Received: 13 September 2018 | Accepted: 13 December 2018

DOI: 10.1002/ppul.24247

ORIGINAL ARTICLE: ASTHMA

Genetic determinants of acute asthma therapy response in

children with moderate-to-severe asthma exacerbations

Sze Man Tse MDCM, MPH1,2 | Maja Krajinovic PhD2 |

Bhupendrasinh F. Chauhan PhD3,4 | Roger Zemek MD5,6 | Jocelyn Gravel MD1,2 |
Dominic Chalut MD7 | Naveen Poonai MD8 | Caroline Quach MD, MSc2,9 |
Sophie Laberge MD, PhD1,2 | Francine M. Ducharme MD, MSc1,2,10 |
for the DOORWAY research group of the Pediatric Emergency Research in Canada
(PERC) network
1 Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada
2 Research Centre, Sainte-Justine University Health Centre, Montreal, Quebec, Canada
3 Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada
4 Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada
5 Department of Pediatrics and Emergency Medicine, University of Ottawa, Ontario, Canada
6 Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
7 Montreal Children's Hospital, McGill University Health Center, Montreal, Quebec, Canada
8 Children's Hospital, London Health Sciences Center, London, Ontario, Canada
9 Department of Microbiology, Infectious Diseases, and Immunology, University of Montreal, Montreal, Quebec, Canada
10 Department of Social and Preventive Medicine, University of Montreal, Montreal, Quebec, Canada

Correspondence
Sze Man Tse, Division of Respiratory Medicine,
Department of Pediatrics, Sainte-Justine
University Hospital Center and University of
Montreal, 3175 chemin de la Côte-Sainte-
Catherine, Montréal H3T 1C5, Quebec, Canada.
Email: sze.man.tse@umontreal.ca
Funding information
Canadian Institutes of Health Research,
Grant number: 102547
Abstract
Background: We documented inter-individual variability in the response to acute
asthma therapy in children, attributed in part to five clinical factors (oxygen
saturation, asthma severity score, virus detection, fever, symptoms between
exacerbations; DOORWAY study). The contribution of genetic determinants of
failure of acute asthma management have not been elucidated.
Objective: We aim to determine single nucleotide polymorphisms (SNP) associated
with emergency department (ED) management failure in children.
Methods: A prospective cohort of 591 Caucasian children aged 1-17 years with
moderate-to-severe asthma managed with standardized protocol were included. We
examined 53 SNPs previously associated with asthma development, phenotypes, or
bronchodilator or corticosteroids response. Associations between SNPs and
management failure (hospitalization, active asthma management ≥8 h in ED, or a
return visit within 72 h for one of two previous criteria) were examined using logistic
regression, adjusting for the five clinical predictors of management failure.
Results: Four-hundred ninety-one subjects had complete clinical data and usable
DNA samples. While controlling for clinical determinants, rs295137 in SPATS2L

Trial registration: This study is registered at Clinicaltrials.gov (NCT02013076).

Pediatric Pulmonology. 2019;1–8. wileyonlinelibrary.com/journal/ppul © 2019 Wiley Periodicals, Inc. | 1

2 | TSE ET AL.

(OR = 1.77, 95%CI: 1.17, 2.68) was significantly associated with increased odds of ED
management failure. Two SNPs in IL33 were associated with decreased odds of ED
management failure: rs7037276 (OR = 0.55, 95%CI: 0.33, 0.90), and rs1342326
(OR = 0.52, 95%CI: 0.32, 0.86). The addition of these three SNPs to the clinical
predictors significantly improved the model's predictive performance (P < 0.0004).
Conclusion: Three SNPs were significantly associated with ED management failure
in addition to clinical predictors, contributing to inter-individual variability. None
has been previously associated with treatment response to acute asthma
management.

KEYWORDS
bronchodilator, emergency department, oral corticosteroids, pharmacogenetics, treatment
response

1 | INTRODUCTIO N explored genetic determinants of acute treatment response. We

Asthma is a chronic inflammatory airway disease affecting as many
as 334 million people worldwide.1 The prevalence of childhood
2 3
asthma is approximately 10% in the United States and Canada,
making it the most common chronic disease in childhood. Asthma-
related hospitalizations account for nearly 33% of national pediatric
asthma cost.4
The mainstay of evidence-based acute asthma management
consists of oral corticosteroids (OCS) and severity-specific bronchodi-
lator therapy,5,6 and prompt initiation of therapy significantly
decreases hospitalization rates in children with moderate-to-severe
asthma presenting to the emergency department (ED).7,8 Yet,
significant inter-individual variability exists in the response to acute
asthma therapy, with up to 19% of children requiring hospitalization
due to ED management failure.9–11 Furthermore, a trial has challenged
the effectiveness of OCS in preschool children presenting with mild-
to-moderate viral-induced wheezing,12 suggesting that age or viral
trigger might be at cause.
To address this variability in acute management response, we
conducted the Determinants of Oral corticosteroid Responsiveness in
Wheezing Asthmatic Youth (DOORWAY) cohort study to identify
determinants of ED management failure, a surrogate measure for
response to oral corticosteroid and bronchodilators.13 This prospec-
tive cohort study enrolled 1012 children presenting to the ED with
moderate-to-severe asthma exacerbations. We identified five signifi-
cant clinical predictors of ED management failure: viral detection,
fever, having a higher baseline Pediatric Respiratory Assessment
Measure (PRAM) score (ie, more severe exacerbation), oxygen
saturation <92%, and symptoms between exacerbations.13
As several studies have previously identified genetic polymor-
phisms associated with inter-individual variability in bronchodilator
14,15
and inhaled corticosteroids response, it is reasonable to
assume that there might also be genetic determinants of the
response to acute asthma pharmacotherapy. To date, no study has
sought to identify the genetic determinants of ED management
failure in the DOORWAY study using a candidate gene approach,
examining the association between 53 single nucleotide polymor-
phisms (SNPs) that have been previously associated with asthma or
asthma pharmacotherapy response and the outcome of acute
asthma management in the ED.
2 | MATERIALS AND METH ODS
2.1 | Design
This was a multicenter prospective cohort study with the primary
objective of identifying clinical factors associated with ED manage-
ment failure of children presenting with moderate-to-severe asthma at
one of five Canadian EDs (Children's Hospital of Eastern Ontario,
Centre Hospitalier Universitaire Sainte-Justine, McGill University
Health Centre, London Health Sciences Centre, Centre Hospitalier
Universitaire de Laval).13 A pre-specified secondary objective of the
study was to explore associations between genetic polymorphisms and
ED management failure. This study was approved by local institutional
review boards. Informed consent for the study and specifically for
genetic analyses was obtained from parents and informed assent was
obtained from participants when appropriate.
2.2 | Subjects
Subject eligibility criteria have been reported previously.16 DOOR-
WAY enrolled 1012 children aged 1-17 years with asthma, defined
as (i) prior physician-diagnosed asthma; (ii) prior documented
episode of wheezing, cough, or dyspnea with significant response
to inhaled β2-agonists or oral corticosteroids; (iii) in children <2 years
of age, ≥3 episodes of wheezing, cough, or dyspnea; or (iv) previous
lung function tests showing significant reversibility after bronchodi-
lator administration or significant airway hyperresponsiveness on a
TSE ET AL..
provocation test. Between February 2011 and December 2013,
children were invited to participate in the study if they presented to
the ED with a moderate or severe asthma exacerbation, defined as
wheeze, cough, or dyspnea, and a PRAM score of >3.17 The PRAM is
a 12-point (0 best, 12 worst) validated clinical measure of asthma
exacerbation severity based on oxygen saturation, suprasternal
retractions, air entry, wheezing, and scalene retraction in children
1-17 years.17 For the current study, we restricted the analyses to the
Caucasian children, given the potential issue of population stratifi-
cation in genetic analyses (ie, the systematic difference in allele
frequencies between subpopulations of different ancestries), and to
those with data on the five clinical variables found to be associated
with ED management failure.
2.3 | Acute treatment protocol
All subjects were treated according to a standardized severity-specific
6
protocol, as per pediatric international guidelines. This included
2 mg/kg (maximum 50 mg) of oral prednisolone or prednisone within
60 min of triage, and inhaled salbutamol with or without concomitant
inhaled ipratropium bromide depending on the asthma severity
(Supplementary Table S1).
2.4 | Assessment of ED management failure
The primary outcome was failure of ED management, defined as: (i) an
asthma-related hospitalization; (ii) an ED stay for active management
of asthma ≥8 h after OCS intake; or (iii) a return visit within 72 h,
meeting one of the two previous criteria. While the need for hospital
5,6
admission is influenced by multiple factors, such as response to
pharmacotherapy, parental anxiety and fatigue, and availability of
hospital beds, we created this composite outcome because of its high
clinical relevance for physicians and its impact on families.
2.5 | Genotyping
DNA was extracted from saliva collected through expectoration or
16
buccal swabs. Based on a literature review at the time of the study
design in 2009 and an updated review in 2015, we selected 53
candidate SNPs in 40 genes that have been previously associated
with asthma development or phenotypes, or responses to inhaled
corticosteroids or bronchodilators (Supplementary Table S2). These
SNPs were genotyped using Sequenom genotyping platform at the
McGill University and Génome Quebec Innovation Center or by
allele-specific oligonucleotides hybridization as described previ-
18 19
ously. GSTM1 null allele was detected by gel electrophoresis. All
SNPs had a completion rate of ≥90% and a minor allele frequency
(MAF) of >0.05.
2.6 | Statistical analysis
We evaluated the association between each of the 53 SNPs and ED
management failure using multivariate logistic regression, while
| 3
adjusting for the five significant clinical determinants of ED failure
(symptoms between episodes of asthma exacerbations, high PRAM
score, oxygen saturation <92% upon ED presentation, fever, and viral
detection for 23 common respiratory viruses during the acute
exacerbation13) and study site. We used an additive genetic model
for all SNPs. SNPs with a P-value <0.1 on the initial logistic regression
were included in a final backward multivariate stepwise logistic
regression, adjusting for the clinical determinants, and study site. Given
that no study previously reported on the genetic association with acute
asthma management outcome, we chose a stepwise regression
approach to select the SNPs that account the most for the outcome.
SNPs were considered to be significantly associated with ED
management failure if they have a nominal P-value of <0.05 in the
final model. Several methods were used to assess the validity and
robustness of our findings: (i) the goodness of fit of the model including
genetic and clinical determinants was evaluated using the Hosmer-
Lemeshow test; (ii) the final model was validated using bootstrapping
methods with 10,000 bootstrap replicates; and (iii) given the possibility
of misclassification of asthma diagnosis in preschool-aged children, a
post hoc subgroup analysis of the final model was performed in
children aged 6 years and older. Although the SNPs were identified a
priori, we conservatively applied the Benjamini-Hochberg false
discovery rate (FDR) method to account for multiple testing in a
sensitivity analysis.
A post hoc joint analysis of the three SNPs in the final model was
performed using a genetic score, defined as the number of risk alleles
(ie, alleles that conferred a risk of ED management failure). If a minor
allele was protective of the outcome, the major allele was considered
the risk allele. The effect of the genetic score on ED management
failure was evaluated using logistic regression, adjusting for the same
clinical variables and study site. Finally, receiver operating character-
istic curves were fitted for both models. The area under the curves
(AUC) of the two models were compared using DeLong's test.20
Analyses were performed in R (version 3.2.1, www.r-project.org).
3 | RESULTS
Of the 591 Caucasian subjects enrolled, 491 (83.1%) were included
and had complete clinical information and usable DNA samples
(Supplementary Figure S1 for flow of patients). The characteristics of
the 491 Caucasians participating in this analysis were similar to the 100
subjects who were not analyzed (Supplementary Table S3). Among
participants, most (73.7%) were preschoolers (<6 years of age), male
(64.6%), had episodic asthma (77.0%), and a virus detected (61.3%)
(Table 1). The median PRAM score was 6, consistent with a moderate
asthma exacerbation. Failure of ED management occurred in 89
(18.1%) children.
3.1 | Genetic predictors of ED management failure
The initial multivariate analyses, each including one of the 53 candidate
SNPs in a model while adjusting for the five aforementioned clinical
4 | TSE ET AL.

TABLE 1 Baseline characteristics of the 491 Caucasians in determinants of ED management failure and study site, revealed five
DOORWAY included in this analysis SNPs with a P-value <0.10 (Table S-2). Following the stepwise
Characteristics n = 491 regression of these five SNPs, three SNPs were included in the final
Age in years, mean (SD) 4.4 (3.8) multivariate model with a P-value <0.05 (Table 2), along with the
Age categories, n (%) clinical predictors of ED management failure and site. Rs295137 in the

<6 years 362 (73.7)

Spermatogenesis Associated Serine Rich 2 Like (SPATS2L) gene was
associated with a 77% increased odds of ED management failure
6-11 years 92 (18.7)
(MAF = 39.9%). Rs7037276 (MAF = 7.1%) and rs1342326
12-17 years 36 (7.3)
(MAF = 23.5%), both in the interleukin-33 (IL33) gene, reduced by
Male, n (%) 317 (64.6)
half the odds of ED management failure. Figure 1 shows the
Asthma phenotype, n (%) percentages of ED management failure by genotype for each of the
No symptoms between episodes 378 (77.0) three SNPs. These associations between the three SNPs and ED
Symptoms between episodes 113 (23.0) management failure were robust and remained unchanged after
PRAM upon presentation to ED, median(IQR) 6 (5,7) validation by bootstrapping (Supplementary Table S4). The Hosmer-
Oxygen saturation upon presentation to ED, n (%) Lemeshow test indicate that models fitted the data appropriately
(P = 0.85 for the clinical model and P = 0.85 for the clinical and genetic
≥95% 342 (70.0)
model).
92-94% 123 (25.1)
The predictive value of the final multivariate model, which
<92% 26 (5.3)
included the three SNPs and five clinical predictors, was
Presence of fever upon presentation to ED, n (%) 148 (30.1)
significantly better than the original model including only clinical
Detection of a virus, n (%) 301 (61.3) predictors (AUC 0.82 vs 0.79, respectively, P = 0.0004, Figure 2).
Salivary cotinine, n (%) Compared to the original model with clinical predictors only, four
<1 ng/mL − no environmental tobacco smoke 333 (67.8) of the five clinical predictors remained significantly associated with
exposure ED management outcome in the combined model. The persistence
≥1 to <4 ng/mL − undetermined exposure 119 (24.2) of symptoms between episodes was no longer significant once
≥4 ng/mL − meaningful exposure 39 (7.9) genetic determinants were added, although its effect size remained
Failure of ED management, n (%) 89 (18.1) similar (Table 2).
When the model was repeated in the subgroup analysis of
ED = emergency department; PRAM = pediatric respiratory assessment
children aged 6 years and older (n = 128, 26% of the original cohort
measure; SD = standard deviation.
of 491 children), we replicated the effect of rs1342326 on ED
management failure. While the associations for rs295137 and

TABLE 2 Final model describing the genetic and clinical predictors of ED management failure, compared to original model including clinical
predictors only
Genetic and clinical model Original clinical model

Adjusted ORa (95%CI) P Adjusted ORb (95%CI) P

rs295137 (SPATS2L) 1.77 (1.17, 2.68) 0.006 − −
rs7037276 (IL33) 0.55 (0.33, 0.90) 0.02 − −
rs1342326 (IL33) 0.52 (0.32, 0.86) 0.01 − −
Symptoms between episodes 1.22 (0.62, 2.38) 0.56 1.73 (1.13, 2.64) 0.01
PRAM score at baseline, per 1 point increase 1.36 (1.14, 1.63) 0.0007 1.38 (1.22, 1.56) <0.0001
Oxygen saturation at baseline, vs ≥95%
92-94% 2.40 (1.21, 4.79) 0.01 1.50 (0.94, 2.38) 0.09
<92% 10.08 (3.16, 32.15) <0.0001 3.94 (1.97, 7.89) 0.0001
Presence of fever at baseline 3.44 (1.89, 6.28) <0.0001 1.96 (1.32, 2.92) 0.0009
Detection of virus 1.99 (1.04, 3.82) 0.04 1.57 (1.04, 2.37) 0.03

CI = confidence interval; ED = emergency department; OR = Odds ratio; PRAM = pediatric respiratory assessment measure.
a
Adjusted odds ratio derived from the multivariate stepwise logistic regression model including all 5 original clinical variables and three SNPs, adjusting for
study site.
b
Adjusted odds ratio for the original model including all 5 clinical variables, adjusting for study site.
TSE ET AL..
| 5

FIGURE 2 Comparison of the areas under the curve (AUC)

between (i) the model with only clinical determinants of ED
management failure (dotted line, AUC = 0.79); and (ii) the model
with genetic and clinical determinants of ED management failure
(solid line, AUC = 0.82), P = 0.0004

significant association between three candidate SNPs and ED

management outcome: two significantly decreasing and one increasing
the risk of failure. Our findings provide insight on the genetic
determinants contributing to the inter-individual variability in acute
asthma management outcomes.
We identified two SNPs in IL33, which were not in significant
linkage disequilibrium, that were protective of ED management

FIGURE 1 Percentage of ED management failure by genotype

for (A) rs295137; (B) rs7037276; (C) rs1342326

rs7037276 with ED management failure were not statistically

significant, the effect sizes (odds ratios) were similar (Supplementary
Table S5).
In the sensitivity analysis on the main cohort, where these three
SNPs were re-examined with the FDR correction, none of the three
SNPs achieved a P < 0.05. However, the aggregate effect of these
three SNPs, represented by the total number of risk alleles for an
individual, on ED management failure was statistically significant
(OR = 1.83 per risk allele, 95%CI: 1.36, 2.45, P < 0.0001; Figure 3). A
total of 30, 230, and 149 subjects had 0-2, 3-4, and 5-6 risk alleles, FIGURE 3 Frequency of ED management failure by number of
risk alleles. A risk allele is defined as the allele that confers risk for
respectively.
ED management failure in this study. The sum of the risk alleles is
calculated from the 3 SNPs associated ED management outcome
(rs295137, rs7037276, and rs1342326; range from 0 to 6 risk
4 | DIS CUS SI ON
alleles). The number of risk alleles was significantly associated with
ED management failure (OR = 1.83, 95%CI 1.36, 2.45; P < 0.0001).
Using a large prospective cohort of children presenting to the ED with The horizontal line indicates the percentage of ED management
an acute moderate or severe asthma exacerbation, we found a failure in the entire study cohort (18.1%)
6 |
failure. Previous studies have not yet reported on the role of IL33 in
response to asthma therapy; however, its central role in inflamma-
tion in patients with allergic diseases21,22 is consistent with our
findings. In a longitudinal study of over 2000 children, rs7037276
and rs1342326 have also been associated with intermediate-onset
23
asthma and persistent asthma, respectively. Recently, a loss-of-
function mutation in IL33 was discovered, which was associated with
decreased blood eosinophils and protected against asthma.24 In fact,
given the importance of IL33 in atopic conditions, it is currently
being investigated as a therapeutic target in the treatment of atopic
diseases.25 Clearly, the functional effect of these SNPs remains to
established to provide better insight in the role of these
polymorphisms in the inflammatory cascade. Our observation that
IL33 polymorphisms modulates asthma treatment response is novel
and lends support to ongoing study efforts to clarify its role.
Only one previous genome-wide association study has identified
an association between rs295137 in SPATS2L and bronchodilator
26
response (BDR). In contrast to our findings, in non-Hispanic white
subjects, the TT genotype was associated with increased BDR with a
median of 16% increase in forced expiratory volume in 1 s compared
to 11% for the CC or CT genotypes. Functional work involving
knockdown of the SPATS2L mRNA resulted in increased β2-
adrenergic receptor protein levels, but little remains known about
the biological role of SPATS2L. Interestingly, our results demonstrate
that the minor allele T was associated with increased odds of ED
management failure. Several differences in study design could
account for the seemingly discrepant results. First, our population
was purely pediatric while the previous study included mostly adult
patients. Because the clinically important threshold for BDR in
27,28
children may be lower than the traditionally used 12%, the
difference in BDR between the genotypes may not be as clinically
important in children. Second, we assessed an outcome that reflects
response to both bronchodilators and systemic corticosteroids,
26
while assessed an isolated response to bronchodilator in the non-
acute setting. Thus, while SPATS2L seems to play a role in asthma
management response, more studies are warranted to replicate our
findings. Collectively, these findings suggests that SPATS2L is
associated with response to bronchodilators, perhaps in the
presence of oral corticosteroids during acute pediatric asthma
exacerbations.
In our population, the odds of ED management failure was
positively associated with the number of risk alleles in these three
significant SNPs. Most genetic studies in asthma have focused on the
individual effect of a SNP on asthma-related outcomes.29–31 However,
the effect size of individual SNPs is often small and thus very large
sample sizes are required to detect such effect. Our findings support
the value of simultaneously exploring the effect of several risk alleles in
prediction models, as this approach provided evidence that individual
SNPs make additive contributions to the risk of ED management
failure.
We evaluated whether a predictive model that includes genetic
polymorphisms in addition to clinical variables would perform better
than one that includes only clinical factors at predicting ED
TSE ET AL.
management failure. While the combined genetic and clinical model
was statistically better than the clinical model, the difference in the
AUC between the two models was modest and its clinical
significance is unclear. Thus, the combined model needs to be
tested in a separate cohort of patients in order to determine its
sensitivity and specificity.
Interestingly, the addition of the genetic determinants did not
alter the statistical association between four of the five clinical
predictors of ED management outcome, and while the persistence of
asthma symptoms was no longer a statistically significant predictor
upon the inclusion of genetic determinants, its effect size remained
similar. A complimentary analysis showed no significant association
between the three candidate SNPs and the clinical variables (data
not shown). Thus, these findings supports the independent effect of
the three candidate SNPs and the measured clinical determinants on
the outcome.
There are noteworthy strengths and limitations to our study.
First, the addition of genetic determinants to previously estab-
lished key clinical predictors not only enabled the identification of
the independent contribution of genetic factors, but also more
accurate quantification of their effect on the treatment response.
Indeed, prior genetic studies have seldom controlled for concomi-
tant clinical factors in their statistical model, even though the
combination of clinical and genetic factors should reflect more
closely the anticipated host-environment interaction occurring in
real-life. Second, our study included a wide age range of children
with asthma, maximizing the generalizability of our findings to
different age groups. However, we acknowledge the potential for
misclassification given that diagnosing asthma in preschool-aged
children may sometimes be difficult. In our subgroup analysis of
children aged 6 years and older, we found similar effect sizes of the
three identified SNPs on ED management failure. This suggests
that misclassification was likely minimal, supporting the robustness
of our original findings. Third, we used a clinically important
composite outcome of ED management outcome. However, given
the nature of the outcome, we were unable to distinguish whether
the SNPs modulate the pharmacological response to acute therapy
(bronchodilator, anticholinergics, systemic corticosteroids) or
whether they influence ED management outcome via an unmea-
sured clinical parameter. While the composite outcome of ED
management failure is novel in genetic studies and does not allow
for the exploration of specific biologic pathways, it is a pragmatic
outcome associated with substantial health burden and a direct
impact on children, their families, and the health care system.
Fourth, while we restricted our study population to Caucasians and
our findings may not be generalizable to other ethnicities, we
nonetheless had a large cohort of well-phenotyped children.
Furthermore, the selection of children with moderate-to-severe
asthma and use of standardized severity-specific treatment
protocol across the participating sites minimized treatment
heterogeneity. Finally, although we had a priori specified the 53
SNPs for our analysis, we acknowledge that this list may not be
exhaustive and that our results may be limited by multiple testing.
TSE ET AL..
Thus, we suggest that these findings be considered as hypothesis-
generating and we call for additional studies to confirm our
observations.
In conclusion, we identified one SNP in SPATS2L and two
SNPs in IL33 that are associated with significantly higher and
lower odds of ED management failure in children presenting with
a moderate-to-severe asthma exacerbation, respectively. While
the exact roles of these SNPs need to be validated in prospective
or functional studies, our findings would support their role in the
modulation of treatment response to acute care in children with
asthma.
ACKNOWLEDGMENTS
This project (#210272) was funded by a grant awarded through a
peer-review process by the Canadian Institutes of Health Research,
Canada under the title “Determinants Of Oral corticosteroid
Responsiveness in Wheezing Asthmatic Youth (DOORWAY).” We
acknowledge the support of the Fonds de la Recherche en Santé du
Québec for the infrastructure support provided to the Research
Institutes of the Centre Hospitalier Universitaire Sainte-Justine
(CHUSJ), the McGill University Health Centre (MUHC), and the
Centre Hospitalier Universitaire de Laval (CHUL). Additional
funding to complete the genetic analysis was provided by the
Academic Chair in Clinical Research and Knowledge Transfer in
Paediatric Asthma. We thank parents of children enrolled in this
study, Marica Reise-Filteau and Vincent Gagné for DNA extraction
and genotyping, and Génome Québec for their genotyping
services. This project is funded by a grant awarded through a
peer-review process by the Canadian Institutes of Health Research
(Fund #102547).
CONFLICTS OF INTEREST
The authors have no conflicts of interest to declare.
ORCID
Sze Man Tse http://orcid.org/0000-0002-0295-0064
REFERENCES
1. Global Asthma Network. 2017 July 4. The Global Asthma Report
2014. Available at: http://www.globalasthmareport.org/burden/
burden.php. Accessed 2017 July 4.
2. Moorman JE, Akinbami LJ, Bailey CM, Zahran HS, King ME, Johnson
CA, Liu X. National surveillance of asthma: United States, 2001-2010.
Vital Health Stat 3. 2012;1–67.
3. Statistics Canada. 2014 September 9. Asthma, by age group and sex
Statistics Canada. Available at: http://www.statcan.gc.ca/tables-
tableaux/sum-som/l01/cst01/health49b-eng.htm. Accessed 2014
September 9.
4. Kamble S, Bharmal M. Incremental direct expenditure of treating
asthma in the United States. J Asthma. 2009;46:73–80.
| 7
5. Ortiz-Alvarez O, Mikrogianakis A. Canadian Paediatric Society ACC.
Managing the paediatric patient with an acute asthma exacerbation.
Paediatr Child Health. 2012;17:251–262.
6. Global Initiative for Asthma. Global Strategy for Asthma Management
and Prevention (2018 update). 2018.
7. Rowe BH, Spooner C, Ducharme FM, Bretzlaff JA, Bota GW. Early
emergency department treatment of acute asthma with systemic
corticosteroids. Cochrane Database Syst Rev. 2001;CD002178.
8. Bhogal SK, McGillivray D, Bourbeau J, Benedetti A, Bartlett S,
Ducharme FM. Early administration of systemic corticosteroids
reduces hospital admission rates for children with moderate and
severe asthma exacerbation. Ann Emerg Med. 2012;60:84–91e3.
9. Lougheed MD, Garvey N, Chapman KR, et al. Variations and gaps in
management of acute asthma in Ontario emergency departments.
Chest. 2009;135:724–736.
10. Lougheed MD, Garvey N, Chapman KR, et al. The Ontario Asthma
Regional Variation Study: emergency department visit rates and the
relation to hospitalization rates. Chest. 2006;129:909–917.
11. Buyuktiryaki AB, Civelek E, Can D, et al. Predicting hospitalization in
children with acute asthma. J Emerg Med. 2013;44:919–927.
12. Panickar J, Lakhanpaul M, Lambert PC, et al. Oral prednisolone for
preschool children with acute virus-induced wheezing. N Engl J Med.
2009;360:329–338.
13. Ducharme FM, Zemek R, Chauhan BF, et al. Factors associated with
failure of emergency department management in children with acute
moderate or severe asthma: a prospective, multicentre, cohort study.
Lancet Respir Med. 2016;4:990–998.
14. Tse SM, Tantisira K, Weiss ST. The pharmacogenetics and pharmaco-
genomics of asthma therapy. Pharmacogenomics J. 2011;11:383–392.
15. Davis JS, Weiss ST, Tantisira KG. Asthma pharmacogenomics: 2015
update. Curr Allergy Asthma Rep. 2015;15:42.
16. Ducharme FM, Zemek R, Gravel J, et al. Determinants Of Oral
corticosteroid Responsiveness in Wheezing Asthmatic Youth (DOOR-
WAY): protocol for a prospective multicentre cohort study of children
with acute moderate-to-severe asthma exacerbations. BMJ Open.
2014;4:e004699.
17. Ducharme FM, Chalut D, Plotnick L, et al. The Pediatric Respiratory
Assessment Measure: a valid clinical score for assessing acute asthma
severity from toddlers to teenagers. J Pediatr. 2008;152:476–480, 480 e1.
18. Bourgeois S, Labuda D. Dynamic allele-specific oligonucleotide
hybridization on solid support. Anal Biochem. 2004;324:309–311.
19. Zhong S, Wyllie AH, Barnes D, Wolf CR, Spurr NK. Relationship
between the GSTM1 genetic polymorphism and susceptibility to
bladder, breast and colon cancer. Carcinogenesis 1993;14:1821–1824.
20. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas
under two or more correlated receiver operating characteristic curves:
a nonparametric approach. Biometrics. 1988;44:837–845.
21. Chu DK, Llop-Guevara A, Walker TD, et al. IL-33, but not thymic
stromal lymphopoietin or IL-25, is central to mite and peanut allergic
sensitization. J Allergy Clin Immunol. 2013;131:187–200, e1-8.
22. Porsbjerg C, Baines K, Gibson P, et al. IL-33 is related to innate immune
activation and sensitization to HDM in mild steroid-free asthma. Clin
Exp Allergy. 2016;46:564–574.
23. Savenije OE, Mahachie John JM, Granell R, et al. Association of IL33-
IL-1 receptor-like 1 (IL1RL1) pathway polymorphisms with wheezing
phenotypes and asthma in childhood. J Allergy Clin Immunol.
2014;134:170–177.
24. Smith D, Helgason H, Sulem P, et al. A rare IL33 loss-of-function
mutation reduces blood eosinophil counts and protects from asthma.
PLoS Genet. 2017;13:e1006659.
25. June 20. Placebo-Controlled Study to Investigate ANB020 Activity in
Adult Patients With Peanut Allergy. Available at: https://clinicaltrials.
gov/ct2/show/NCT02920021. Accessed 2017 June 20.
26. Himes BE, Jiang X, Hu R, et al. Genome-wide association analysis in
asthma subjects identifies SPATS2L as a novel bronchodilator response
gene. PLoS Genet. 2012;8:e1002824.
8 | TSE ET AL.

27. Tse SM, Gold DR, Sordillo JE, et al. Diagnostic accuracy of the SUPPORTING INFORMATION
bronchodilator response in children. J Allergy Clin Immunol.
2013;132:554–559 e5. Additional supporting information may be found online in the
28. Dundas I, Chan EY, Bridge PD, McKenzie SA. Diagnostic accuracy of Supporting Information section at the end of the article.
bronchodilator responsiveness in wheezy children. Thorax.
2005;60:13–16.
29. Vonk JM, Nieuwenhuis MAE, Dijk FN, et al. Novel genes and insights in
complete asthma remission: a genome-wide association study on
clinical and complete asthma remission. Clin Exp Allergy. How to cite this article: Tse SM, Krajinovic M, Chauhan BF,
2018;48:1286–1296. et al. Genetic determinants of acute asthma therapy
30. Sarnowski C, Sugier PE, Granell R, et al. Identification of a new locus at response in children with moderate-to-severe asthma
16q12 associated with time to asthma onset. J Allergy Clin Immunol.
exacerbations. Pediatric Pulmonology. 2019;1–8.
2016;138:1071–1080.
31. Moffatt MF, Gut IG, Demenais F, et al. A large-scale, consortium-based https://doi.org/10.1002/ppul.24247
genomewide association study of asthma. N Engl J Med.
2010;363:1211–1221.