Original Article
The Association of Early Life Viral Respiratory Illness and Atopy on Asthma in Children: Systematic Review and Meta-Analysis

https://doi.org/10.1016/j.jaip.2020.03.032Get rights and content

Background

The interaction between early life viral respiratory illness and atopy in the genesis of asthma has been widely discussed in the literature as the “two-hit hypothesis.”

Objective

To synthesize evidence regarding the association of childhood viral respiratory illness and atopy in the development of persistent wheezing and asthma.

Methods

A systematic review was performed, according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Human studies investigating early life associations between atopy and viral respiratory illness with outcomes of asthma and wheezing were included. Meta-analysis was performed to investigate the association of viral illness across atopic and nonatopic groups. Subgroup analysis was undertaken to investigate potential effect modification of age at outcome.

Results

Nine cohort studies were included, with data available for meta-analysis in 4 birth cohort studies. There was a stronger association of viral respiratory illness with persistent asthma/wheeze in atopic (odds ratio [OR], 4.02; 95% CI, 1.46-11.06) compared with nonatopic (OR, 2.32; 95% CI, 1.22-4.40) individuals; however, the evidence for this was limited. In 3 studies amenable to subanalysis based on outcome age, a stronger effect was observed up to 7 years for those with atopy (OR, 7.27; 95% CI 4.65-11.36) compared with those without atopy (OR, 3.19; 95% CI, 2.09-4.87).

Conclusions

There was a stronger association between viral respiratory illness and asthma/wheeze outcomes in individuals with atopy as compared with those without atopy. When outcomes were considered at younger ages, a greater differential effect was observed. Within the limitations of the few available studies however, definite conclusions cannot be made. There was also insufficient evidence for differential effects of early versus late atopy. Further research, in particular regarding virus type, timing of atopy, and atopic phenotype, would contribute to untangling this complex association.

Introduction

Asthma is the most common chronic disease in childhood, with large and varying global prevalence, affecting up to 14% of all children.1, 2, 3, 4 It has a diverse and heterogeneous phenotypic expression,5 related to airway inflammation, reversible obstruction, and hyperresponsiveness. Multiple interconnected gene-environmental and epigenetic risk factors are implicated in its causation.6, 7, 8, 9, 10, 11 The “two-hit hypothesis” suggests that atopy and viral respiratory infections interact in asthma development.4, 5, 6, 7, 8, 9, 10, 11, 12,12 These factors are both common and have opportunities to exert effects on immature and developing respiratory systems.13, 14, 15

Different mechanisms have been proposed to explain the hypothesized synergy between viral respiratory illness and atopy in asthma risk.13,15, 16, 17 In vitro studies of human respiratory epithelial cells confirm disruption to airway barrier function and greater paracellular permeability by rhinovirus infection.18 Defects in innate immunity may further predispose some individuals to altered responses to viral infections, thereby facilitating the genesis of asthma.19 Differences between respiratory viruses such as respiratory syncytial virus (RSV) and human rhinovirus (HRV) and their relationships with underlying atopy have also been noted.13 Evidence that supports greater susceptibility to asthma in atopic children has been predominantly focused on IgE and TH2 responses; however, there is likely to be greater complexity in immune mechanisms, which may determine eventual asthma phenotypes.20,21

We aimed to synthesize the evidence regarding the hypothesis that for children with atopy, viral respiratory illness in early life (age up to 5 years) results in increased risk of subsequent wheezing, asthma, and lung function impairment, compared with children without atopy. Secondary aims were to determine whether these relationships were influenced by (1) age of confirmed atopy, (2) age at outcome measurement, and (3) frequency of early life respiratory illness.

Section snippets

Search strategy

PubMed and Embase (Elsevier) databases were searched for original articles that explored associations between exposures to viral respiratory illness and atopy with outcomes of asthma and wheezing. Searches were refreshed until the final date of July 16, 2018. Key terms included “asthma,” “wheezing,” “allergic sensitization,” “atopy,” “virus,” and “illness” (see this article's Online Repository at www.jaci-inpractice.org). Cross-checking reference lists of published articles was undertaken to

Results of electronic database searches

Database searches revealed a total of 1935 records. After removal of 281 duplicates, 1654 records were screened according to their title and abstract, and 1565 of these were removed as not meeting inclusion criteria for the systematic review. Full text was obtained for the remaining 89 articles. Of these, 80 articles did not meet inclusion criteria and a total of 9 studies were retained for analysis (Figure 1).

Study designs and locations

From the 9 included studies, there were 8 birth cohort studies13, 14, 15, 16, 17,27,

Discussion

This is the first systematic review that considers the association of viral respiratory illnesses with and without atopy in children, in an attempt to determine effects on the outcomes of wheezing and asthma. In the 4 cohort studies included in the qualitative review,13,14,17,30 greater effects with the combination of both factors were observed. Within the meta-analysis, there was some difference in the association of viral respiratory illnesses with asthma and wheeze across atopic and

Conclusions

In this systematic review and meta-analysis, we observed a differential effect of viral respiratory illnesses across nonatopic and atopic groups, particularly when outcome analyses were limited to studies conducted at younger ages. There was also a differential effect within individual studies that considered atopy early in life. Within limitations of the small number of studies available for inclusion in this systematic review and meta-analysis we found some but insufficient evidence to

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    Conflicts of interest: The authors declare that they have no relevant conflicts of interest.

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