Persistent ventilation inhomogeneity after an acute exacerbation in preschool children with recurrent wheezing

Preschool children with recurrent wheezing suffer high morbidity. It is unclear whether objective measures of asthma control, such as pulmonary function tests (PFTs), provide additional information to the clinical assessment.


| INTRODUC TI ON
Asthma is the most common chronic disease in children, imposing a high burden on the health system through frequent emergency department (ED) visits, hospital admissions, and repeated treatment bursts. 1 Despite a decline in asthma hospitalization rates in children and youth by 50% over the past decade in Canada, preschoolers under the age of five continue to experience significantly higher rates of hospitalization than children over the age of 5 years. 2 Diagnosis of asthma in preschoolers is challenging, leading to delays in treatment. Yet, it is well known that 75% of all asthmatics trace their onset of wheeze to the first three years of life [3][4][5] and persistence of wheeze symptoms is the strongest preschool risk factor for asthma.
Furthermore, persistent wheezing in preschool children is associated with significant morbidity, high levels of atopy, bronchial hyper-responsiveness, and impaired lung function. 3 Preschool children suffering from recurrent wheezing exacerbations and who have persistence of symptoms suffer a significant loss of pulmonary function between preschool and mid-school age. 6,7 Few studies have examined the utility of pulmonary function test (PFT) measures for monitoring preschool children with wheezing disorders. 8,9 Spirometry-derived forced expiratory volume in one second (FEV 1 ) is the most commonly reported PFT measure in asthma. 10 Reduced FEV 1 is associated with asthma severity and predictive of exacerbations in older children and persistence of symptoms into adulthood. 11 Multiple breath washout (MBW) has gained attention due to its relative ease of use in preschool children. Lung clearance index (LCI), the primary outcome measure of MBW, provides a sensitive estimate of ventilation heterogeneity.
The clinical value of LCI in preschool children with wheezing disorders is not clearly established in the existing literature. A British cross-sectional study of preschoolers with wheeze reported that LCI was more sensitive than spirometry at detecting abnormal pulmonary function, and could differentiate between viral wheeze and multi-trigger wheeze. 8 However, a Danish cross-sectional study reported that LCI did not discriminate between preschool children in the community with wheezing symptoms and healthy controls. 9 Most recently, another Danish study suggested that preschool LCI may detect children with wheezing syndromes who experience more severe exacerbations. 12 Given the discrepancy between symptom scores and clinical outcomes and the potential role of PFTs, we designed an observational cohort study, the WheezyER study, to evaluate preschool pulmonary function changes over a 12-week period among children identified during an acute wheezing exacerbation and to evaluate its added value to clinical assessment of symptoms. Our research group has also studied changes in LCI in both healthy controls and preschool patients with cystic fibrosis (CF) to understand its role in monitoring CF lung disease. 13 We compared changes in LCI measures and FEV 0.75 z-scores (a more sensitive measure of airflow obstruction and disease control in preschool children compared to FEV 1 ) 14 to similarly timed measurements from our published healthy control data. 13

| ME THODS
The study was approved by the Hospital for Sick Children Research Ethics Board (REB 1000041089, ClinicalTrials.gov ID: NCT02743663), and informed consent was obtained from a parent or legal guardian. This was a prospective single-center observational cohort study. The primary objective was to evaluate changes in PFT outcome measures, namely FEV 0.75 z-scores and nitrogen washout-based LCI, during acute wheezing exacerbations, and to determine whether they provided additional clinical information lung clearance index (LCI) improved from 9.86 to 8.31 (P = .003); however, 46% had an LCI in the abnormal range. FEV 0.75 z-score improved from −1.66 to −1.17 (P = .05) but remained in the abnormal range in 24%. LCI was abnormal in more than half of the children with "well-controlled" asthma based on the TRACK score. There was no correlation between PFT measures and TRACK scores at either visit.

Conclusions:
Lung clearance index demonstrates a persistent deficit post-exacerbation in a large proportion of preschoolers with recurrent wheezing, highlighting that symptom scores alone may not suffice for monitoring these children.

K E Y W O R D S
asthma, lung clearance index, multiple breath washout, preschool children, pulmonary function test, symptom assessment, test for respiratory and asthma control in kids, wheeze

Key Message
Lung clearance index (LCI) revealed persistent pulmonary function abnormalities in preschool children after recovery from acute wheeze exacerbations, thus providing additional insight into preschool asthma control beyond mere symptom assessment measures. about preschool wheezing exacerbations not captured by symptom assessment alone. Please refer to Appendix S1 for a detailed account of the Methods.

| Study population
We screened 575 patients attending the ED and enrolled 100 preschool children with recurrent wheezing in our WheezyER study, 20 of whom took part in the pilot study and 80 were assigned to the final WheezyER study. Out of the 80 enrolled, symptom data were missing for six; hence, 74 (92.5%) were included in the analysis (see Figure 1 for details). The participant demographics at the first study visit are shown in Table 1.
Most children (58%, 39/67) had at least one parent with a diagnosis of asthma (Table 1). Almost 80% of the children (57/74) had a diagnosis of food allergy, allergic rhinitis, or atopic dermatitis, and more than half (40/68) had positive allergy skin tests (Table 1).
A third of the children (31%, 23/74) had an additional presentation to the ED for acute wheezing between the first and second study visits. Standard medical therapy for acute exacerbation of asthma 15 (salbutamol and ipratropium bromide) was administered to all children at the additional ED visit; furthermore, all but one child were treated with an additional course of oral corticosteroids (OCS) at the ED visit. These children had atopic characteristics similar to the rest of the preschool wheeze cohort. There were no significant differences in clinical parameters among those who had exacerbations between the two visits and those who did not (Table S1).

| TRACK score
Most children (88%, 65/74) had parent-reported TRACK scores suggestive of uncontrolled symptoms at the first study visit [mean (SD) score of 52.64 (22.10)] ( Table 2). Twelve percent (9/74) of parents reported TRACK scores in the "controlled" symptom range at their first study visit despite their child's recent visit to the ED (Table 1).
At the second study visit (12 ± 2 weeks after the ED visit), most children (66%, 49/74) had TRACK scores that remained in the uncon-

| Pulmonary function tests
The feasibility of the preschool PFTs is shown in Table 2. Feasibility was not age-dependent and was similar for spirometry and MBW at the first study visit and improved at the second study visit. Paired

Excluded 238 ineligible paƟents
• Not diagnosed with asthma -n =156 • Did not meet age criteria (3 to 6 years) -n = 6 • <2 wheezing episodes in the last year -n = 37 • Salbutamol was not administered within 4 hours before or during the ED visit or was not prescribed/administered post-discharge -n = 5 • No current wheeze -n = 2 • Born pre-term (< 35 weeks of gestaƟonal age) -n = 3 • History of renal, chronic pulmonary, cardiac, neurological, or systemic disease -n = 3 • Insufficient command of the English language -n = 1 • Met > 1 exclusion criterion -n = 25 100 paƟents enrolled in the WheezyER study 74 paƟents included in the analysis

Not included in this analysis:
• Pilot cohort -n = 20 • Missing data in reporƟng symptoms -n = 6 longitudinal measures were achieved in 50% (37/74) and 46% (34/74) of children for FEV 0.75 and LCI measures, respectively. The characteristics of this subcohort were similar to the overall cohort (Table S2).
The generalized linear mixed-effect model with repeated measure was used to compare the changes in FEV 0.75 between preschool children with wheeze and healthy controls; the difference between the two groups was statistically significant (P = .02).

| Multiple breath washout (MBW)
Lung clearance index measures improved from the first study visit to the second study visit in the 34 children with paired measures (Table 2). At the first study visit, the mean (SD) LCI was 9.86 (1.  and M 0 /M 2 ) were less sensitive to airway disease than LCI and did not add any additional information to LCI (see Appendix S1).

| TRACK score and PFT outcome measures
Lung clearance index, FEV 0.75 z-scores, and TRACK scores all improved significantly between the two visits (Table 2). However, there were no significant correlations between TRACK scores and either LCI (ρ = 0.26, P = .11) or FEV 0.75 z-score (ρ = 0.04, P = .82; Figure 2). There was also no correlation between LCI and FEV 0.75 z-scores (ρ = −0.24, P = .05). This finding is illustrated in Figure 3.
At the second study visit, 38 children had paired FEV 0.75 and LCI measurements. Twenty-one (55%) had abnormal PFT results.

| D ISCUSS I ON
This study showed that almost half of preschool children with recurrent wheezing who had parent-reported "well-controlled" asthma symptoms using the TRACK score demonstrated an abnormal LCI measure, which is consistent with existing literature. 16,17 In contrast to the literature, 9,12,18 we observed significant differences in LCI between preschool children with recurrent wheezing and healthy controls. Notably, previous studies focused on children from the general population or in asthma clinics, where the preschool wheezing phenotype may have been milder or well controlled. A recent publication, using a similar LCI methodology, supports the observation that LCI may be more discriminative in children with more severe or symptomatic disease. 12 Our population had a greater proportion of children who had received OCS or suffered from repeated exacerbations, which represents a more severe preschool wheeze phenotype. We also found an association between abnormal LCI and ED visits for an acute wheezing exacerbation in the previous 12 months, which is suggestive of a correlation with disease severity. 19 Finally, LCI was feasible in the majority (68%) of our children at the second study visit and improved with training and age, a finding previously reported in the literature. 18 Taken together, preschool LCI measurement is feasible during monitoring visits and offers complementary insights into the control of recurrent wheezing disorder in preschool children that are not available using symptom scores alone.
The management of preschool recurrent wheezing is controversial and has been the subject of four separate guidelines.
Most of the controversy surrounds the diagnosis of asthma due to the heterogeneity in wheeze phenotypes as well as response to treatment. However, despite these controversies, all guidelines consistently urge close monitoring between exacerbations. In this age-group, symptom monitoring through standardized symptom assessment is promoted. However, our study offers some insights into the limitations of this approach. We found that at their second visit, after recovery from an exacerbation, 16 Larger multicenter studies are needed to assess the role of MBW in the clinical management of preschool children with asthma.
Magnetic resonance imaging (MRI) of the lungs is a rapidly advancing imaging modality, which can provide regional functional and anatomical lung data. Recently, a number of small studies have shown correlation between quantitative and enhanced functional MRI biomarkers and MBW and spirometry abnormalities in pediatric and adult patients with CF 20,21 and adults with asthma. 22 Insight derived from the combination of these complementary multi-modality techniques is greater than the sum of individual modalities. This is an exciting avenue for future clinical trials as multi-modality biomarkers of disease will facilitate personalized precision medicine and individualized targeted therapy.
In conclusion, we have demonstrated that PFT outcomes are abnormal in a significant number of preschool children with wheezing three months post-ED visit for acute wheeze exacerbation. This indicates that symptom scores alone are insufficient for monitoring recovery from severe exacerbations in a select cohort of preschoolers with asthma, and PFT outcomes could provide additional insight into preschool asthma control beyond symptom assessment alone.
Further studies utilizing multi-modality biomarkers that characterize both the lung physiology and inflammation are necessary to improve our understanding of the heterogeneity of wheezing phenotypes in this age-group.

ACK N OWLED G M ENTS
Funding for this study was provided by the Ontario Thoracic Society, Don and Debbie Morrison, and the SickKids Foundation.

CO N FLI C T O F I NTE R E S T S
TE is involved in a sponsored trial by DBV, receives grants from Innovation Fund Denmark, and is the Co-I or scientific lead in three investigator-initiated oral immunotherapy trials supported by the Allergy and Anaphylaxis Program SickKids and serves as associate editor for Allergy and on an advisory board of ALK. The rest of the authors declare no relevant conflicts of interest associated with this publication and no financial support for the work that could have influenced its outcome.