Clinical Profile of Episodic Wheezing and Multiple Trigger Wheezing in Preschool Children: A Cross-Sectional Study

Abstract The objectives of our study were to identify the relative frequency of episodic viral wheeze (EVW) and multiple trigger wheeze (MTW) in preschool children of 1 to 5 years of age with recurrent wheezing and to compare the relevant clinical and sociodemographic parameters in the above phenotypes. This cross-sectional study included 165 children aged 1 to 5 years with recurrent wheeze. Participants were categorized into EVW and MTW based on history according to European Respiratory Society Task Force recommendations 2008. Symptom control was assessed by Global Initiative for Asthma guidelines 2015. Of the total participants, EVW was seen in 55% and MTW in 45%. Children with MTW were significantly older than those with EVW, more atopic, and had higher eosinophil counts. The dominant phenotype seen in our study was EVW. The absence of ocular/nasal allergy and exclusive breastfeeding predicted well-controlled symptoms in EVW and in all preschool wheezers, respectively.


Introduction
Preschool wheezers are twice more likely to visit hospitals and thrice more likely to be admitted compared with older children. 1 An essential requirement for better management of these children is to classify them as either episodic viral wheezers (EVWs) or multiple trigger wheezers (MTWs) based on European Respiratory Society (ERS) Task Force recommendations 2008. 2 Although these phenotypes were found by some authors to change over time, [3][4][5] a recent study by Spycher et al indicates that they remain stable. 6 A significant number of them, particularly the MTW, are likely to have symptoms consistent with asthma and reduced lung capacity later in life. 7,8 The identification of these phenotypes help in predicting long-term outcomes and also to identify high-risk children who might benefit from secondary preventive interventions. There are only few studies comparing the clinical and sociodemographic profiles of these two phenotypes and none among Indian children. Hence, this study was performed to identify the relative frequency of EVW and MTW in preschool children 1 to 5 years of age with wheezing and to compare the relevant clinical and sociodemographic parameters in the above phenotypes.
suggestive of gastroesophageal reflux disease, congenital heart disease, stridor, history suggestive of foreign body, bronchopulmonary dysplasia, bronchiectasis, immunodeficiency, and anatomic abnormalities leading to recurrent aspiration were not enrolled.
We recruited 165 children, who fulfilled the inclusion criteria during the study period (►Fig. 1). The participants were classified into EVW and MTW as per ERS Task Force guidelines 2008. Children who had history of wheezing during discrete time periods, following viral infections, with absence of wheeze between episodes were categorized as EVW. Children who had history of discrete exacerbations of wheeze and also had symptoms in between episodes of viral infections were categorized as MTW. 2 For all participants, data on rural or urban location and parental literacy were recorded. Socioeconomic status (SES) was classified based on modified Kuppuswamy scale 2014. 9 History regarding the age of onset, frequency of symptoms, bronchiolitis in the past, frequency of wheeze exacerbations, triggers, seasonality, personal and family history of atopy, exposure to environmental smoke, prematurity, low birth weight, neonatal respiratory distress, breastfeeding status, immunization status, investigation, and treatment details were noted. Weight and height were measured and classified according to the World Health Organization guidelines. 10 Symptom control was assessed based on Global Initiative for Asthma (GINA) 2015 guidelines. 11 In our study, we classified the well-controlled symptom group in GINA 2015 as "well-controlled symptom group" and the partly and uncontrolled groups together as "uncontrolled symptom group." The Institute Ethics Committee-Human Studies of our institute approved the study (JIP/IEC/2015/22/776).

Statistical Analysis
Continuous variables were expressed as median with interquartile range (IQR). Categorical variables were expressed as proportions. Mann-Whitney's U test was done for quantitative variables and chi-square test was used for categorical variables. Multiple logistic regression analysis was done for factors associated with symptom control for both EVW and MTW and also for all the participants combined. For statistical analysis, Statistical Package for the Social Sciences (SPSS) version 19 by International Business Machines (IBM) Corporation was used.

Results
The median age of the study population was 42 months with an IQR of 27.5 to 51.5. Boys were 110 (66.7%) in number; children belonging to rural areas were 98 (59.4%). Two children (1.2%) belonged to lower, 38 (23%) belonged to upper lower, 72 (43.8%) belonged to lower middle, 35 (21%) belonged to upper middle, and 18 (11%) belonged to upper socioeconomic classes. Majority were born at term (91.5%) with normal birth weight (78.1%), were exclusively breastfed (92.1%) in the first 6 months, and were completely immunized (97%) for age as per national schedule. EVW was seen in 91 (55%) and MTW in 74 (45%) children. Median age was significantly higher in the MTW group. The two groups did not significantly differ in breastfeeding status, immunization status, prematurity, low birth weight, neonatal respiratory distress, bronchiolitis in infancy, age of onset, and duration of treatment (►Table 1). The number of children on montelukast was higher in EVW group; those on inhaled corticosteroids (ICSs) were higher in MTW group and this finding was statistically significant. A significantly higher proportion of parental atopy and high absolute eosinophil count (AEC) was seen in children with MTW. Seasonality of exacerbation was present in 35 (47.3%) children with MTW. Viral infections in 67 (90.5%) children, dust allergy in 46 (62.1%) children, environmental smoke exposure in 23 (31.1%) children, and food allergens in 21 (28.3%) children were the common triggers identified in MTW group. Out of 91 children with EVW, 79 (86.8%) had well-controlled symptoms, whereas 12 (13.2%) had uncontrolled symptoms. Among the 74 MTW, 58 (78.4%) had well-controlled symptoms and 16 (21.6%) had uncontrolled symptoms. There was no significant difference in the symptom control among EVW and MTW.
On univariate analysis of factors associated with symptom control in EVW group (►Table 2), it was found that children with either parent or both graduates had a higher percentage of uncontrolled symptoms with an odds ratio (OR) of 8.5 (95% confidence interval [CI]: 2.2-32.1). Those with history of ocular/nasal allergies had more uncontrolled symptoms (OR: 12.8, 95% CI: 1.8-87.3). Other factors such as gender, SES, anthropometric parameters, prematurity, birth weight, breastfeeding, neonatal respiratory distress, bronchiolitis, environmental smoke exposure, AEC, and type and duration of treatment were not significantly associated. Among MTW (►Table 3), only exclusive breastfeeding in the first 6 months of life predicted well-controlled symptoms (OR: 6.1, 95% CI: On univariate analysis among all participants (►Table 4), wheezers with both parents being graduates had higher chance of having uncontrolled symptoms (OR: 2.5, 95% CI: 1-5.9), and so were those who had nasal/ocular allergy (OR: 2.5, 95% CI: 1-5.9) and those not exclusively breastfed (OR: 5, 95% CI: 1.5-16.4). On multiple (binomial) logistic regression

Discussion
From our study results, we find that EVW is the dominant phenotype. Children with MTW were older than EVW, were mostly on ICS, and had more parental atopy, personal atopy, and higher AEC. In the EVW group, symptoms were more likely to be significantly well controlled in the absence of ocular or nasal allergy. In preschool wheezers as a whole, exclusive breastfeeding in the first 6 months of life was associated with well-controlled symptoms.
It is generally known that the proportion of MTW increases and EVW decreases over time. 12,13 In a study involving 109 children in the age group of 2 to 6 years, Schultz et al found that 35% had EVW and 65% had MTW at baseline and 31% had EVW, 47% had MTW, and 22% had no wheeze at 1-year follow-up. 4 We did not find significant difference in the age of onset, frequency of exacerbations, or duration of treatment between EVW and MTW, but there was difference in the type of treatment, AEC, and parental    14 Significantly higher AEC and family history of atopy were seen in MTW in our study as MTW represents an atopic phenotype. 5,12,13,[15][16][17][18] On univariate analysis, we found that more children whose parents were graduates had uncontrolled symptoms. These children also had higher parental allergy and environmental smoke exposure. Previous studies have found that parental allergies were independent risk  factors for developing persistent wheeze. 19,20 It is also known that lower parental education and low SES are associated with poorer symptom control. 19,21 However, in our study, we find that parents who were graduates were a risk factor for uncontrolled symptom on univariate analysis, but it was not confirmed in multiple logistic regression indicating that the discrepancy may be probably due to confounders. We also found that EVW without ocular/nasal allergy were more likely to have well-controlled symptoms. It is a well-known fact that allergic rhinitis can have a negative effect on symptom control. 22 Although atopy is more often associated with MTW, in our study, we found they may be associated with EVW also and further serves to support the observations of the ERS Task Force statement that there may be overlap between the two phenotypes. 2 Consistent with the conclusions of previous studies, [23][24][25] we also found that exclusive breastfeeding predicted well-controlled symptoms in all preschool wheezers in general. The limitations of our study are that the sample was drawn from an asthma clinic and not from the community. It was a cross-sectional design and AEC was not available for 92 children. Information regarding breastfeeding and immunization was obtained based on history obtained from parents and information available in the case records (for immunization).

Conclusion
To conclude, EVW is the dominant wheezing phenotype found in preschool children. Children with MTW phenotype tend to be older than EVW phenotype and tend to have higher AECs. Atopy in the form of ocular and nasal allergies can also be seen in children with EVW and its absence predicts well-controlled symptoms. Exclusive breastfeeding predicts well-controlled symptoms in children with preschool wheeze in general irrespective of the phenotypes.