Wheeze in preschool children: the predictive value of episodic viral wheeze and multiple-trigger wheeze in the development of childhood asthma.

Recurrent wheezing is common in preschool children. It shows more often a
transient course over time than it results in the more persistent pattern of
asthma in children over 6 years of age (1, 2). Based on these differences, the
common perception is that preschool wheezing disorders are a heterogeneous
group of syndromes with different pathophysiology. However, subsequent
attempts to distinguish different clinical phenotypes have had little success,
partly due to a lack of reliable data (3). In 2008, an ERS task force
recommended the use of two pragmatic clinical phenotypes based on symptom
patterns: *episodic viral wheeze* (EVW) and *multiple trigger wheeze* (MTW),
although the task force acknowledged that this recommendation was based on
little evidence and that it was likely to change when new evidence became
available (4). EVW was defined as wheeze in discrete episodes, associated with
a viral upper respiratory tract infection, whilst children were classified as
MTW when they also wheezed in response to other triggers. Although this
phenotype distinction appears straightforward, a Canadian study showed
considerable variation between physicians in the phenotype assessment of the
same patient vignettes (5). In addition, considerable within-patient phenotype
switching has been reported in two prospective cohort studies in primary and
hospital-based paediatric care, with up to 80% of phenotype changing in
children with recurrent wheeze over a period of 1 to 2 years (6, 7).
Conversely, in two large population-based birth cohort studies, Spycher et al.
recently reported a tendency of wheeze phenotypes to track in children who
continued to wheeze between the ages of 2 and 7 years (8).
These conflicting findings underscore the limited evidence base for the concept
of EVW and MTW (9).

Several predictive models have been developed in order to identify children
that are most at risk of having persistent symptoms later in life, such as the
Asthma Predictive Index (API) and Prevention and Incidence of Asthma and Mite
Allergy (PIAMA)(10, 11). Studies investigating the probability of developing
childhood asthma in the case of a MTW or EVW phenotype are rare. Van Wonderen
found that if stable, MTW in 1-3-year-olds was associated with an increased
risk of childhood asthma (7). Kappelle et al. showed a majority of children < 4
years referred with severe EVW to be diagnosed with asthma at the age of 5-10
years (12).
Viral infections appear to play an important role not only in exacerbations of
preschool wheezing, yet also in the development of childhood asthma. Rhinovirus
and respiratory syncytial virus (RSV) infections are associated with an
increased prevalence of asthma persisting into early adulthood (13, 14).
Colonizing commensal bacteria play an important role in immunity and resistance
against pathogens. Recently, it has been hypothesized that the susceptibility
to and severity of respiratory disease is influenced by the respiratory
microbiome early in life, and that microbiome composition is associated with
wheeze and asthma (15, 16). So far, little is known about the causal mechanisms
underlying the observed associations. Acquiring more insight in microbial
colonization patterns in children in relation to asthma might eventually have
diagnostic and therapeutic potential.

In the original WHEEP study, we evaluated whether EVW and MTW are clinically
distinguishable and stable phenotypes, by the use of symptom diaries, clinical
assessments and nasal samples. We performed an observational 12-month
prospective cohort study of 1- to 4-year old children with recurrent wheezing,
treated by hospital-based paediatricians. Parents were instructed to record
respiratory symptoms (cough, wheeze and dyspnoea) and symptoms of viral upper
respiratory infections (rhinorrhoea, ear- and/or throat pain and fever > 38 *C)
on a weekly basis during 12 months. At the beginning of the study period and
after 3, 6, 9 and 12 months, a scheduled clinical assessment by the patient*s
own paediatrician took place. The paediatrician was asked to classify the
child*s wheezing phenotype based on the clinical history taken during the
visit. At the last visit, paediatricians were asked to predict whether or not a
child would develop childhood asthma.
For each 3-month period ending at the date of the clinical assessment, the
diary-based phenotype was re-assessed by the researchers by evaluating the
prospectively reported symptoms, using the following definitions. A respiratory
episode was defined as reported cough, wheeze or dyspnoea (at least 2 of these)
for at least 2 consecutive days. A viral upper respiratory tract infection
(URTI) episode was defined as rhinorrhoea and/or ear-/ throat pain and/or fever
> 38 *C (at least 2 of these) during at least 2 consecutive days (17).
Symptom patterns were classified as EVW if respiratory episodes exclusively
coincided with URTI episodes; the respiratory episode had to begin at or until
2 days after the start of the URTI episode. MTW was assigned when respiratory
episodes also occurred outside URTI episodes. We compared prospectively
reported symptoms to clinical assessments by the patient*s own physician.
Also, parents were instructed by the electronic diary to take nasal swab
samples in prespecified random periods. During the study period, 503 nasal
samples were taken from 154 children: 290 samples were taken during URTI
episodes, 108 during only respiratory symptoms, and 105 in complete absence of
symptoms. semi-quantitative real-time PCR was used to detect human rhinovirus,
respiratory syncytial virus (RSV), human metapneumovirus (HMPV), influenzavirus
A and B, parainfluenzaviruses and Mycoplasma pneumoniae (18).

A total of 189 children were included. Our study showed a very weak agreement
between phenotypes derived from prospectively recorded symptoms by parents at
home, and phenotype classification by paediatricians based on parental history
taking over the same 3-month periods. Prospective symptom diaries showed
phenotype switching between periods in 32% of the study subjects. Presence of
viral DNA or RNA was found in 71% of episodes with symptoms of viral infection
and in 66% of episodes with only respiratory symptoms, compared to 38% in
completely symptom-free episodes. The poor agreement between symptom patterns
proving from symptom diaries and the pattern that the paediatrician apparently
deduces from the clinical history, the phenotype instability and the limited
relation of symptoms of viral infection to PCR positivity challenge current
paradigms on the phenotype classification of preschool wheeze.

The aim of this follow-up study is to evaluate the predictive value of the
initial phenotype (clinical as well as diary-based), the presence of stable EVW
or stable MTW (clinical as well as diary-based), the prognosis according to the
paediatrician and the occurrence of viral upper airway infections in the
development of childhood asthma.

1. Morgan WJ, Stern DA, Sherrill DL, Guerra S, Holberg CJ, Guilbert TW, et al.
Outcome of asthma and wheezing in the first 6 years of life: follow-up through
adolescence. Am J Respir Crit Care Med. 2005;172(10):1253-8.
2. Lougheed MD, Garvey N, Chapman KR, Cicutto L, Dales R, Day AG, et al. The
Ontario Asthma Regional Variation Study: emergency department visit rates and
the relation to hospitalization rates. Chest. 2006;129(4):909-17.
3. Ducharme FM, Tse SM, Chauhan B. Diagnosis, management, and prognosis of
preschool wheeze. Lancet (London, England). 2014;383(9928):1593-604.
4. Brand PL, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez JA, Custovic A,
et al. Definition, assessment and treatment of wheezing disorders in preschool
children: an evidence-based approach. The European respiratory journal.
2008;32(4):1096-110.
5. Ducharme FM, Morin J, Davis GM, Gingras J, Noya FJ. High physician adherence
to phenotype-specific asthma guidelines, but large variability in phenotype
assessment in children. Curr Med Res Opin. 2012;28(9):1561-70.
6. Schultz A, Devadason SG, Savenije OE, Sly PD, Le Souef PN, Brand PL. The
transient value of classifying preschool wheeze into episodic viral wheeze and
multiple trigger wheeze. Acta Paediatr. 2010;99(1):56-60.
7. van Wonderen KE, Geskus RB, van Aalderen WM, Mohrs J, Bindels PJ, van der
Mark LB, et al. Stability and predictiveness of multiple trigger and episodic
viral wheeze in preschoolers. 2016;46(6):837-47.
8. Spycher BD, Cochrane C, Granell R, Sterne JAC, Silverman M, Pedersen E, et
al. Temporal stability of multitrigger and episodic viral wheeze in early
childhood. The European respiratory journal. 2017;50(5).
9. Brand PL, Caudri D, Eber E, Gaillard EA, Garcia-Marcos L, Hedlin G, et al.
Classification and pharmacological treatment of preschool wheezing: changes
since 2008. The European respiratory journal. 2014;43(4):1172-7.
10. Caudri D, Wijga A, CM AS, Hoekstra M, Postma DS, Koppelman GH, et al.
Predicting the long-term prognosis of children with symptoms suggestive of
asthma at preschool age. The Journal of allergy and clinical immunology.
2009;124(5):903-10.e1-7.
11. Castro-Rodriguez JA, Holberg CJ, Wright AL, Martinez FD. A clinical index
to define risk of asthma in young children with recurrent wheezing. American
journal of respiratory and critical care medicine. 2000;162(4 Pt 1):1403-6.

12. Kappelle L, Brand PL. Severe episodic viral wheeze in preschool children:
High risk of asthma at age 5-10 years. European journal of pediatrics.
2012;171(6):947-54.
13. Sigurs N, Aljassim F, Kjellman B, Robinson PD, Sigurbergsson F, Bjarnason
R, et al. Asthma and allergy patterns over 18 years after severe RSV
bronchiolitis in the first year of life. Thorax. 2010;65(12):1045-52.
14. Rubner FJ, Jackson DJ, Evans MD, Gangnon RE, Tisler CJ, Pappas TE, et al.
Early life rhinovirus wheezing, allergic sensitization, and asthma risk at
adolescence. The Journal of allergy and clinical immunology. 2017;139(2):501-7.
15. Teo SM, Mok D, Pham K, Kusel M, Serralha M, Troy N, et al. The infant
nasopharyngeal microbiome impacts severity of lower respiratory infection and
risk of asthma development. Cell host & microbe. 2015;17(5):704-15.
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The Journal of infection. 2017;74 Suppl 1:S84-s8.
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respiratory infection on the severity and recovery from an asthma exacerbation.
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2014;8(2):243-9.

We aim to investigate the predictive value of the wheezing phenotypes EVW and
MTW at preschool age (based on prospectively reported symptoms of wheezing,
dyspnoea and cough or based on clinical assessments) and the predictive value
of viral upper respiratory infections in the development of childhood asthma.
Our hypothesis is that children with a stable MTW phenotype have an increased
risk of asthma at the age of 6-8 years compared to children with EVW. We also
expect children in whom a rhinovirus or RSV was detected to have an increased
risk of asthma.
Secondly, we wish to evaluate differences in microbiome at preschool age
between children who develop childhood asthma and children who do not. The
sensitivity and specificity of the Asthma Predictive Index (API) and the
Prevention and Incidence of Asthma and Mite Allergy risk score (PIAMA) in our
cohort will be analysed.

In the previous study, respiratory symptoms and symptoms of viral infections
were reported by parents on a weekly basis during 12 months, by the use of an
electronic diary. For each 3 month-period, the diary-based phenotype was
reassessed by evaluating the prospectively reported symptoms. Besides the
registration of symptoms of viral infections, the occurrence of viral upper
respiratory infections was investigated by the collection of nasal samples.
Semi-quantitative real-time PCR was used to detect human rhinovirus,
respiratory syncytial virus (RSV), human metapneumovirus (HMPV), influenzavirus
A and B, parainfluenzaviruses and Mycoplasma pneumoniae.
Symptom patterns were classified as EVW if respiratory episodes exclusively
coincided with viral episodes and as MTW when respiratory episodes happened
also outside viral episodes. A third category was used for 3 month-periods in
which no respiratory episodes occurred. At the beginning of the study period
and after 3, 6, 9 and 12 months, a clinical assessment by the patient*s own
pediatrician took place. The pediatrician was blinded for the content of the
electronic registration of symptoms.
The clinically assessed phenotype was compared to the diary-based
*prospectively assessed phenotype* for every 3 month-period.

Meanwhile, the children in this cohort are 6- to 8- years old. For the follow
up study, a follow-up visit will be planned for each patient. During this
visit, a pulmonary function test (FEV1, FVC, FEF75) will be performed before
and after administration of Salbutamol aerosol. as well as exhaled NO (FeNO)
will be measured. Blood testing for eosinophilia, total IgE and RAST test for
inhaled allergens will take place. A throat swab will be collected to evaluate
the microbiome. The ISAAC (International Study of Asthma and Allergies in
Childhood) standardized questionnaire on asthma will be completed. Moreover,
information on medication use, hospital admissions, courses of prednisone,
number of wheezing episodes in the past 2 years, wheezing in relation to viral
infections, other triggers and symptom-free intervals will be collected.

The burden for the patients participating in this study is judged to be
minimal. Patients and parents will have to visit the outpatient clinic only
once. The blood drawing, throat swab and pulmonary function test may cause
slight transient discomfort but do not expose the patient to relevant health
risks.