TABLE 1

Summary of key study characteristics of included studies

First author, year [reference]Study designStudy settingData collection periodPopulation/inclusion criteriaSample size (n)Definition of acute exacerbationResults
Emerman, 2001 [13]#Prospective cohort combining two studies with identical protocols44 EDs in USA and CanadaStudies performed 1997–1998
Follow-up 2 weeks after index ED visit
Children aged 2–17 years with ED visit for acute asthma
Mean age 7.99 years
59% male
19% White, 55% Black, 24% Hispanic, 2% other
1184 recruited; follow-up data available for 762ED visit with physician diagnosed acute asthmaFactors associated with acute asthma relapse:
ED visits for asthma in past year (per 5 visits) OR 1.2 (1.0–1.5)
Urgent clinic visits for asthma in past year (per 5 visits) OR 1.1 (0.9–1.3)
Lafata, 2002 [14]Retrospective cohort study using routinely acquired dataMichigan, USA1992–1996
2-year observation: 1 baseline year and 1 follow-up year
Children aged 5–14 years, with 1 hospitalisation or 2 outpatient encounters for asthma and ≥1 paediatrician office visit for each year of inclusion
Mean age 8.7 years
63% male
49% White, 44% African American, 7% other
452ED visit or hospitalisation for asthmaFactors associated with ED use:
ED visit for asthma in prior year OR 8.26 (4.79–14.25)
Hospital admission for asthma in prior year OR 0.85 (0.32–2.22)
Factors associated with ED or hospital admission for asthma:
Prior ED visit for asthma OR 7.97 (4.64–13.71)
Chen, 2003 [15]Prospective cohortChildren's Hospital, St Louis, MO, USAAdmissions between June and December 1999
1 year follow-up
Children aged 4–18 years, hospitalised for asthma
Mean age 8.22 years
65% male
77% African American, 21% White, 2% other
115Hospitalisation for asthmaLifetime history of hospitalisations as a predictor of future hospitalisation: OR 5.36 (1.90–15.14)
Schatz, 2003 [16]Retrospective cohort study using routinely acquired dataCalifornia, USA1998–1999
2-year observation: 1 baseline year and 1 follow-up year
Individuals aged 3–64 years with asthma
Children
62.2% male
11 101 in total; 6904 children aged 3–17 yearsHospitalisation or ED visit for asthmaIn children aged 3–17 years, 1998 hospitalisations as a predictor for asthma hospitalisation in 1999 OR 3.37 (1.61–7.04)
McCoy, 2006 [17]Data from RCT used as an observational study19 American Lung Association clinical research centres, USARecruitment from 15 September to 30 November 2000
Follow-up for 14 days after each injection (28 days total)
Volunteers aged 3–64 years with physician-diagnosed asthma
Of children originally enrolled,
60% male
60.5% White, 28.7% Black, 5.6% Hispanic, 4.4% other
2032 enrolled, 1949 completed trial; 353 children aged 3–10 yearsNew or increased OCS or an unscheduled healthcare encounter for asthmaHistory of intubation for asthma, hospitalisation ≥2 times for asthma, ≥3 courses of OCS for asthma in past year, or ≥2 unscheduled health contacts for asthma in past year in children aged 3–10 years as a predictor of exacerbations OR 2.19 (1.18–4.06)
Reznik, 2006 [18]Retrospective case–controlChildren's hospital, New York, USAAdmissions between January 1998–December 2004
30-day follow-up
Cases: children aged 0–21 years hospitalised for asthma and readmitted within 30 days of discharge for same reason
Controls: children aged 0–21 years hospitalised for asthma, but not readmitted within 30 days of discharge
Mean age 5.99 years
61% male
62.2% Hispanic, 34.2% African American, 3.6% other
445
Cases: 152
Controls: 293
Hospitalisation for asthmaPredictors of early asthma readmission:
ED visit for asthma in past year OR 3.28 (1.55–6.94)
Multivariate analysis of predictors of early asthma readmission:
Hospital admission for asthma in past year OR 1.89 (1.10–3.25)
Prior ICU admission for asthma OR 1.99 (0.93–4.27)
Covar, 2008 [19]#Data from PACT RCT used as an observational studyUSARecruited between October 2002 and January 2004
Trial period: 48 weeks
Children aged 6–14 years with documented mild–moderate persistent asthma, screening FEV1 ≥80% predicted and methacholine reactivity
61.4% male
44.9% from a minority ethnic group
285Systemic corticosteroids or emergency care (ED visit or hospitalisation) for acute asthmaLogistic regression analysis of factors at baseline predictive of exacerbation:
History of exacerbation requiring corticosteroid course in past year OR 2.28 (1.59–3.26)
Multivariable model of factors associated with exacerbations:
Prednisone course in year prior to study OR 2.10 (1.42–3.09)
Miller, 2008 [20]Prospective cohortMichigan, USAEnrolment over 1-year period
Follow-up at 2 weeks and 6 months post-ED visit
Children aged 2–17 years presenting to ED for acute asthma
Mean age 8.1 years
61.5% male
71.7% White, 50% Black, 26% Hispanic, 7% American Indian or Alaska native, 2% Asian, 2% other
197 enrolled; follow-up data available for 166Signs/symptoms compatible with asthma exacerbation (shortness of breath, coughing, wheezing, chest tightness) in a diagnosed asthmaticPrevious severe disease (e.g. systemic corticosteroids, ED visit or hospitalisation for asthma) as a predictor of 6-month morbidity (urgent care, ED or hospital admissions for asthma) Pearson correlation coefficient 0.17
To, 2008 [21]Prospective cohortChildren's hospital, Toronto, CanadaED visit between January 2003 and June 2004
Follow-up at 1 and 6 months post-ED visit
Children aged 2–17 years visiting ED for acute asthma
70% aged <7 years
59% male
269 enrolled;
247 completed 1-month follow-up,
220 completed 6-month follow-up
Sudden worsening of symptoms resulting in difficulty breathing often requiring extra medicine to relieve symptoms, with/without unscheduled ED/doctor visitPredictors of acute asthma episode at 6-month follow-up:
Acute asthma episode 6 months prior to baseline OR 4.73 (2.25–9.97)
Predictors of ED visit at 6-month follow-up:
ED visits in 12 months prior to baseline OR 6.27 (1.54–7.12)
Haselkorn, 2009 [22]Prospective cohort
Data from TENOR study
USATENOR conducted from 2001 to 2004
Follow-up with semi-annual visits for 3 years
Children with severe asthma or mild/moderate asthma considered difficult to treat
Had ≥2 OCS bursts in past year; ≥2 unscheduled clinic or hospital visits for asthma in past year; requirement for chronic, daily high doses of ICS; or ≥5 mg oral prednisone or current use of ≥3 medications to control asthma
69% male
62% White, 38% other
4756
637 children aged 6–11 years
Data available for 563 children
Use of a corticosteroid burstMultivariate model including 6- and 12-month events
Recent exacerbation as a predictor of future exacerbation OR 1.99 (1.51–2.61)
Multivariate model including only 6-month events:
Recent exacerbation as a predictor of future exacerbation OR 3.08 (2.21–4.28)
Tolomeo, 2009 [23]Retrospective cohort study using routinely acquired dataChildren's hospital, New England, USAHospitalisation between January and December 2006
Data for 1 year before and after hospitalisation
Children aged 2–15 years admitted to hospital for asthma
Mean age 6.35 years
66% male
36% White, 35% Black, 24% Hispanic, 5% other
298Hospital admission with primary diagnosis of asthmaPrevious asthma-related ED visit as a predictor of:
Subsequent ED visit OR 3.3 (1.39–7.96)
Subsequent hospitalisation for asthma OR 3.1 (1.17–8.33)
Triasih, 2011 [24]#Retrospective cohortChildren's hospital, Melbourne, AustraliaICU admission between January 1990 and December 2004
Mean follow-up 10.3 years
Children aged 2–18 years with asthma admitted to ICU
Median age at admission 7.0 years
59% male
410ICU admission for asthmaRisk factors for readmission to hospital:
Previous hospital admission OR 3.3 (2.1–5.3)
Admission in year prior to index admission aOR 4.5 (2.5–8.4)
Multiple previous hospital admissions OR 2.4 (1.3–4.2)
Risk factors for readmission to ICU:
Previous hospital admission OR 16.9 (4.1–70.4)
Admission in year prior to index admission aOR 4.7 (2.4–9.3)
Multiple previous hospital admissions OR 3.2 (1.6–6.7)
Previous ICU admission aOR 2.4 (0.8–6.7)
Wu, 2011 [25]#Data from CAMP RCT used as an observational studyUSAEnrolment between December 1993 and September 1995
Follow-up over 4 years
Children aged 5–12 years with mild/moderate persistent asthma
60% male
68% White, 14% Black, 9% Hispanic, 9% other
1041 enrolled
1019 completed daily diary cards
Episode requiring ≥3 days use of OCS, hospitalisation, or ED visit due to asthma (ATS/ERS statement)History of ED visits or hospitalisations in prior year as a predictor of having ≥1 severe exacerbations regression coefficient 0.73 (0.50–0.96)
History of ≥3 days of treatment with OCS in prior 3 months as a predictor of having ≥1 severe exacerbations regression coefficient 0.40 (0.17–0.62)
Li, 2012 [26]Retrospective cohort
study using routinely acquired data
Ontario, CanadaED visit between 14 April 2006 and 28 February 2009
Follow-up for 1 year
Children aged 2–17 years with prevalent asthma with unplanned visit to ED for asthma
38.4% aged 2–5 years
63.1% male
29 391ED visit for asthmaAdjusted hazard ratios for ED re-visits:
Asthma admission(s) in prior 2 years HR 1.45 (1.35–1.55)
Asthma ED visit(s) in prior 2 years HR 2.03 (1.91–2.14)
Adjusted hazard ratios for hospital admissions:
Asthma admission(s) in prior 2 years HR 2.87 (2.43–3.39)
Asthma ED visit(s) in prior 2 years HR 1.85 (1.57–2.19)
van den Bosch, 2012 [27]#Retrospective case–control4 hospitals in the NetherlandsJanuary 1994–October 2006Cases: children with doctor-diagnosed asthma admitted to PICU for acute asthma
Controls: patients with asthma who never needed PICU admission for any reason
Median age at PICU admission 5.2 years
77% White
230
Cases: 66
Controls: 164
PICU admission for acute asthmaEarlier hospitalisation for asthma (non-PICU) as a risk factor for PICU admission OR 5.4 (1.34–21.45)
Visitsunthorn, 2013 [28]Retrospective case–controlChildren's hospital, Bangkok, ThailandJanuary 2006–December 2007
1 year follow-up
Children aged ≤14 years admitted to hospital for acute asthma
50% aged >6 years
64.5% male
76
1 admission: 56
Readmission: 20
Acute asthma that was severe or did not improve after 3 doses of bronchodilator nebulisationICU admission at first admission as a risk factor for readmission OR 29.62 (3.35–262.18)
Kenyon, 2014 [29]Retrospective cohort study using routinely acquired dataUSADischarges between 1 July 2008 and 30 June 2010
1 year follow-up
Children aged ≥2 years discharged from hospital after admission for asthma
61% aged 5–18 years
61.1% male
46.6% Black, 27.3% White, 16.8% Hispanic, 7.9% other
36 601, contributing 44 203 hospitalisationsHospital admission for asthmaPrior-year admission as a risk factor for asthma rehospitalisation
7 days OR 2.0 (1.4–2.7)
15 days OR 2.7 (2.1–3.3)
30 days OR 2.9 (2.5–3.4)
60 days OR 3.5 (3.1–3.9)
180 days OR 3.5 (3.3–3.8)
365 days OR 3.6 (3.4–3.8)
Zeiger, 2015 [30]Retrospective cohort study using routinely acquired dataCalifornia, USA2010–2011: 1 baseline year and 1 outcome yearChildren aged 5–11 years who met HEDIS criteria for persistent asthma
Blood eosinophil level determined in 2010
With eosinophil level:
Mean age 7.7 years
61.9% male
45.3% Hispanic, 24.6% White, 17.4% Black
2451
With eosinophil count: 333
Asthma outpatient visits requiring systemic corticosteroids within ±7 days or asthma ED visits or hospitalisationHistory of exacerbation as a risk factor for exacerbation:
Adjusted rate ratio 2.35 (1.61–3.44)
Adjusted risk ratio 1.94 (1.37–2.73)
Engelkes, 2016 [31]#Retrospective cohort study using routinely acquired dataThe Netherlands1 January 2000 to 1 January 2012
Mean follow-up 2.46 years
Children with asthma aged 5–18 years
Mean age: 10.5 years
58.7% male
14 303Hospitalisation, ED visit or prescription of systemic corticosteroids for ≥3 days for asthmaPrior exacerbations as a risk factor for exacerbation:
Total cohort model 1: relative rate 1.99 (1.40–2.83), model 2: relative rate 2.17 (1.30–3.60)
Children with ≥1 exacerbation ever model 1: relative rate 1.60 (1.37–1.88), model 2: relative rate 1.52 (1.19–1.94)
Exacerbations as a risk factor for nonfrequent exacerbations compared to frequent exacerbations
<2 versus ≥2 OR 2.11 (1.66–2.68) versus OR 1.93 (1.42–2.63)
<3 versus ≥3 OR 2.43 (1.84–3.23) versus OR 1.99 (1.35–2.94)
Quezada, 2016 [32]#Data from SARCA and SARA RCTs used for an observational studyUSA2007–2011
24-week treatment period
SARCA trial:
children aged 6–17 years, with poor asthma control, being treated with inhaled glucocorticoids
62% male
39% White, 49% Black, 12% other
718 enrolled
Data for 295 from SARCA
Requirement for OCS or urgent healthcare visit for asthma symptoms83% of children with an exacerbation had an unscheduled visit for asthma in the previous year and 80% had been treated with OCS
69% of children without an exacerbation had an unscheduled visit for asthma in the previous year and 61% had been treated with OCS
Costa, 2018 [33]#Retrospective case–controlGoiania, BrazilJune 2012–August 2013
Data collected for 1 year prior to ED visit
Cases: children aged 4–14 years, admitted to ED for asthma who had ≥3 previous episodes of bronchospasm
Controls: asthmatic children without exacerbation recruited during outpatient appointment
Cases:
Median age 7 years
56% male
62% White
Controls:
Median age 8 years
42% male
28% White
153
Cases: 92
Controls: 61
Increased symptoms requiring change in medication, judged by physician according to ATS/ERS statement
Severe exacerbation: hospital admission or course of OCS for asthma
≥3 ED visits in past year for asthma as a risk factor for asthma exacerbation incidence risk ratio 1.40 (1.01–1.95)
Grunwell, 2018 [34]Retrospective case–control
Data from outpatient asthma clinical research studies at Emory University
Georgia, USAJanuary 2004–December 2015Cases: children aged 6–18 years with historical admission to PICU for acute asthma
Controls: asthmatic children without prior PICU admission
Cases:
Median age 10 years
56.7% male
52.3% Black, 35.2% White, 12.5% other
Controls:
Median age 12 years
61.8% male
71.8% Black, 17.1% White, 11.2% other
579
Cases: 170
Controls: 409
PICU admission, hospitalisation or ED visit for asthmaHospitalisation for asthma in year prior to data collection was associated with increased odds of PICU admission OR 8.19 (4.83–13.89)
To, 2018 [35]Retrospective cohort study using routinely acquired dataToronto, CanadaApril 2008–March 2014
1 year follow-up
Individuals aged 5–99 years with ED visit for asthma
Aged 5–19 years
Mean age 12.15 years
57% male
31% in most marginalised ethnic concentration quintile
58 366
18 352 aged 5–19 years
ED visit for asthmaAdjusted relative risk of asthma ED return visit within 1 year of ED discharge in children aged 5–19 years 1.13 (1.03–1.25)
Turner, 2018 [36]#Retrospective cohort study using routinely acquired dataUKJanuary 1999–December 2012
1 baseline year and 1 outcome year
Children aged 5–12 years diagnosed with asthma
Mean age 9 years
57% male
3776Hospitalisation, ED admission or OCS for asthma (ATS/ERS)Previous asthma attack as a risk factor for ≥1 attack
1 OR 3.74 (2.92–4.80)
≥2 OR 7.72 (5.55–10.74)
Alsheri, 2020 [37]#Retrospective case–controlAbha Hospital, Saudi ArabiaJanuary 2014–December 2018Cases: children aged 2–14 years admitted to PICU for acute asthma
Controls: children admitted to the ward for acute asthma
Cases
Mean age 6.3 years
41.7% male
Controls
Mean age 4.6 years
42.7% male
320
Cases: 72
Controls: 248
PICU or hospital admission for asthmaPrevious admission to PICU as a risk factor for PICU admission OR 7.83 (2.58–23.76)
Engelkes, 2020 [38]#Retrospective cohort study using routinely acquired data from the Netherlands, Italy, UK, Denmark and SpainThe NetherlandsJanuary 2008–December 2013Patients aged 5–17 years with asthma
Subcohort with severe asthma (requiring high dose ICS+second controller and/or systematic corticosteroids for ≥120 consecutive days)
Mean age 10.4 years (7.2–14.8 years across databases)
Male preponderance across all databases
212 060
Severe asthma 14 283
Use of systemic corticosteroids, ED visit and/or hospitalisation, for worsening asthmaRelative rates of exacerbation in those with history of exacerbation
CPRD 5.76 (5.25–6.33)
SIDIAP 2.53 (2.27–2.81)
IPCI 20.04 (12.91–31.10)
AUH 45.71 (31.2–66.92)
PEDIANET 29.36 (16.25–53.05)
HSD 10.07 (4.56–22.20)

Data are presented with 95% confidence intervals in brackets where provided. ED: emergency department; RCT: randomised controlled trial; OCS: oral corticosteroids; ICU: intensive care unit; PACT: Pediatric Asthma Controller Trial; FEV1: forced expiratory volume in 1 s; TENOR: The Epidemiology and Natural History of Asthma; ICS: inhaled corticosteroids; aOR: adjusted odds ratio; CAMP: Childhood Asthma Management Program; ATS: American Thoracic Society; ERS: European Respiratory Society; HR: hazard ratio; PICU: paediatric intensive care unit; HEDIS: Healthcare Effectiveness Data and Information Set; SARCA: Study of Acid Reflux in Children with Asthma; SARA: Study of Acid Reflux in Adults with Asthma; CPRD: Clinical Practice Research Datalink; SIDIAP: Sistema d'Informació per al Desenvolupament de la Investigació en Atenció Primària; IPCI: Integrated Primary Care Information; AUH: Aarhus University prescription database; HSD: Health Search Database. #: included in meta-analysis.