT, Evans MD, Thorsen J, Waage J, Vissing NH, Carlsson CJ, Stokholm J, Chawes BL, Jessen LE, Fischer TK, Bochkov YA, Ober C, Lemanske RF Jr, Jackson DJ, Gern JE, Bisgaard H	CDHR3 Genetics and Rhinovirus C Respiratory Illnesses	2018	AM J RESP CRIT CARE	29121479	13,204	1	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.	Asthma; Child; Genetics; Viral infections
Schoos AM	Chawes BL	Schoos AM, Christiansen CF, Stokholm J, Bønnelykke K, Bisgaard H, Chawes BL	FeNO and Exercise Testing in Children at Risk of Asthma	2017	J ALLERGY CLIN IMMUN	29133224	13,081	1	BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.	Asthma; Children; Exercise test; Exercise-induced bronchoconstriction; FeNO
Demenais F	Nicolae DL	Demenais F, Margaritte-Jeannin P, Barnes KC, Cookson WOC, Altmüller J, Ang W, Barr RG, Beaty TH, Becker AB, Beilby J, Bisgaard H, Bjornsdottir US, Bleecker E, Bønnelykke K, Boomsma DI, Bouzigon E, Brightling CE, Brossard M, Brusselle GG, Burchard E, Burkart KM, Bush A, Chan-Yeung M, Chung KF, Couto Alves A, Curtin JA, Custovic A, Daley D, de Jongste JC, Del-Rio-Navarro BE, Donohue KM, Duijts L, Eng C, Eriksson JG, Farrall M, Fedorova Y, Feenstra B, Ferreira MA; Australian Asthma Genetics Consortium (AAGC) collaborators, Freidin MB, Gajdos Z, Gauderman J, Gehring U, Geller F, Genuneit J, Gharib SA, Gilliland F, Granell R, Graves PE, Gudbjartsson DF, Haahtela T, Heckbert SR, Heederik D, Heinrich J, Heliövaara M, Henderson J, Himes BE, Hirose H, Hirschhorn JN, Hofman A, Holt P, Hottenga J, Hudson TJ, Hui J, Imboden M, Ivanov V, Jaddoe VWV, James A, Janson C, Jarvelin MR, Jarvis D, Jones G, Jonsdottir I, Jousilahti P, Kabesch M, Kähönen M, Kantor DB, Karunas AS, Khusnutdinova E, Koppelman GH, Kozyrskyj AL, Kreiner E, Kubo M, Kumar R, Kumar A, Kuokkanen M, Lahousse L, Laitinen T, Laprise C, Lathrop M, Lau S, Lee YA, Lehtimäki T, Letort S, Levin AM, Li G, Liang L, Loehr LR, London SJ, Loth DW, Manichaikul A, Marenholz I, Martinez FJ, Matheson MC, Mathias RA, Matsumoto K, Mbarek H, McArdle WL, Melbye M, Melén E, Meyers D, Michel S, Mohamdi H, Musk AW, Myers RA, Nieuwenhuis MAE, Noguchi E, O'Connor GT, Ogorodova LM, Palmer CD, Palotie A, Park JE, Pennell CE, Pershagen G, Polonikov A, Postma DS, Probst-Hensch N, Puzyrev VP, Raby BA, Raitakari OT, Ramasamy A, Rich SS, Robertson CF, Romieu I, Salam MT, Salomaa V, Schlünssen V, Scott R, Selivanova PA, Sigsgaard T, Simpson A, Siroux V, Smith LJ, Solodilova M, Standl M, Stefansson K, Strachan DP, Stricker BH, Takahashi A, Thompson PJ, Thorleifsson G, Thorsteinsdottir U, Tiesler CMT, Torgerson DG, Tsunoda T, Uitterlinden AG, van der Valk RJP, Vaysse A, Vedantam S, von Berg A, von Mutius E, Vonk JM, Waage J, Wareham NJ, Weiss ST, White WB, Wickman M, Widén E, Willemsen G, Williams LK, Wouters IM, Yang JJ, Zhao JH, Moffatt MF, Ober C, Nicolae DL	Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks	2018	NAT GENET	29273806	27,959	0	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.	0
Jorup C	Bisgaard H	Jorup C, Lythgoe D, Bisgaard H	Budesonide/formoterol maintenance and reliever therapy in adolescent patients with asthma	2018	EUR RESPIR J	29301922	10,569	1	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.	0
Medina-Gomez C	Rivadeneira F	Medina-Gomez C, Kemp JP, Trajanoska K, Luan J, Chesi A, Ahluwalia TS, Mook-Kanamori DO, Ham A, Hartwig FP, Evans DS, Joro R, Nedeljkovic I, Zheng HF, Zhu K, Atalay M, Liu CT, Nethander M, Broer L, Porleifsson G, Mullin BH, Handelman SK, Nalls MA, Jessen LE, Heppe DHM, Richards JB, Wang C, Chawes B, Schraut KE, Amin N, Wareham N, Karasik D, Van der Velde N, Ikram MA, Zemel BS, Zhou Y, Carlsson CJ, Liu Y, McGuigan FE, Boer CG, Bønnelykke K, Ralston SH, Robbins JA, Walsh JP, Zillikens MC, Langenberg C, Li-Gao R, Williams FMK, Harris TB, Akesson K, Jackson RD, Sigurdsson G, den Heijer M, van der Eerden BCJ, van de Peppel J, Spector TD, Pennell C, Horta BL, Felix JF, Zhao JH, Wilson SG, de Mutsert R, Bisgaard H, Styrkársdóttir U, Jaddoe VW, Orwoll E, Lakka TA, Scott R, Grant SFA, Lorentzon M, van Duijn CM, Wilson JF, Stefansson K, Psaty BM, Kiel DP, Ohlsson C, Ntzani E, van Wijnen AJ, Forgetta V, Ghanbari M, Logan JG, Williams GR, Bassett JHD, Croucher PI, Evangelou E, Uitterlinden AG, Ackert-Bicknell CL, Tobias JH, Evans DM, 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	2	0	0
Beaumont RN	Freathy RM	Beaumont RN, Warrington NM, Cavadino A, Tyrrell J, Nodzenski M, Horikoshi M, Geller F, Myhre R, Richmond RC, Paternoster L, Bradfield JP, Kreiner-Møller E, Huikari V, Metrustry S, Lunetta KL, Painter JN, Hottenga JJ, Allard C, Barton SJ, Espinosa A, Marsh JA, Potter C, Zhang G, Ang W, Berry DJ, Bouchard L, Das S; Early Growth Genetics (EGG) Consortium, Hakonarson H, Heikkinen J, Helgeland Ø, Hocher B, Hofman A, Inskip HM, Jones SE, Kogevinas M, Lind PA, Marullo L, Medland SE, Murray A, Murray JC, Njølstad PR, Nohr EA, Reichetzeder C, Ring SM, Ruth KS, Santa-Marina L, Scholtens DM, Sebert S, Sengpiel V, Tuke MA, Vaudel M, Weedon MN, Willemsen G, Wood AR, Yaghootkar H, Muglia LJ, Bartels M, Relton CL, Pennell CE, Chatzi L, Estivill X, Holloway JW, Boomsma DI, Montgomery GW, Murabito JM, Spector TD, Power C, Järvelin MR, Bisgaard H, Grant SF, Sørensen TI, Jaddoe VW, Jacobsson B, Melbye M, McCarthy MI, Hattersley AT, Hayes MG, Frayling TM, Hivert MF, Felix JF, Hyppönen E, Lowe WL Jr, Evans DM, Lawlor DA, Feenstra B, Freathy RM	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	5,34	1	0	0
Vrijlandt EJLE	Bisgaard H	Vrijlandt EJLE, El Azzi G, Vandewalker M, Rupp N, Harper T, Graham L, Szefler SJ, Moroni-Zentgraf P, Sharma A, Vulcu SD, Sigmund R, Chawes B, Engel M, 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 RESP MED	29361462	19,287	2	BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Boehringer Ingelheim.	0
Stokholm J	Bisgaard H	Stokholm J, Blaser MJ, Thorsen J, Rasmussen MA, Waage J, Vinding RK, Schoos AM, Kunøe A, Fink NR, Chawes BL, Bønnelykke K, Brejnrod AD, Mortensen MS, Al-Soud WA, Sørensen SJ, Bisgaard H	Maturation of the gut microbiome and risk of asthma in childhood	2018	NAT COMMUN	29321519	12,124	2	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.	0
Rahman Fink N	Bisgaard H	Rahman Fink N, Chawes BL, Thorsen J, Stokholm J, Krogfelt K, Schjørring S, Kragh M, Bønnelykke K, Brix S, Bisgaard H	Neonates colonized with pathogenic bacteria in the airways have a low-grade systemic inflammation	2018	ALLERGY	29672858	7,361	0	BACKGROUND AND OBJECTIVES: The development of childhood asthma is associated with neonatal colonization with pathogenic bacteria in hypopharynx. Furthermore, established asthma is associated with systemic low-grade inflammation. We here report on the association between neonatal colonization with pathogenic bacteria in hypopharynx and the development of systemic low-grade inflammation. METHODS: Bacterial colonization of the hypopharynx with M. catharralis, H. influenzae and/or S. pneumoniae was assessed in asymptomatic children from the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000 ) cohort at age 1 month by culturing technique (N=238) and by quantitative polymerase chain reaction (qPCR) technique (N=249) and in the COPSAC2010 cohort by culturing at age 1 month (N=622) and again at age 3 months (N=613). Systemic low-grade inflammation was determined in both cohorts at age 6 months by measuring plasma levels of high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α) and interleukine-6 (lL-6). RESULTS: In both cohorts, bacterial colonization was associated with increased levels of hs-CRP: COPSAC2000 , 1 month culturing (geometric mean ratio of colonized/non-colonized [95% CI]), 1.39 [0.97-2.01], p=0.08, 1 month qPCR, 1.55 [1.14-2.10], p<0.01; COPSAC2010 , 1 month, 1.52 [1.23-1.87], p<0.01, and 3 month, 1.57 [1.30-1.90], p<0.01. A multi-parametric principal component analysis incorporating hs-CRP, TNF-α and IL-6 confirmed a systemic inflammatory profile in children colonized with M. catharralis, H. influenzae and/or S. pneumoniae in the hypopharynx compared to non-colonized children (p-values<0.05). CONCLUSION: The composition of the upper airway microbiome in early life may cause systemic low-grade inflammation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.	asthma; clinical immunology; environment and hygiene hypothesis; innate immunity; pediatrics
Vissing NH	Bisgaard H	Vissing NH, Chawes BL, Rasmussen MA, Bisgaard H	Epidemiology and Risk Factors of Infection in Early Childhood	2018	PEDIATRICS	29794229	5,705	0	BACKGROUND: There is a large, unexplained variation in the frequency of childhood infections. We described incidence and risk factors of infections in early childhood. METHODS: Simple infections were captured during the first 3 years of life in the Copenhagen Prospective Studies on Asthma in Childhood 2000 birth cohort. Environmental exposures were analyzed by quasi-Poisson regression and sparse principal component analysis. RESULTS: The 334 children experienced a median of 14 (range 2-43) infectious episodes at ages 0 to 3 years. The overall rate of infections was associated with the number of children in the day care (adjusted incidence rate ratio [aIRR] 1.09 [1.2-1.16]) and the m2 per child in the day care (aIRR 0.96 [0.92-0.99]). Upper respiratory infections were also associated with the number of children in the day care (aIRR 1.11 [1.03-1.20]) and the m2 per child in the day care (aIRR 0.95 [0.91-0.99]), whereas lower respiratory infections were associated with caesarean section (aIRR 1.49 [1.12-1.99]), maternal smoking (aIRR 1.66 [1.18-2.33]), older siblings (aIRR 1.54 [1.19-2.01]), and the age at entry to day care (aIRR 0.77 [0.65-0.91]). The sparse principal component analysis revealed a risk factor profile driven by tobacco exposure, social circumstances, and domestic pets, but could only be used to explain 8.4% of the infection burden. CONCLUSIONS: Children experienced around 14 infections during the first 3 years of life, but incidences varied greatly. Environmental exposures only explained a small fraction of the variation, suggesting host factors as major determinants of infectious burden.	0
Chawes B	Bisgaard H	Chawes B, Bønnelykke K, Bisgaard H	Prenatal Vitamin D Supplementation to Improve Health in Offspring	2018	JAMA PEDIATR	29813164	10,251	0	Editorial
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