Multisystem phenotyping of severe ACUte asthma at the Paediatric Intensive Care Unit

Amongst children, asthma is the most prevalent chronic disease. It is
characterized by stable phases and exacerbations, the latter caused by numerous
triggers. Although a lot has been gained in the treatment of these
exacerbations with inhalation of steroids and bronchodilators, some patients
have exacerbations which are refractory to this standard therapy. This is seen
as severe acute asthma and for these patients intensification of treatment and
admittance to a paediatric intensive care unit (PICU) is necessary.
Unfortunately, these refractory exacerbations can progress to respiratory
insufficiency and still lead to fatalities. Worldwide, PICU admissions of
children with severe acute asthma have increased substantially, surprisingly
without an increase in prevalence of asthma, suggesting a change in phenotype.
Thus far, therapy for all children admitted to a PICU with severe acute asthma
is equal with intensification of bronchodilation (preferably intravenously) and
systemic corticosteroids. This one-size-fits-all principle does not seems right
for a heterogeneous disease such as asthma and will probably influence time to
relief of symptoms as well as length of stay. It can be expected that the
immunological basis of the asthma exacerbation differs, depending on age of the
child, the trigger of the exacerbation and genetic characteristics, thereby
influencing treatment response.
The aim of this study is to identify phenotypes of severe acute asthma in
children, using a non-invasive multisystem approach including microbiomics,
breathomics, viromics, genomics and immunological biomarkers. Identifying these
asthma profiles may lead to individualized treatment and to new targets for
novel therapies.

Despite seeing an increase in children admitted to the paediatric intensive
care unit for severe acute asthma, we still do not know what the cause of this
increase is, and we still only have few drugs we can give these children,
regardless of the age of the child and regardless of the trigger, being it a
virus, an allergen, or tobacco smoke for instance, causing the severe asthma
attack.
Childhood asthma has always been a challenging disease to phenotype, since
access to tissue and molecular systems are hampered by the often invasive
nature of the techniques necessary to obtain biological samples. Novel
techniques now give us the unique opportunity to research various tissues and
molecular systems in a non-invasive manner. Although these techniques are now
being used in a couple of studies where a multisystem approach is used to
phenotype the different forms of childhood asthma, none of these focus on the
children with severe acute asthma at the paediatric intensive care unit, a
patient group known for having the highest mortality rate.
We hypothesise that severe acute asthma at the paediatric intensive care unit
is a clinical diagnosis of a heterogeneous disease which can be characterised
by novel biomarkers identified by a non-invasive multisystem approach, leading
to personalised treatment.

The study is designed as an observational cross-sectional diagnostic
case-control study for which we use a multisystem -omics approach with easily
and non-invasive obtainable tissues and materials to phenotype children with
severe acute asthma at the PICU. We will sample 60 children with asthma
exacerbations: 30 admitted to the PICU (cases) and 30 age-matched children
admitted with asthma to a general ward (controls). Although we hypothesize that
children with severe acute asthma at the PICU present heterogeneous phenotypes
of asthma, making an observational cohort study possible, we also think these
children bear a different phenotype of asthma compared to those with asthma who
are not being admitted at the PICU. Therefore we want to add these controls to
explore differences between groups presenting with varying severities of
illness.

Apart from the blood-sampling, which only will be done when a necessary
intravenous line is being placed as a standard of care for children with a
severe acute asthma attack, all the measurements are non-invasive. There are no
risks associated with the participation in this study. Benefit for the
individual patient could be related to the recognition of a phenotype
associated with a certain response to treatment, which will enable personalized
medicine in the future. As said, since these asthma phenotypes are different in
children and adults, and severe acute asthma attacks differ from an asthma
exacerbation because the exacerbation seems refractory to treatment, it is
important to perform the study in this specific group of patients.