Evidence for a Causal Relationship between Allergic Sensitization and Rhinovirus Wheezing in Early Life

Abstract

Rationale: Aeroallergen sensitization and virus-induced wheezing are risk factors for asthma development during early childhood, but the temporal developmental sequence between them is incompletely understood. Objective: To define the developmental relationship between aeroallergen sensitization and virus-induced wheezing. Methods: A total of 285 children at high risk for allergic disease and asthma were followed prospectively from birth. The timing and etiology of viral respiratory wheezing illnesses were determined, and aeroallergen sensitization was assessed annually for the first 6 years of life. The relationships between these events were assessed using a longitudinal multistate Markov model. Measurements and Main Results: Children who were sensitized to aeroallergens had greater risk of developing viral wheeze than nonsensitized children (hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.2-3.1). Allergic sensitization led to an increased risk of wheezing illnesses caused by human rhinovirus (HRV) but not respiratory syncytial virus. The absolute risk of sensitized children developing viral wheeze was greatest at 1 year of age; however, the relative risk was consistently increased at every age assessed. In contrast, viral wheeze did not lead to increased risk of subsequent allergic sensitization (HR, 0.76; 95% CI, 0.50-1.1). Conclusions: Prospective, repeated characterization of a birth cohort demonstrated that allergic sensitization precedes HRV wheezing and that the converse is not true. This sequential relationship and the plausible mechanisms by which allergic sensitization can lead to more severe HRV-induced lower respiratory illnesses support a causal role for allergic sensitization in this developmental pathway. Therefore, therapeutics aimed at preventing allergic sensitization may modify virus-induced wheezing and the development of asthma.Keywords: virus; wheezing; allergic sensitization; RSV; human rhinovirus Aeroallergen sensitization and virus-induced wheezing episodes during infancy and early childhood are risk factors for subsequent asthma development, and children with both risk factors in early life are at particularly high risk of having asthma at school age (1, 2). Understanding the sequence of events that lead to sensitization and virus-induced wheezing during early life is important to identifying potential causal relationships in the development of atopic asthma. Early allergic sensitization has consistently been identified as a risk factor for asthma development, and plausible mechanisms by which allergic sensitization leads to greater severity of viral respiratory illnesses have also been proposed (3). If allergic sensitization causes subsequent virus-induced wheezing and asthma inception, then preventing or interrupting the development of allergic sensitization would be a potential strategy for asthma prevention.In contrast to this concept, some animal models of early life infection suggest that virus infection could lead to allergic sensitization (4, 5). In clinical studies, S...

Infantile respiratory syncytial virus and human rhinovirus infections: respective role in inception and persistence of wheezing

“…The synergistic nature of allergic sensitisation and viral infections in infants relative to the onset of obstructive airway diseases was also demonstrated in a clinical study [107], which showed that current wheeze and asthma at 5 years of age were associated with virus-induced acute respiratory illness in children who displayed early allergic sensitisation (⩾2 years of age) but was not observed in nonatopic patients or those sensitised later. Finally, a causal role for allergic sensitisation in favouring or leading to more severe HRV-induced illness is supported by a subsequent evaluation of the COAST study, showing that allergic sensitisation may precede HRV-associated wheezing and may lead to an increased risk of wheezing illness caused by HRV but not RSV [108], while neither HRV-nor RSV-induced wheeze increase the risk of subsequent allergic sensitisation [10,[105][106][107][108]. In agreement with these epidemiological data are the results of a study comparing the immune responses during acute asthma exacerbation and convalescence in children sensitised to house dust mite (HDM).…”

Early-life origins of chronic respiratory diseases: understanding and promoting healthy ageing

“…Synergistic interactions between allergic sensitisation and viral respiratory infections in early life appear to be important in exacerbating the risk [99]. Allergic sensitisation precedes wheezing illness induced by human rhinovirus (HRV) in children who subsequently develop asthma [100]; this typically occurs in children with a genetic predisposition [101]. Trials aimed at preventing the onset of asthma by avoiding contact with allergens have had conflicting results.…”

“…HRV infection usually causes only mild illness [127]. The authors of the Childhood Origins of Asthma (COAST) birth cohort study among 259 children with an atopic background showed that allergic sensitisation preceded HRV wheezing illness, arguing against a causative role for HRV in the inception of asthma [100]. However, HRV-associated wheezing illness has an even stronger relationship with impaired lung function and asthma at school age (6-8 years) than does RSV infection [128,129].…”

Monitoring asthma in childhood

“…Triggers of asthma development are likely to differ from triggers of exacerbations. Recent studies suggest that respiratory viruses, possibly (sub-types of) human rhinovirus in particular, may play a role in triggering the immune system, particularly in children who are already sensitised to allergens [37]. The mechanisms are currently not known but allergic sensitisation appears to be an important underlying feature of triggering disease development; although several hypotheses exist, including an immune circle in asthma development in which repeated airborne irritant stimuli (such as allergens or viruses) evoke cycles of inflammation giving intermittent inflammation resulting in episodic symptoms at first, later turning into more persistent inflammation and disease expression [16].…”