Causal Direction Between Respiratory Syncytial Virus Bronchiolitis and Asthma Studied in Monozygotic Twins

doi:10.1378/chest.10-0365

Chest

Volume 138, Issue 2, August 2010, Pages 338-344

https://doi.org/10.1378/chest.10-0365 Get rights and content

Background

Respiratory syncytial virus (RSV) bronchiolitis has been associated with later development of asthma, wheezing, abnormal pulmonary function, and sensitization. Our aim was to determine the differential effect within monozygotic (MZ) twin pairs discordant for severe RSV bronchiolitis in infancy on the subsequent development of asthma, pulmonary function, and allergy.

Methods

Thirty-seven MZ twin pairs discordant for RSV hospitalization in infancy (mean age 10.6 months) were compared at the mean age of 7.6 years for lung function, bronchial responsiveness, fractional exhaled nitric oxide (Feno), asthma diagnosis, use of asthma medication, and skin prick test to common inhalant allergens.

Results

There were no differences within MZ twin pairs discordant for RSV hospitalization in infancy with respect to pulmonary function, Feno, asthma prevalence, asthma medication use, or sensitization (P > .1 for all comparisons).

Conclusions

We found no differential effect from severity of RSV infection on the development of asthma and allergy in MZ twin pairs discordant for RSV hospitalization in infancy. This argues against a specific effect of severe RSV infection in the development of asthma and allergy. Because of the small sample size, this study must be considered as a hypothesis-generating study.

Section snippets

Materials and Methods

The study was approved by the ethics committee of Copenhagen (KA-20060022) and by the Danish Data Protection Agency (J.nr. 2005-41-5163 and J.nr. 2005-2311-0121). The children were enrolled after written consent was obtained from the parents or guardians.

Results

During the period from January 1, 1994, to December 31, 2003, 12,349 twin pairs were born in Denmark. The proband-wise concordance rate of hospitalization for RSV bronchiolitis was significantly higher in MZ (0.66) than in dizygotic twin pairs (0.53), P = .02.²⁰ Fifty-seven MZ twin pairs (26 boys) were discordant for RSV hospitalization (Fig 1). Nine pairs were unavailable because of death or address protection. Five pairs were excluded based on their hospital records because the RSV infection

Discussion

We found no difference within cohabiting MZ twin pairs discordant for hospitalization for RSV bronchiolitis in infancy on asthma prevalence, baseline lung function, bronchial responsiveness, biomarker of airway inflammation (Feno), and sensitization 7 years after such severe RSV bronchiolitis. Though a number of criticisms may be raised, including the small study population, it is noteworthy that no trends suggested a differential effect from severe RSV infection. Therefore a strong effect from

Acknowledgments

Author contributions: Dr Poorisrisak: contributed to the planning of the visits, performed the experimental work, and contributed to the presentation, interpretation, and discussion of the obtained data.

Dr Halkjaer: contributed to the planning of the visits, was involved in the experimental work, and contributed to the discussion of the obtained data.

Dr Thomsen: contributed to the formulation of the scientific problem, the methodology design, and discussion of the obtained data.

Dr Stensballe:

References (35)

RT Stein et al.
Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years
Lancet
(1999)
RL Smyth et al.
Bronchiolitis
Lancet
(2006)
H Bisgaard et al.
Plethysmographic measurements of specific airway resistance in young children
Chest
(2005)
H Bisgaard et al.
Determinants of lung function and airway hyperresponsiveness in asthmatic children
Respir Med
(2007)
DW Cockcroft et al.
Determination of histamine PC20. Comparison of linear and logarithmic interpolation
Chest
(1983)
LG Stensballe et al.
The causal direction in the association between respiratory syncytial virus hospitalization and asthma
J Allergy Clin Immunol
(2009)
M Eriksson et al.
Wheezing following lower respiratory tract infections with respiratory syncytial virus and influenza A in infancy
Pediatr Allergy Immunol
(2000)
BJ Selwyn et al.
The epidemiology of acute respiratory tract infection in young children: comparison of findings from several developing countries
Rev Infect Dis
(1990)
JT McBride
Pulmonary function changes in children after respiratory syncytial virus infection in infancy
J Pediatr
(1999)
N Sigurs et al.
Asthma and immunoglobulin E antibodies after respiratory syncytial virus bronchiolitis: a prospective cohort study with matched controls
Pediatrics
(1995)

N Sigurs et al.

Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13

Am J Respir Crit Care Med

(2005)

J Henderson et al.

Hospitalization for RSV bronchiolitis before 12 months of age and subsequent asthma, atopy and wheeze: a longitudinal birth cohort study

Pediatr Allergy Immunol

(2005)

CB Pedersen et al.

The Danish Civil Registration System. A cohort of eight million persons

Dan Med Bull

(2006)

L Christiansen et al.

Age- and sex-differences in the validity of questionnaire-based zygosity in twins

Twin Res

(2003)

KO Kyvik et al.

The new Danish Twin Registry: establishment and analysis of twinning rates

Int J Epidemiol

(1995)

LG Stensballe et al.

Diagnosis coding in The Danish National Patient Registry for respiratory syncytial virus infections

Scand J Infect Dis

(2005)

E Von Mutius

Presentation of new GINA guidelines for paediatrics. The Global Initiative on Asthma

Clin Exp Allergy

(2000)

Cited by (47)

The full value of immunisation against respiratory syncytial virus for infants younger than 1 year: effects beyond prevention of acute respiratory illness
2023, The Lancet Infectious Diseases
Respiratory syncytial virus (RSV) is a leading cause of severe respiratory illness and death among children worldwide, particularly in children younger than 6 months and in low-income and middle-income countries. Feasible and cost-effective interventions to prevent RSV disease are not yet widely available, although two new products aimed at preventing RSV disease—long-acting monoclonal antibodies and maternal vaccines—have been licensed within the past 2 years. The primary target of these products is reduction of the substantial burden of RSV-associated acute lower respiratory tract infections (LRTI) in infants younger than 1 year. However, other important public health benefits might also accrue with the prevention of RSV-associated LRTI during the first year of life. Mounting evidence shows that preventing RSV-associated LRTI in infants younger than 1 year could prevent secondary pneumonia caused by other pathogens, reduce recurrent hospitalisations due to other respiratory diseases in later childhood, decrease all-cause infant mortality, ameliorate the burden of respiratory diseases on health-care systems, reduce inappropriate antibiotic use, and possibly improve lung health beyond infancy. We herein review current evidence and suggest approaches to better assess the magnitude of these potential secondary effects of RSV prevention, which, if proven substantial, are likely to be relevant to policy makers in many countries as they consider the use of these new products.
Moderate-to-severe lower respiratory tract infection in early life is associated with increased risk of polysensitization and atopic dermatitis: Findings from the CHILD Study
2022, Journal of Allergy and Clinical Immunology: Global
Respiratory infections in infancy are associated with the development of allergic asthma and atopy. Delineating whether symptomatic infections are a marker of atopic predisposition or contribute to atopic development is important for preventive strategies. We hypothesized that early, severe lower respiratory tract infections (LRTIs) may be a risk factor for the development of atopic disease.
Our aim was to determine whether clinically defined, moderate-to-severe LRTIs in infancy are associated with the development of atopic dermatitis and allergic sensitization at preschool age.
LRTI timing and severity in the first 18 months of life was defined by using the Canadian Healthy Infant Longitudinal Development study questionnaires. Polysensitization and atopic dermatitis were determined by standardized skin prick testing and structured clinical assessments. Longitudinal associations between LRTI severity and clinical outcomes at ages 3 years and 5 years were determined by adjusted repeated measures generalized estimation equations.
Moderate-to-severe LRTIs were associated with increased odds of polysensitization (odds ratio = 1.91 [95% CI = 1.16-3.15]; P = .014) and atopic dermatitis (odds ratio = 2.19 [95% CI 1.41-3.39]; P < .001) as compared with the odds in children with no history of LRTI in the first 18 months of life. The association between moderate-to-severe LRTI and polysensitization or atopic dermatitis remained robust after adjusting for sex; study site; breast-feeding duration; and mother, father, or both-parent atopy or asthma.
These results highlight severe infant LRTI as an important risk factor for allergic and atopic disease (ie, polysensitization and atopic dermatitis), and they suggest that this risk is independent of maternal in utero environment, both-parent history of asthma, and both-parent genetic predisposition.
Early-life respiratory syncytial virus lower respiratory tract infection in a South African birth cohort: epidemiology and effect on lung health
2020, The Lancet Global Health
Citation Excerpt :
A key unresolved question is whether the association of RSV LRTI with recurrent wheezing reflects an underlying genetic or physiological susceptibility to wheezing, with RSV being the initial manifestation of such susceptibility, or whether RSV is part of a causal pathway leading to recurrent wheezing.4,23 The former possibility is supported by data from twin registry studies.4,24,25 Several lines of evidence from our study suggest that the link between RSV and recurrent wheezing might not simply reflect underlying susceptibility.
Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection (LRTI) in children. Early-life RSV LRTI might affect long-term health but there are few data from low-income and middle-income countries. We investigated the epidemiology and effect of early-life RSV LRTI on lung health in a South African birth cohort.
We conducted the Drakenstein Child Health Study (DCHS), an ongoing birth cohort longitudinal study in the Western Cape province, South Africa. We enrolled pregnant women aged 18 years or older during their second trimester of pregnancy at two public health clinics. We followed up study children from birth to 2 years. The primary outcome of the study was LRTI and RSV LRTI. LRTI and wheezing episodes were identified through active surveillance; respiratory samples were tested for RSV and other pathogens. Wheezing was longitudinally identified by caregiver report and ascertainment at health facilities. Lung function was measured from 6 weeks to 2 years. We analysed the associations between RSV LRTI and subsequent LRTI, wheezing, and lung function using generalised estimating equations and mixed-effects linear regression.
We enrolled 1137 mothers between March 5, 2012, and March 31, 2015. Among their 1143 infants, accruing 2093 child-years of follow-up, there were 851 cases of LRTI (incidence 0·41 episodes per child-year, 95% CI 0·38–0·43). Admission to hospital owing to LRTI occurred in 169 (20%) cases (incidence 0·08 episodes per child-year, 0·07–0·09), with a case-fatality ratio of 0·5%. RSV was detected in 164 (21%) of 785 LRTI events with a specimen available for qPCR, an incidence of 0·08 episodes per child-year (0·07–0·09); highest at age 0–6 months (0·15 episodes per child-year, 0·12–0·19). Children with a first RSV LRTI were three times as likely to develop recurrent LRTI compared with those with non-RSV LRTI (0·32 [0·22–0·48] vs 0·10 [0·07– 0·16] episodes per child-year; p<0·0001), particularly following hospitalised RSV LRTI. RSV LRTI and hospitalisation for all-cause LRTI were independently associated with recurrent wheezing (adjusted incident rate ratio 1·41, 95% CI 1·25–1·59, for RSV LRTI and 1·48, 1·30–1·68, for hospitalisation). LRTI or recurrent LRTI was associated with impaired lung function, but a similar outcome was observed following RSV LRTI or non-RSV LRTI. All-cause LRTI was associated with an average 3% higher respiratory rate (95% CI 0·01–0·06; p=0·013) and lower compliance (–0·1, −0·18 to 0·02) at 2 years compared with no LRTI. Recurrent LRTI was associated with further increased respiratory rate (0·01, 0·001–0·02), resistance (0·77 hPa s L⁻¹, 0·07–1·47), and lower compliance (–0·6 mL hPa⁻¹, −0·09 to −0·02) with each additional event.
RSV LRTI was common in young infants and associated with recurrent LRTI, particularly after hospitalised RSV. Hospitalisation for all-cause LRTI, especially for RSV-LRTI, was associated with recurrent wheezing. Impairments in lung function followed LRTI or recurrent episodes, but were not specific to RSV. New preventive strategies for RSV might have an effect on long-term lung health.
Bill & Melinda Gates Foundation; South African Medical Research Council; National Research Foundation South Africa; National Institutes of Health, Human Heredity and Health in Africa; Wellcome Trust.
Assessing the strength of evidence for a causal effect of respiratory syncytial virus lower respiratory tract infections on subsequent wheezing illness: a systematic review and meta-analysis
2020, The Lancet Respiratory Medicine
Citation Excerpt :
First, RSV-LRTI exposure studies controlling for genetic influences produced smaller effect estimates, consistent with what we would expect if RSV-LRTI were at least partly a marker of genetic susceptibility rather than a purely causal association. Although this finding was not fully robust in a leave-one-out sensitivity analysis, all but one16 of the studies controlling for genetic influences measured genetic risk using imperfect proxies (eg, familial asthma history) and could only partly remove heritable influences. Consequently, our models probably underestimated the influence of adjusting for genetics.95,96
Although a positive association has been established, it is unclear whether lower respiratory tract infections (LRTIs) with respiratory syncytial virus (RSV) cause chronic wheezing illnesses. If RSV-LRTI were causal, we would expect RSV-LRTI prevention to reduce the incidence of chronic wheezing illnesses in addition to reducing acute disease. We aimed to evaluate the strength of evidence for a causal effect of RSV-LRTI on subsequent chronic wheezing illness to inform public health expectations for RSV vaccines.
We did a systematic review and meta-analysis of observational studies evaluating the association between RSV-LRTI and subsequent wheezing illness (exposure studies) and studies evaluating the association between RSV immunoprophylaxis and subsequent wheezing illness (immunoprophylaxis studies). Exposure studies were included if the exposure group members had an LRTI with laboratory-confirmed RSV and if the exposure ascertainment period began before 2 years of age and ended before 5 years of age. We required a wash-out period of more than 30 days between the index RSV-LRTI and the outcome measurement to allow for resolution of the acute illness. Comparisons between RSV-LRTI and non-RSV-LRTI were not included. Immunoprophylaxis studies were included if they measured the association with subsequent wheezing illness relative to a control group, either in a randomised controlled trial (RCT) or an observational design. For the immunoprophylaxis drugs in question, we required evidence of efficacy in targeting RSV-LRTI from at least one RCT to ensure biological plausibility. All variations of wheezing illness were combined into a single outcome that refers broadly to asthma or any other respiratory illness with wheezing symptoms. Ovid MEDLINE and Embase databases were searched from inception up to Aug 28, 2018. We evaluated whether data from exposure studies could provide evidence against the most viable non-causal theory that RSV-LRTI is a marker of respiratory illness susceptibility rather than a causal factor. Additionally, we tested whether RSV immunoprophylaxis reduces the odds of subsequent wheezing illnesses. We used a random-effects modelling framework and, to accommodate studies providing multiple correlated estimates, robust variance estimation meta-regressions. Meta-regression coefficients (b) quantify differences between exposure and comparator groups on the log_e odds ratio (log_e OR) scale.
From 14 235 records we identified 57 eligible articles that described 42 studies and provided 153 effect estimates. 35 studies estimated the direct effect of RSV-LRTI on wheezing illnesses (exposure studies) and eight evaluated the effect of RSV immunoprophylaxis (immunoprophylaxis studies). Exposure studies that adjusted for genetic influences yielded a smaller mean adjusted OR estimate (aOR₊ 2·45, 95% CI 1·23–4·88) compared with those that did not (4·17, 2·36–7·37), a significant difference (b 0·53, 95% CI 0·04–1·02). Infants who were not protected with RSV immunoprophylaxis tended to have higher odds of subsequent wheezing illness, as we would expect if RSV-LRTI were causal, but the effect was not significant (OR₊ 1·21, 95% CI 0·73–1·99). There was generally a high threat of confounding bias in the observational studies. Additionally, in both the observational studies and immunoprophylaxis RCTs, there was high risk of bias due to missing outcome data.
Our findings, limited to exposure and immunoprophylaxis studies, do not support basing policy decisions on an assumption that prevention of RSV-LRTI will reduce recurrent chronic wheezing illnesses.
Bill & Melinda Gates Foundation.
Does respiratory syncytial virus lower respiratory illness in early life cause recurrent wheeze of early childhood and asthma? Critical review of the evidence and guidance for future studies from a World Health Organization-sponsored meeting
2020, Vaccine
Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection (LRTI) and hospitalization in infants and children globally. Many observational studies have found an association between RSV LRTI in early life and subsequent respiratory morbidity, including recurrent wheeze of early childhood (RWEC) and asthma. Conversely, two randomized placebo-controlled trials of efficacious anti-RSV monoclonal antibodies (mAbs) in heterogenous infant populations found no difference in physician-diagnosed RWEC or asthma by treatment group. If a causal association exists and RSV vaccines and mAbs can prevent a substantial fraction of RWEC/asthma, the full public health value of these interventions would markedly increase. The primary alternative interpretation of the observational data is that RSV LRTI in early life is a marker of an underlying predisposition for the development of RWEC and asthma. If this is the case, RSV vaccines and mAbs would not necessarily be expected to impact these outcomes. To evaluate whether the available evidence supports a causal association between RSV LRTI and RWEC/asthma and to provide guidance for future studies, the World Health Organization convened a meeting of subject matter experts on February 12–13, 2019 in Geneva, Switzerland. After discussing relevant background information and reviewing the current epidemiologic evidence, the group determined that: (i) the evidence is inconclusive in establishing a causal association between RSV LRTI and RWEC/asthma, (ii) the evidence does not establish that RSV mAbs (and, by extension, future vaccines) will have a substantial effect on these outcomes and (iii) regardless of the association with long-term childhood respiratory morbidity, severe acute RSV disease in young children poses a substantial public health burden and should continue to be the primary consideration for policy-setting bodies deliberating on RSV vaccine and mAb recommendations. Nonetheless, the group recognized the public health importance of resolving this question and suggested good practice guidelines for future studies.
Determining the outcomes of interventions to prevent respiratory syncytial virus disease in children: what to measure?
2018, The Lancet Respiratory Medicine
Respiratory syncytial virus (RSV) is the most common cause of viral acute lower respiratory tract illness (LRTI) in young children, and a major cause of hospital admissions and health-care utilisation globally. Substantial efforts have been made to develop RSV vaccines and vaccine-like monoclonal antibodies to prevent acute RSV LRTI. Prevention of acute disease could improve long-term lung health, with potential effects on wheezing, asthma, and chronic lung disease. This Personal View describes assessments that should be initiated during clinical trials and continued after licensure to fully evaluate the effect of RSV preventive interventions. These assessments include recording the incidence of RSV-specific LRTI and all-cause LRTI through two RSV seasons, and assessment of the prevalence and severity of recurrent wheezing or asthma in children aged up to 6 years. Standardised assessments in diverse settings are needed to fully determine the effect of interventions for the prevention of RSV disease.

View all citing articles on Scopus

: Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).

View full text

Chest

Original ResearchAsthmaCausal Direction Between Respiratory Syncytial Virus Bronchiolitis and Asthma Studied in Monozygotic Twins

Background

Methods

Results

Conclusions

Section snippets

Materials and Methods

Results

Discussion

Acknowledgments

Lancet

Lancet

Chest

Respir Med

Chest

J Allergy Clin Immunol

Wheezing following lower respiratory tract infections with respiratory syncytial virus and influenza A in infancy

Pediatr Allergy Immunol

The epidemiology of acute respiratory tract infection in young children: comparison of findings from several developing countries

Rev Infect Dis

Pulmonary function changes in children after respiratory syncytial virus infection in infancy

J Pediatr

Asthma and immunoglobulin E antibodies after respiratory syncytial virus bronchiolitis: a prospective cohort study with matched controls

Pediatrics

Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13

Am J Respir Crit Care Med

Hospitalization for RSV bronchiolitis before 12 months of age and subsequent asthma, atopy and wheeze: a longitudinal birth cohort study

Pediatr Allergy Immunol

The Danish Civil Registration System. A cohort of eight million persons

Dan Med Bull

Age- and sex-differences in the validity of questionnaire-based zygosity in twins

Twin Res

The new Danish Twin Registry: establishment and analysis of twinning rates

Int J Epidemiol

Diagnosis coding in The Danish National Patient Registry for respiratory syncytial virus infections

Scand J Infect Dis

Presentation of new GINA guidelines for paediatrics. The Global Initiative on Asthma

Clin Exp Allergy

Original Research
Asthma
Causal Direction Between Respiratory Syncytial Virus Bronchiolitis and Asthma Studied in Monozygotic Twins