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Received: 5 November 2021    Revised: 11 January 2022    Accepted: 31 January 2022

DOI: 10.1111/pai.13741

ORIGINAL ARTICLE

The role of respiratory syncytial virus-­and rhinovirus-­induced

bronchiolitis in recurrent wheeze and asthma—­A systematic
review and meta-­analysis

Heidi Makrinioti1,2  | Kohei Hasegawa3 | John Lakoumentas4 |

Paraskevi Xepapadaki4  | Maria Tsolia5 | Jose A. Castro-­Rodriguez6  |
Wojciech Feleszko7  | Tuomas Jartti8 | Sebastian L. Johnston9 | Andrew Bush2,9 |
Vasiliki Papaevangelou10 | Carlos A. Camargo Jr.3 | Nikolaos G. Papadopoulos4,11
1
West Middlesex University Hospital, Chelsea and Westminster Foundation Trust, London, UK
2
Centre for Paediatrics and Child Health, Imperial College, London, London, UK
3
Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
4
Allergy & Clinical Immunology Laboratory, Second Department of Pediatrics, National and Kapodistrian University of Athens (NKUA), School of Medicine, P.
and A. Kyriakou Children’s Hospital, Athens, Greece
5
Second Department of Paediatrics, P. and A. Kyriakou Children’s Hospital, Athens, Greece
6
Department of Paediatric Pulmonology, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
7
Department of Pediatric Pneumology and Allergy, The Medical University of Warsaw, Warsaw, Poland
8
Department of Pediatrics, Turku University Hospital and Turku University, Turku, Finland
9
National Heart and Lung Institute, Imperial College, London, London, UK
10
Third Department of Paediatrics, Attikon University General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
11
Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK

Correspondence
Heidi Makrinioti, West Middlesex
University Hospital, Chelsea and
Westminster Foundation Trust, London,
UK.
Email: heidimakrinioti@gmail.com
Editor: Jon Genuneit
Abstract
Introduction: Respiratory syncytial virus (RSV) is the most common cause of bron-
chiolitis. RSV-­induced bronchiolitis has been associated with preschool wheeze and
asthma in cohort studies where the comparison groups consist of healthy infants.
However, recent studies identify rhinovirus (RV)–­induced bronchiolitis as a potentially
stronger risk factor for recurrent wheeze and asthma.
Aim: This systematic review and meta-­analysis aimed to compare the associations of
RSV-­ and RV-­induced bronchiolitis with the development of preschool wheeze and
childhood asthma.
Methods: We performed a systematic search of the published literature in five data-
bases by using a MeSH term-­based algorithm. Cohort studies that enrolled infants with
bronchiolitis were included. The primary outcomes were recurrent wheeze and asthma
diagnosis. Wald risk ratios and odds ratios (ORs) were estimated, along with their 95%
confidence intervals (CIs). Individual and summary ORs were visualized with forest plots.

Heidi Makrinioti, Jose A. Castro-­Rodriguez, Wojciech Feleszko, Carlos A. Camargo Jr., and Nikolaos G. Papadopoulos: Members of the European Academy of Allergy and Clinical
Immunology (EAACI) Task Force on Preschool Wheeze.

© 2022 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

Pediatr Allergy Immunol. 2022;33:e13741.  |

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https://doi.org/10.1111/pai.13741
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Results: There were 38 studies included in the meta-­analysis. Meta-­analysis of eight

studies that had data on the association between infant bronchiolitis and recurrent
wheeze showed that the RV-­bronchiolitis group were more likely to develop recurrent
wheeze than the RSV-­bronchiolitis group (OR 4.11; 95% CI 2.24–­7.56). Similarly, meta-­
analysis of the nine studies that had data on asthma development showed that the RV-­
bronchiolitis group were more likely to develop asthma (OR 2.72; 95% CI 1.48–­4.99).
Conclusion: This is the first meta-­analysis that directly compares between-­virus dif-
ferences in the magnitude of virus-­recurrent wheeze and virus-­childhood asthma
outcomes. RV-­induced bronchiolitis was more strongly associated with the risk of de-
veloping wheeze and childhood asthma.

KEYWORDS
asthma, bronchiolitis, respiratory syncytial virus, rhinovirus, wheeze

1  |  I NTRO D U C TI O N
Bronchiolitis is the most common lower respiratory tract infection in
infancy. Epidemiological data show that 3%–­5% of infants develop
severe bronchiolitis (bronchiolitis requiring hospitalization) during
the first year of life.1 Severe bronchiolitis is associated with an in-
creased impact on healthcare resources and family quality of life. 2
However, the health impact of bronchiolitis goes beyond the acute
phase, since more than 30% of infants hospitalized with bronchiolitis
will develop recurrent wheeze and asthma.1
Respiratory viruses are very commonly detected in upper airway
samples in infants with bronchiolitis.2 There is increasing evidence
linking specific virus types detected during an episode of hospital-
ized bronchiolitis to preschool wheeze and asthma.3 Respiratory
syncytial virus (RSV)-­bronchiolitis has been strongly linked to the
development of post-­bronchiolitis wheeze and asthma.4,5 However,
most cohort studies associating RSV-­bronchiolitis and preschool
wheeze and asthma development report increased risk compared to
healthy infants rather than infants hospitalized with other than RSV-­
bronchiolitis.6 On the other hand, an increasing number of studies
are associating rhinovirus (RV)-­bronchiolitis in infancy with preschool
wheeze and asthma development.4,7,8 This association seems stronger
in infants with an allergic predisposition and with evidence of allergic
sensitization.9,10 It is unknown though, whether there are between-­
virus differences in the magnitude of virus long-­term outcome link.
To date, there is no systematic review or meta-­analysis that di-
rectly compares the between-­virus differences in the magnitude of
virus long-­term outcome link. A quality management system utilized
respiratory virus testing in bronchiolitis diagnosis and highlighted
its potential in replacing the current standard of care.11 Respiratory
virus testing is an easily accessible and relatively low-­cost tool. By
understanding the associations between RSV and RV and recurrent
wheeze and asthma, we could utilize respiratory virus testing as a
tool to define candidate groups for intervention studies in bronchi-
olitis and/or as a tool to identify infants with bronchiolitis who will
benefit from closer follow-­up in the first years of life. This study aims
Key Message
This meta-­analysis shows that infants with rhinovirus-­
induced bronchiolitis are more likely to develop recurrent
wheeze and asthma as compared to infants with respira-
tory syncytial virus–­induced bronchiolitis and represent a
group for possible intervention studies in the future.
to assess between-­virus differences in the magnitude of recurrent
wheeze and school-­age asthma incidence.
1.1  |  Search strategy and selection criteria
We performed a search of the published literature via five
databases—­PubMed-­NCBI, Google Scholar, Embase, the Cochrane
Library, and the Scopus database—­by using the algorithm ((bronchi-
olitis AND (asthma OR wheez* OR bronchial OR bronch*) AND (virus
OR rhinovirus OR influenza OR corona OR syncytial OR metapneu-
movirus OR bocavirus)) up to 01st of October 2021. The algorithm
used included both MeSH (Medical Subject Headings) and “free
text” terms. Figure 1 describes the literature search strategy and
the results of the search. The study has been registered in Prospero
database (reference number CRD42017071189) and is reported fol-
lowing the Meta-­analysis of Observational Studies in Epidemiology
(MOOSE) guidelines.12
2  |  DATA E X TR AC TI O N
Two reviewers (HM and NGP) independently assessed the articles
and relevant data were extracted without cross-­referencing. The in-
clusion and exclusion criteria and outcome measures are described
below. The quality of the included studies was assessed by using the

MAKRINIOTI et al.
F I G U R E 1  Flowchart describing the identification, screening, assessment of eligibility, and inclusion criteria
Newcastle-­Ottawa Scale (NOS) quality assessment tool for cohort
studies (NOSGEN.PDF (ohri.ca)). Table S1 at the online supplement
contains detailed information around the quality assessment of each
included study. The one study that was included for meta-­analysis
and which had a randomized control trial design was assessed for
13,14
quality by the Critical Appraisal Skills Programme (CASP) tool.
3  |   S T U D I E S I N C LU D E D FO R
QUA LITATI V E S Y NTH E S I S
3.1  |  Participants
In this meta-­analysis, we included infants hospitalized with bron-
chiolitis aged <2  years old. A wider definition of bronchiolitis was
used, encompassing the British Thoracic Society (BTS/SIGN) and the
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American Academy of Pediatrics (AAP) definitions. Also, we included
infants from birth cohort studies who developed bronchiolitis during
the first 2 years of life. The incidence of bronchiolitis in the birth co-
hort studies was confirmed either through parental interviews and/
or healthcare activity data. Detailed information on the definition of
bronchiolitis in each study can be found in Tables S3–­S8.
Studies that included infants with no bronchiolitis presenta-
tion during the follow-­up period, defined these infants as “healthy
controls.”
The COAST and Tucson Children's Respiratory Study are birth
cohort studies that were included in the meta-­analysis.10,15,16 More
specifically, this meta-­analysis included data from the COAST study
on acute wheezing illnesses during the first 2 years of life. These two
studies did not enroll only hospitalized infants but were included in
the meta-­analysis and sensitivity analysis including removal of these
studies did not affect the overall OR.
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Inclusion and exclusion criteria are briefly described in Table 1 3.3  |  Studies included for meta-­analysis
using the Population, Intervention or Exposure, Comparators, and (observational cohort studies and randomized
Outcomes (PICO) format. controlled trials (RCTs))

3.2  |  Outcomes
The outcomes for the meta-­analysis included recurrent wheeze and
childhood asthma, as per physician diagnosis, caregiver report of
physician diagnosis, and/or evidence of asthma medication use in
healthcare services’ datasets. Definitions were as follows:
a. recurrent wheeze (three or more episodes of wheeze through-
out follow-­up or two or more episodes of wheeze during the
last year of follow-­up) requiring either inpatient or outpatient
management.
The Hunderi et al. study17 used as an outcome the incidence of three
or more episodes of wheeze throughout the follow-­up period (in-
cluding the first episode). This was different from the other stud-
ies; therefore, the outcome that was used to estimate the odds
ratio (OR) was the use of wheeze medications during the last year
of follow-­up.
In the Marlow et al. study, the outcome that was used to estimate
the OR was the incidence of persistent wheeze (at least one epi-
sode of wheeze every year throughout follow-­up), consistent with
the definition of recurrent wheeze in our meta-­analysis.18
b. asthma at school years (parental-­reported use of asthma med-
ications or asthma diagnosis during the last year of follow-­up,
with or without lung function measurement tests or physician-­
confirmed episodes of wheezing over the last year of follow-­up,
13
that were relieved by the use of bronchodilators ).
For the quantitative analysis, we included all the studies that as-
sessed the outcomes described above. We organized the studies in
subgroups as described in Table S2.
3.4  |  Statistical analysis
The meta-­analysis procedure included the steps of summarizing,
pooling, visualizing, and performing regression modeling. The meta-­
analysis was implemented with the R statistical software (using the
packages “epitools,” “meta,” “metafor,” and “dmetar”).
The characteristics of each study were summarized sepa-
rately. The dependency tests that were executed included Mid-­P
exact, Fisher's exact, and chi-­s quared tests. A two-­t ailed p < .05
was considered statistically significant. Wald risk ratios and ORs
were estimated, along with their 95% CIs. Some studies reported
other adjusted ratio-­b ased effect estimates (adjusted risk ratios
or hazard ratios). These estimates were neither excluded nor re-
placed with unadjusted ORs and were included in the analysis as
a positive control for the R code. When required, the authors of
the studies kindly provided a raw summary of data to calculate
the ORs.
No simple pooling was performed. Data from each study were
weighted and analyzed separately. A single OR was estimated per
study. The pooling estimate was calculated by using the Mantel-­
Haenszel method along with a random-­effects model and the

TA B L E 1  Table describing inclusion and exclusion criteria using the PICO format

RSV-­bronchiolitis studies RV-­bronchiolitis studies

Population characteristics human participants (infants under 2 years old)
Intervention or exposure RSV-­induced bronchiolitis during the first 2 years of life
(exposure)
Comparator(s) 1. bronchiolitis absent and/or undetected during the
exposure period
2. non-­RSV bronchiolitis during the exposure period
3. RV-­bronchiolitis during the exposure period
Outcomes 1. recurrent wheeze (more than 3 episodes of wheeze
during follow-­up or more than 2 episodes of wheeze
during the last year)
2. asthma at school years (parental-­reported or asthma
medications use or asthma diagnosis during the last
year of follow-­up)
Study design observational cohort study or randomized controlled trial
with cohort design
exposure and comparator groups sampled from the
same population
methods for ascertaining exposures and outcomes were
the same for exposure and comparator groups
human participants (infants under 2 years old)
RV-­induced bronchiolitis during the first 2 years of
life (exposure)
1. bronchiolitis absent and/or undetected during the
exposure period
2. non-­RSV bronchiolitis during the exposure period
3. RV-­bronchiolitis during the exposure period
1. recurrent wheeze (more than 3 episodes of wheeze
during follow-­up or more than 2 episodes of
wheeze during the last year)
2. asthma at school years (parental-­reported or
asthma medications use or asthma diagnosis
during the last year of follow-­up)
observational cohort study or randomized controlled
trial with cohort design
exposure and comparator groups sampled from the
same population
methods for ascertaining exposures and outcomes
were the same for exposure and comparator
groups

MAKRINIOTI et al.
Knapp-­Hartung adjustment. The statistical heterogeneity of pool-
ing was measured with tau squared, I squared and tested with
Cochrane's Q test (25% absence of bias; 26–­39% unimportant; 40–­
60% moderate; and 60–­100% substantial bias).19 Finally, prediction
intervals were estimated at an 80% confidence level per study.
Individual and summary ORs were visualized with forest plots,
while the funnel plot approach was used to check for publication
bias, along with Egger's test for detecting symmetry. The corre-
sponding p-­curve plots were also generated, where feasible.
Influence analysis based on the “leave-­one-­out-­method” was
performed, in which the meta-­analysis was performed K-­1 times,
each time leaving out one study, and the effect on the overall esti-
mate was assessed.
Multiple regression modeling was also performed per study and
included a set of potential predictors—­the age at the outcome, the
outcome assessment (telephone questionnaire or physician face-­
to-­face visit or healthcare activity data), the study type, the assess-
ment of the family history of allergies, and the assessment of allergic
sensitization. Parameters of the modeling process included the use
of Sidik-­Jonkman estimator (SJ), and a random-­effects model with
the Knapp-­Hartung adjustment (estimating residual heterogeneity
meta-­regression.pdf).
4  |   R E S U LT S
4.1  |  Search outcomes
Following systematic search through the five databases (Embase,
Cochrane Library, Google Scholar, PubMed, Scopus) with ad-
vanced search criteria, there were 24,265 results as described
in Figure 1. The remaining 50 citations were downloaded in full
text and were included in the qualitative synthesis of the sys-
tematic review. Only peer-­reviewed (not on online repositories)
studies were included in the meta-­analysis. There were 14 out of
the 50 studies that were not included in the meta-­analysis.7,20–­31
F I G U R E 2  Forest plot depicting the associations between RSV-­bronchiolitis and recurrent wheeze development as compared with
healthy controls (OR 6.86, 95% CI 2.20–­21.35, I2 = 58%), the right side of the vertical line favors RSV-­positive bronchiolitis. OR: odds ratio,
CI: confidence interval, PI: prediction interval, I2: heterogeneity statistic, X62: chi-­squared heterogeneity statistics with 6 degrees of freedom
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The reasons why these 14 studies were excluded from the meta-­
analysis are explained below. Firstly, out of the five citations based
on the Sigurs et al. cohort studies, only two were included in the
meta-­analysis as these were assessing recurrent wheeze and
school-­age asthma as outcomes and included the larger number
of participants.4,32 Also, one of two citations based on the Midulla
et al. cohort was included in the meta-­analysis as describing the
larger number of participants. 8 Using similar reasoning related to
outcome assessment and a maximum number of participants, spe-
cific citations from the MARC cohort studies, the Finnish cohort
studies, and the COAST studies were not included in the meta-­
analysis.7,25,26,30,31 James et al. 20 study was not included in the
meta-­analysis as RSV-­p ositive groups were not defined through
virology testing but season of bronchiolitis episode incidence.
Finally, Rubner et al. and Sigurs et al.’s studies were not included in
the meta-­analysis as these assessed as an outcome the incidence
of asthma during adolescent years. 26,27
4.2  |  Meta-­analysis outcomes
4.2.1  |  Overall impact of RSV-­bronchiolitis on
recurrent wheeze development when compared with
healthy controls
When considering all seven cohort studies, 32–­38 investigating as-
sociations between RSV-­bronchiolitis and recurrent wheeze devel-
opment, the RSV-­bronchiolitis group were more likely to develop
recurrent wheeze than the control group (OR 6.86; 95% CI 2.20–­
21.35). The Forest plot shown in Figure  2 demonstrates moderate
heterogeneity (I2  =  58%, p  =  .03). Influence analysis showed that
there was no effect on the overall estimate of the meta-­analysis if
any of the studies was removed (Figure S1). The funnel plot repre-
senting the effect estimates accompanies the Forest Plot in Figure
Ia (Online Supplement) and the p-­curve analysis in Figure Ib (Online
Supplement).
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4.2.2  |  Overall impact of RSV-­bronchiolitis on
recurrent wheeze development when compared with
RSV-­negative bronchiolitis
There were three studies5,18,39 investigating associations between
RSV-­bronchiolitis and recurrent wheeze development as compared
to RSV-­negative bronchiolitis. Although the number of studies was
small and one study had a significantly higher number of partici-
pants, a meta-­analysis was attempted. The overall OR was 1.5 (95%
CI 0.03–­78.08) but there was significant heterogeneity (I2  =  99%).
The funnel plot was unable to distinguish from real asymmetry and
the p-­curve could not be calculated. Therefore, no forest plot was
depicted from this meta-­analysis as more studies are required for
quantitative analysis.
4.2.3  |  Overall impact of RSV-­bronchiolitis on
recurrent wheeze development when compared with
RV-­bronchiolitis
There were eight studies9,10,17,22,40–­42 and Makrinioti et al. (https://
doi.org/10.3389/falgy.2021.728389) investigating associations
between RSV-­bronchiolitis and recurrent wheeze development as
compared to RV-­bronchiolitis. All studies included in this meta-­
analysis reported data for coinfections. The Hasegawa et al. study
included a significantly higher number of participants and the
Hunderi et al. study used as an outcome measure the incidence of 3
or more episodes of wheeze at follow-­up period (including the first
episode). This was different from the other studies; therefore, the
outcome that was used to calculate the OR was the use of wheeze
medications during the last year of follow-­up. We found that the
RV-­bronchiolitis group was more likely to develop recurrent wheeze
than the RSV group (OR 4.11; 95% CI 2.24–­7.56). The Forest plot
is shown in Figure 3 and demonstrates significant heterogeneity
F I G U R E 3  Forest plot depicting the associations between RSV-­bronchiolitis and recurrent wheeze development as compared with
RV-­bronchiolitis (OR 4.24; 95% CI 2.15–­8.36, I2 = 85%), the right side of the vertical line favors RV-­positive bronchiolitis. OR: odds ratio, CI:
confidence interval, PI: prediction interval, I2: heterogeneity statistic, X62: chi-­squared heterogeneity statistics with 6 degrees of freedom
13993038, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pai.13741 by Cochrane Colombia, Wiley Online Library on [07/04/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
(I2 = 82%, p < .001). Influence analysis showed that there was a signif-
icant effect on the overall estimate of the meta-­analysis if the study
including the highest number of patients was removed (Figure S2).31
Upon removal of this study, a subanalysis was performed with the
rest six studies including similar numbers of patients. The subanaly-
sis confirmed that the RV-­bronchiolitis group were still more likely
to develop recurrent wheeze than the RSV group (OR 5.11; 95% CI
2.96–­8.92) (Figure S3). Repeat influence analysis showed that with
the removal of Hunderi et al. study,17 the level of heterogeneity was
significantly decreased (I2 = 33%). Therefore, the influencers in this
meta-­analysis were identified and addressed, but the overall OR re-
mained positive showing the RV-­positive infants have higher risk to
develop recurrent wheeze as compared to RSV-­positive infants (OR
6.35; 95% CI 3.43–­11.73). The p-­curve analysis following leave-­one-­
out analysis showed a right skewness of the plot indicating that all
5 p-­values sit at <.05. This p-­curve analysis points toward a more
likely existing effect.
The funnel plot representing the effect estimates accompanies
the Forest Plot (4c) in Figure IIa (Online Supplement) and the p-­curve
analysis in Figure IIb (Online Supplement).
4.2.4  |  Overall impact of RSV-­bronchiolitis on
asthma development when compared with healthy
control infants
When considering the four cohort studies 4,43–­45 investigating associ-
ations between RSV-­bronchiolitis and asthma development in com-
parison to healthy controls, the RSV-­bronchiolitis group were more
likely to develop asthma than the healthy control group (OR 7.21;
95% CI 3.92–­13.28). The Forest plot for this is shown in Figure 4 and
demonstrates no heterogeneity and high p-­value (I2 = 0%, p = .46).
The funnel plot and the p-­curve analysis are shown in Figures IIIa
and IIIb (Online Supplement).
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F I G U R E 4  Forest plot depicting the associations between RSV-­bronchiolitis and asthma development as compared with healthy controls
(OR 7.21; 95% CI 3.92–­13.28, I2 = 0%), the right side of the vertical line favors RSV-­positive bronchiolitis

F I G U R E 5  Forest plot depicting the associations between RSV-­bronchiolitis and asthma development as compared with healthy controls
(OR 0.87; 95% CI 0.26–­2.92, I2 = 84%), the right side of the vertical line favors RSV-­positive bronchiolitis. OR: odds ratio, CI: confidence
interval, PI: prediction interval, I2: heterogeneity statistic, X52: chi-­squared heterogeneity statistics with 5 degrees of freedom

4.2.5  |  Overall impact of RSV-­bronchiolitis on
asthma development when compared with RSV-­
negative bronchiolitis
When considering the six studies16,46–­50 investigating associations
between RSV-­b ronchiolitis and asthma development in compari-
son to RSV-­n egative bronchiolitis, no differences were found (OR
0.87; 95% CI 0.26–­2 .92) (Figure 5). There was significant hetero-
geneity (I2 = 84%, p < .001) but no effect on the overall estimate
if any of the studies was removed (Figure S4). The funnel plot and
the p-­curve analysis are shown in Figures IVa and IVb (Online
Supplement).
4.2.6  |  Overall impact of RSV-­bronchiolitis on
asthma development when compared with RV-­
bronchiolitis
When considering the nine studies13,15,51–­57 investigating associa-
tions between RSV bronchiolitis and asthma development in com-
parison to RV-­bronchiolitis, the RV-­bronchiolitis group were more
likely to develop asthma than the RSV group (OR 2.72; 95% CI 1.48–­
4.99). The Forest plot for this is shown in Figure 6 and demonstrates
significant heterogeneity (I2  =  65%, p  =  .004). There was an ef-
fect on the overall estimate if the Kusel et al. study51 was removed
(Figure  S5). The funnel plot and the p-­curve analysis are shown in
Figures Va & Vb (Online Supplement).
4.3  |  Meta-­regression modeling and sensitivity
analysis with removal of birth cohort studies
The lack of data around allergic sensitization and family history of al-
lergies made it difficult for us to set up a meta-­regression model with
continuous predictor. Therefore, we set up a metaregression model
with categorical predictors (age of outcome assessment, assessment
of allergic sensitization, assessment of family history of allergies, and
study type) (as described in the Methods section) that did not give
any statistically significant results.
A sensitivity analysis for the “f subsection” (Results section) with
the removal of the Jackson et al. study showed that there was no ef-
fect on the overall OR (OR 2.51; 95% CI 1.31–­4.79). Equally, a sensi-
tivity analysis for the “c and e subsections” (Results section) with the
removal of the Lemanske et al. and Stein et al. studies, respectively,
showed that there was no effect on the overall OR (OR 4.11; 95% CI
1.80–­9.36 and OR 0.71; 95% CI 0.16–­3.09, respectively).).
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F I G U R E 6  Forest plot depicting the associations between RSV-­bronchiolitis and asthma development as compared with RV-­bronchiolitis
(OR 2.72; 95% CI 1.48–­4.99, I2 = 65%) the right side of the vertical line favors RV-­positive bronchiolitis. OR: odds ratio, CI: confidence
interval, PI: prediction interval, I2: heterogeneity statistic, X82: chi-­squared heterogeneity statistics with 8 degrees of freedom

5  |  D I S C U S S I O N bronchiolitis severity is contradictory. 59 Moreover, it is unclear

To our knowledge, this is the first systematic review and meta-­
analysis directly comparing between-­virus differences in the
magnitude of virus-­recurrent wheeze and virus-­childhood asthma
outcomes. A recent meta-­analysis failed to show an association
between early-­life RSV-­induced lower respiratory tract infections
and asthma inception.17 Our meta-­analysis suggests an association
between RV-­induced bronchiolitis and subsequent development of
recurrent wheeze and asthma, more so than RSV-­induced bronchi-
olitis. The number of available studies included in our meta-­analysis
was small (<10) and there was moderate heterogeneity (I2 around
62% to 82%). However, when comparing associations between
RV-­ and RSV-­induced bronchiolitis and recurrent wheeze, the
overall OR of 4.11 remained positive in a leave-­one-­out sensitivity
analysis when the studies that varied in the number of subjects
and in the assessment of the outcome were excluded (overall OR
4.11). The sensitivity analysis attempted to address heterogeneity.
More specifically, the Hunderi et al. study had a heterogeneous
outcome assessment. This study defined “recurrent wheeze” as
three or more episodes of wheeze during the follow-­up period (in-
cluding the bronchiolitis episode). The initial bronchiolitis episode
was considered as a wheezing episode, but only 8.1% of recruited
patients had evidence of allergic sensitization, and 82% of them
were RSV-­p ositive. Also, when comparing associations between
RV-­ and RSV-­induced bronchiolitis and asthma, the overall OR
of 2.72  remained positive in a leave-­one-­out sensitivity analysis
when the study that varied in the number of subjects was excluded
(overall OR 2.72). It is possible however that this association could
be partially attributed to residual atopic predisposition or allergic
sensitization. Also, recent studies have shown that RSV-­RV coin-
fection can be detected in up to 30% of infants with bronchioli-
tis. 58 However, the association between RSV-­RV coinfection and
whether RSV-­RV coinfection in severe bronchiolitis is linked to
increased risk for recurrent wheeze or asthma development.60
This meta-­analysis focused on comparisons between single viruses
(RSV and RV) rather than single viruses and coinfections in the
magnitude of virus-­long-­term outcome link.
The other interesting finding of this meta-­analysis was that RSV-­
bronchiolitis was associated with recurrent wheeze or asthma de-
velopment when compared with healthy subjects (OR 6.86; 95% CI
2.20–­21.35 and OR 7.21; 95% CI 3.92–­13.28 respectively). However,
this finding was based on studies that did not assess other than RSV
viruses.61 Therefore, these findings could not differentiate clearly
between RSV and RV effects. What these findings show is that all
viral exposures are associated with similar risk for asthma develop-
ment in the exposed population (infants with severe bronchiolitis).
The non-­RSV bronchiolitis group in these studies could potentially
include infants positive for RV but not only RV. As these studies
did not perform testing for RV, direct comparisons between RSV-­
positive and RV-­positive groups were not possible.
Concerning the definition of recurrent wheeze, this meta-­
analysis followed a homogeneous assessment apart from one
study.17 Recurrent wheeze was defined as three or more episodes
of wheeze throughout follow-­up or two or more episodes of wheeze
during the last year of follow-­up.
Regarding the asthma diagnosis, the 2019 BTS/SIGN Asthma
Guidelines’ definition was not followed. This definition should ide-
ally include lung function measurement tests (with bronchodilator
reversibility testing to add greater sensitivity in diagnosis). However,
in primary and secondary care, the diagnosis of asthma is most often
based on a history of symptoms and response to asthma therapy.62
Data from the Manchester Asthma and Allergy birth cohort study
showed that only one tenth of children with asthma symptoms
had positive results in spirometry and bronchodilator reversibility

MAKRINIOTI et al.
testing.63 More specifically, the role of spirometry in asthma diag-
64
nosis has been challenged since many years now. Therefore, the
asthma outcome definition used in this meta-­analysis was not limited
to the use of lung function measurement tests. With this approach,
we cannot differentiate between asthma phenotypes in any study
reported in this meta-­analysis. Future randomized controlled trials
or longitudinal studies in children with and without asthma symp-
toms will clarify the role of pulmonary function testing in asthma
diagnosis.
This study has notable strengths. It is the first meta-­analysis com-
paring direct evidence for RSV-­ and RV-­induced bronchiolitis associa-
tions with recurrent wheeze and asthma outcomes. This study did not
use adjusted ORs from the reported data but used raw summary of
data to recalculate individual study ORs and, for the summary of data
that were not directly derived from the published studies, authors of
relevant citations were contacted to release these data. In the anal-
yses, studies that contributed to heterogeneity were identified and,
upon removal of these studies, the overall OR remained positive.
This study has three main limitations. The first limitation is the
small number of studies that were included in the meta-­analysis.
The strict criteria in the age definition of bronchiolitis, which aimed
to provide a more homogeneous group of participants, led to a
reduced number of studies that were considered relevant for the
meta-­analysis. The commonly used method for a random effects
meta-­analysis is the DerSimonian and Laird approach (DL method).
However, this method is suboptimal and may lead to too many sta-
tistically significant results when the number of studies is small and
there is moderate or substantial heterogeneity.65 For this reason,
the Hartung, Knapp, Sidik, and Jonkman (HKSJ method) was fol-
lowed. Data simulation studies have shown that the HKSJ method
performs better than DL, especially when there is heterogeneity
and the number of studies in the meta-­analysis is small.66 The
second limitation is the assessment of the outcomes (preschool
wheeze and asthma). Assessment of the outcome through a tele-
phone questionnaire is different than the assessment during a face-­
to-­f ace clinic appointment and/or through healthcare activity data.
However, a leave-­one-­out sensitivity analysis was carried out with
the removal of the studies that varied in the number of subjects
and the assessment of the outcome and the results are presented in
the manuscript. The third limitation is the lack of assessment of the
impact of a common effect modifier (allergic sensitization or fam-
ily history of allergies) on the meta-­analysis outcome. Due to the
limited number of studies that provided data on this effect modi-
fier, no sub-­analysis could be performed. With upcoming relevant
research evidence, this limitation could be addressed in a future
meta-­analysis.
What is known from interventional studies for RSV bronchiolitis
prevention, treatment with palivizumab in at-­risk populations would
affect incidence of caregiver-­reported wheeze episodes but would
67,68
not impact on asthma development in early and later childhood.
We do not have equivalent data for RV. This meta-­analysis is sug-
gesting that the group of infants with RV-­induced bronchiolitis could
be a suitable group for future intervention studies.
|
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      9 of 11
6  |  CO N C LU S I O N
This is the first meta-­analysis directly assessing between-­virus dif-
ferences in the magnitude of virus long-­term respiratory sequelae.
We demonstrated that the associations of RV-­induced bronchiolitis
with preschool wheeze and asthma are stronger than those for RSV-­
induced bronchiolitis. Infants with RV-­induced bronchiolitis repre-
sent a high-­risk group for recurrent wheeze and school-­age asthma
and could be suitable for interventions studies in the future.
AC K N OW L E D G M E N T S
Dr Hasegawa and Prof Camargo were supported by grant UH3 OD-­
023253 from the National Institutes of Health (Bethesda, MD, USA).
AU T H O R C O N T R I B U T I O N S
Heidi Makrinioti: Conceptualization (lead); data curation (support-
ing); formal analysis (supporting); funding acquisition (support-
ing); methodology (lead); writing –­ original draft (lead); writing
–­ review and editing (lead). Kohei Hasegawa: Conceptualization
(supporting); data curation (supporting); formal analysis (sup-
porting); methodology (supporting); supervision (lead); writing
–­ original draft (lead); writing –­ review and editing (lead). John
Lakoumentas: Data curation (lead); formal analysis (lead); method-
ology (supporting); software (lead); visualization (lead). Paraskevi
Xepapadaki: Writing –­ original draft (supporting); writing –­ review
and editing (supporting). Maria Tsolia: Writing –­ original draft (sup-
porting); writing –­ review and editing (supporting). Jose A. Castro-­
Rodriguez: Methodology (supporting); writing –­ original draft
(supporting); writing –­ review and editing (supporting). Wojciech
Feleszko: Writing –­ original draft (supporting); writing –­ review
and editing (supporting). Tuomas Jartti: Writing –­ original draft
(supporting); writing –­ review and editing (supporting). Sebastian
L. Johnston: Writing –­ original draft (supporting); writing –­ review
and editing (supporting). Andrew Bush: Methodology (support-
ing); supervision (supporting); writing –­ original draft (supporting);
writing –­ review and editing (supporting). Vassiliki Papaevangelou:
Writing –­ original draft (supporting); writing –­ review and edit-
ing (supporting). Carlos A. Camargo Jr: Conceptualization (sup-
porting); methodology (supporting); supervision (lead); writing
–­ original draft (lead); writing –­ review and editing (lead). Nikos
G. Papadopoulos: Conceptualization (lead); funding acquisition
(lead); resources (lead); supervision (lead); writing –­ original draft
(supporting); writing –­ review and editing (supporting).
PEER REVIEW
The peer review history for this article is available at https://publo​
ns.com/publo​n/10.1111/pai.13741.
ORCID
Heidi Makrinioti  https://orcid.org/0000-0003-0832-2744
Paraskevi Xepapadaki  https://orcid.org/0000-0001-9204-1923
Jose A. Castro-­Rodriguez  https://orcid.org/0000-0002-0708-4281
Wojciech Feleszko  https://orcid.org/0000-0001-6613-2012
 |

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10 of 11       MAKRINIOTI et al.

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S U P P O R T I N G I N FO R M AT I O N
Additional supporting information may be found in the online
version of the article at the publisher’s website.
How to cite this article: Makrinioti H, Hasegawa K, Lakoumentas
J, et al. The role of respiratory syncytial virus-­ and rhinovirus-­
induced bronchiolitis in recurrent wheeze and asthma—­A
systematic review and meta-­analysis. Pediatr Allergy Immunol.
2022;33:e13741. doi:10.1111/pai.13741