By Mathias Melgaard
Principal supervisor: Professor Klaus Bønnelykke, COPSAC
Co-supervisors: Professor Bo Chawes and Professor Jakob Stokholm, COPSAC and Professor Søren Sørensen, University of Copenhagen
Chairperson: Professor Lone Stensballe, Mary Elizabeth’s Hospital, Copenhagen University Hospital, Copenhagen, Denmark
Opponent: Professor Kohei Hasegawa, Harvard Medical School, Department of Emergency Medicine, Massachusetts General Hospital, Boston, USA
Opponent: Professor Christian Kanstrup Holm, Department of Biomedicine, Aarhus University, Aarhus, Denmark
Summary
Asthma is one of the most common chronic diseases worldwide and currently affects over 300 million
people globally. Recently, due to advances in molecular and biochemical sciences, asthma is increasingly being recognized as a range of different phenotypical diseases sharing a common trait of immune dysfunction with a clinical presentation of airway obstruction. Supporting this hypothesis,
evidence now points to asthma originating in early life when the child’s immune system is developing.
Respiratory illnesses with troublesome lung symptoms affect up to half of young children in western
countries in the first three years of life and are a well-established risk factor for later asthma.
Wheeze in particular has been a focus for numerous studies trying to determine the risk of developing
asthma later in life. In parallel, early viral respiratory infections how been suspected to play a causal
role in asthma development, particularly respiratory syncytial virus (RSV) and rhinoviruses (RV).
The emerging evidence indicates a complex interplay between viruses, host factors, and local and
systemic immunomodulation10 which raises new questions of causality and disposition. So far, only
limited data is available to assess early life immune responses in situ coupled with longitudinal follow-
up on asthma development. The overarching aim of this thesis is to help fill in some of these gaps
using non-invasive immune assessment of the upper airways and provide new insights into the origin
of asthma and the immunological processes involved.
The foundation of this thesis is two separate studies, both of which are rooted in data collected from
a large prospective mother-child cohort: the Copenhagen Prospective Studies of Asthma in Childhood
2010 (COPSAC2010). Here, 700 children were followed from birth through their first 6 years of life,
attending several pre-scheduled visits as well as ad hoc acute care visits during episodes of respiratory
illness from birth through their 3rd year of life. During ad hoc visits, a trained physician assessed
clinical symptoms and collected microbiological and immunological samples (i.e. cytokines and
chemokines) of the upper airways. In parallel, parents continuously monitored symptoms of disease
on daily diary cards, while physicians assessed asthma development at all visits. The data presented
here includes 533 total episodes of respiratory illness from a total of 294 unique children.
In study I, we set out to investigate in situ virus-specific differences in immune mediator levels of the
upper airways during episodes of respiratory illness and the association with asthma development by
age 6 years. We first demonstrated a virus-specific response characterized by upregulation of
regulatory and type 1 immune mediators, together with downregulation of type 17 and type 2
immune mediators relative to non-viral illness. We then went on to demonstrate that an aberrant
regulatory IL-10 response during episodes of viral respiratory illness was associated with asthma
development by age 6. These findings gives mechanistic clues into the pathophysiology surrounding
early life viral infections as a possible trigger for dysregulated immune modulation resulting in asthma
development and points to IL-10 as a candidate for further studies.
In study II, we investigated whether wheeze, was associated with asthma development and if it
represented a distinct immunological phenotype in response to respiratory infection. Interestingly
our data indicated that wheeze, only as a symptom of the first episode of respiratory illness, and not
wheezing in general was associated with asthma development by age 6. Sub analysis revealed that
this was mainly driven by RV associated wheeze. In parallel, we demonstrated that immune mediator
profiles of wheezing episodes did not associate with any distinct immune profile overall, whereas sub
analysis of RV-associated wheeze revealed a association to a perturbed CXCL-10 and CCL4 response.
Our findings seem to support the hypothesis suggesting that the first wheezing episode represents a
unique timeframe in which disease progression and immune modulation could be taking place. This
could be driven by a perturbed immature immune response to certain pathogens, particularly
rhinoviruses.
Collectively, our findings provide insights into the complex interplay between microbial and host
immunological factors that could set the stage for later asthma development. As such, it fills in
important gaps in current literature where very limited data is available. However, as our findings are
purely observational using post hoc analysis, future studies using a priori selected outcomes based on
