An innovative breath test for better care for children with asthma-like symptoms, ADEM2 (Asthma Diagnosis with Exhaled Markers)

Rationale: About 40% of all young children suffer from asthma-like symptoms,
such as wheeze, chronic cough, breathlessness, and sputum. However, the
majority (2/3 of this group) of wheezing children will not develop asthma but
has so called *transient or viral wheeze*. They will outgrow their symptoms
when they are 5-6 years and are overtreated with asthma medication. 1/3 of the
group with asthma-like symptoms really has asthma and remains to have chronic
symptoms at 5-6 years and over. Preschool children with asthma are frequently
underdiagnosed and undertreated. Currently, it is not possible to discriminate
between asthma and viral wheeze at preschool age: there is no accurate
diagnostic test available. In the ADEM1 study, we proofed the principle that an
exhaled breath test, based on exhaled inflammation markers (volatile organic
compounds, VOCs) in combination with a simple clinical index (asthma predictive
index, API) enabled a reliable asthma diagnosis in young wheezing children. In
the current ADEM2 project, we proceed with the development and application of
the breath test in wheezing preschool children. The first hypothesis of the
ADEM2 study is that an early asthma diagnosis with the breath test will improve
disease control, quality of life of children and parents, optimise treatment
and thereby improve the prognosis of wheezing children. Moreover, we
hypothesize that the use of the breath test will considerably reduce
unnecessary burden and costs of the health care system by significantly
reducing referral to secondary/tertiary care centres, diminishing use of asthma
medication in *viral wheeze* children, and by reducing loss of asthma
control/exacerbations/hospital admissions in children with asthma. Thereby, the
asthma breath-test will be a sustainable health care solution in the large
group of children with asthma-like symptoms. We used GC-MS for exhaled breath
analysis in the ADEM1 study but more simple, cheaper, and faster VOC sensing
techniques became available. Therefore, the second hypothesis is that the GC-MS
breath test can be developed into a point-of-care breath test which provides
immediate results and is affordable for both primary care and specialist care.
Our third hypothesis is that the predictive VOCs of an early diagnosis
(discovered in the ADEM1 study) point to important underlying pathogenetic
pathways of an early asthma development.

Objectives: 1) The development of an optimal point-of-care (POC) breath test
for an early asthma diagnosis in preschool wheezing children; 2) To unravel
important pathogenetic mechanisms in the early development of viral wheeze and
asthma by studying predictive VOCs and applying a multi-omics approach; 3) To
assess health gain (disease control, quality of life, reduction of
exacerbations/hospital admissions), improvement of pharmacotherapy, and
reduction in costs of care with the application of the breath test in wheezing
preschool children;

The project will consist of several work packages (WP).
WP1: Aim: To assess potential pathogenetic pathways based on discriminative
VOCs in the early development of asthma. Design: Observational study in 220
wheezing preschool children (2-3 years of age) and 100 non-wheezing preschool
children. Samples of breath (VOCs), blood (immunological markers,
gene-expression, epigenomics), and nasopharyngeal swabs (gene expression and
microbiota) and faeces (microbiota) will be assessed at 2-3 yrs and 6 yrs and
related to an algorithm based asthma diagnosis.

WP2: Aim: To assess feasibility, accuracy and reproducibility of VOC techniques
(mentioned under WP2) for an early asthma diagnosis in comparison with the gold
standard technique (GC-MS). Design: prospective 4-year observational study in
220 wheezing children. Breath samples will be collected and analysed for VOCs
with SIFT-MS, sensors, and GC-MS (gold standard) to develop a point of care
(POC) breath test. Exhaled VOCs will be related to an asthma diagnosis, based
on the algorithm diagnosis of ADEM1.

WP3: Wheezing preschool children of WP1 and WP2 will be randomised in WP3. Aim:
to assess the improvement in health gain, pharmacotherapy, and costs of care
with the application of the breath test in wheezing preschool children. Design:
Multicentre RCT in 220 wheezing preschool children during a maximum of 4 years.
Exhaled breath will be collected and analysed with the gold standard (GC-MS).
Based on the validated ADEM1 algorithm, a diagnosis of asthma or viral wheeze
will be made. Children will be randomised into an intervention group (n=110),
in which the doctors and parents will be informed about the diagnosis, or a
*usual care* (control) group (n=110), in which the diagnosis is masked for the
parents/treating doctors until the end of the trial. Children diagnosed with
asthma in the intervention group will receive medication according to the
asthma guidelines, whereas medication use and referral to a specialist can be
avoided in children with a viral wheeze diagnosis. The usual care group will be
treated according to the current clinical practice. Children will be followed
up until 6 years of age, at which age a definite diagnosis (asthma versus viral
wheeze) is made based on respiratory symptoms and extensive lung function
measurements.

In WP3, 220 children with asthma-like symptoms will be randomised in an
intervention group and an usual care group. In the intervention group at the
start of the study, the breath test will be taken in the children and the test
result (asthma or *viral wheeze*) will be given within 1 week to the parents
and the treating doctors. The breath test result will provide extra guidance to
the treating doctors: In children with asthma, asthma drugs will be prescribed
in accordance with (inter)national guidelines.In case of suboptimal asthma
control, the next level of asthma treatment will be given. Preschool children
with more severe asthma can be referred to a specialist (paediatrician or
paediatric pulmonologist). In children with a *viral wheeze* diagnosis, use of
asthma medication is allowed. However, in many viral wheeze children, asthma
medication probably is not effective. When there is no improvement in symptoms
with asthma medication (bronchodilators, inhaled corticosteroids, leukotriene
antagonists), the treating doctors will stop this medication. Treating doctors
will generally not refer children to secondary/tertiary care. Additional
examinations like allergy testing, X-rays, and cultures of sputum or
nasopharyngeal swabs are mostly not informative in these children and will be
avoided. In the usual care group, no early diagnosis of asthma/viral wheeze
will be available during the trial period. The care and treatment of these
children will be in accordance with the (inter)national guidelines (*usual care
or standard care*) and will be comparable to current clinical practice before
the introduction of the breath test. The use of asthma medication is allowed.

The collection of exhaled breath is safe and non-invasive. At preschool age
and at 6 years of age, blood and swabs will be collected, and lung function
tests will be assessed which predominantly are non-invasive too. Children in
the intervention group of the RCT will benefit from the early diagnosis
followed by better treatment. Children of the usual care group will benefit
too, but at a later phase.