The Relationship Between Respiratory Syncytial Virus and Asthma

Epidemiology

RSV is a seasonal virus in temperate climates with infection rates peaking during winter months. However, in tropical climates, RSV infection can occur year-round. ⁸ While virtually all children eventually become infected with RSV, only 0.5% to 2% of infants require hospitalization during their initial exposure. ⁷⁶ Hospitalizations during RSV infection are a result of airway dysfunction caused by inflammation of the bronchioles resulting in bronchiolitis. Reinfection by RSV can occur throughout one’s lifetime as sterilizing immunity is not generated following infection. ^22,25,28 However, subsequent RSV exposures are believed to be less severe in healthy adults.

Link Between Severe RSV Infection and Development of Recurrent Wheezing or Asthma

A large number of studies have identified a link between severe RSV infection and an increased likelihood to develop either recurrent wheezing or asthma.* The Avon Longitudinal Study of Parents and Children by Henderson et al ²⁹ revealed that children admitted to the hospital for RSV-induced bronchiolitis prior to the age 1 year were at increased risk of developing recurrent wheezing at 30 to 42 and 69 to 81 months compared with the control group (28.1% vs 13.1% and 22.6% vs 9.6%, respectively). Furthermore, 38.4% of the severe RSV group developed asthma by age 7 years compared with only 20.1% of the control group. Similar results were observed in a long-term Swedish study of 140 children by Sigurs et al. ⁸⁰ Children who experienced a severe RSV infection prior to 1 year of age were at a much greater risk of developing asthma by age 7.5 years (30% vs 3% of control group). In addition, recurrent wheezing symptoms were more likely to occur in the children who experienced RSV-induced bronchiolitis (28%) compared with the control group (11%). A 5-year and a 10-year follow-up study of the same cohort revealed similar trends. Children who had experienced a severe RSV infection during infancy exhibited a significantly greater incidence of either recurrent wheezing (30% vs 16.3%) or asthma (37% vs 5.4%) by age 13 years. ⁸¹ The incidence of recurrent wheezing (30% vs 1%) remained significantly higher in children with an early severe RSV infection by age 18 years. ⁷⁹ The authors also noted that children who had experienced an early severe RSV infection were more likely to develop allergic sensitization to common inhaled or food allergens at any of the 3 age time points investigated. ^{79 –81} Since allergen sensitization is a major risk factor associated with asthma inception, severe RSV infection during early childhood may contribute to the development of asthma through sensitization to common allergens. ^60,68,84,86 Overall, these studies suggest that experiencing a severe RSV infection during early childhood increases the likelihood of developing asthma later in life.

While numerous studies indicate a link between early severe RSV infection and an increased risk in developing asthma, the exact nature of the relationship is unclear. The results from the Tennessee Asthma Bronchiolitis Study (TABS) of 95 310 children by Carroll et al ¹⁰ and Wu et al ⁹⁸ suggest that a causal relationship exists between severe RSV infection and the development of asthma. This study assessed the relationship between the risk of developing asthma by age 5.5 years and the time of year at which there was the greatest number of bronchiolitis-related hospitalizations (BRHs). The number of BRHs peaks every year during the winter months in temperate climates. If there was no relationship between the risk of developing asthma and severe bronchiolitis, then rates of asthma among children would be expected to be similar year-round irrespective of patterns of BRH. However, the authors observed similar patterns between the timing of the peak of BRHs and the likelihood of infants developing asthma. Children born 4 months prior to the annual peak of BRHs were 29% more likely to develop asthma compared with infants born 1 year from this time point. This relationship was similar across the 5-year study even though the peak of BRHs shifted by up to 6 weeks. It was not determined if children were infected with a specific virus such as RSV, although up to 70% of severe bronchiolitis cases are associated with RSV infection. ⁵⁸ The TABS suggests that viral infection during childhood directly contributes to an increased risk of developing asthma.

Influence of Age in Longitudinal RSV and Asthma Studies

Although a number of studies indicate an increased risk of developing recurrent wheezing later during childhood following a severe RSV infection, a few longitudinal studies suggest these changes are transient. A study by Pullan and Hey ⁶⁵ determined that children with severe RSV infections prior to 1 year of age experienced recurrent wheezing symptoms primarily during the first 4 years of life (38% vs 15% of control group). However, by age 10 years, there was no longer a significant difference in rates of wheezing (6.2% vs 4.5%). Similar results were observed in the Tucson Children’s Respiratory Study of 1246 children. ^87,91 Infants who experienced a severe RSV infection in the first 3 years of life were at a significantly increased risk of exhibiting recurrent wheezing symptoms at ages 6 and 11 years. However, there was no significant difference in infrequent or frequent wheezing symptoms by age 13 years. These data are in contrast to the longitudinal study by Sigurs et al ⁸¹ that demonstrated a significant increase in children with asthma by age 13 years. The differential findings reported in these studies could be due to many factors, including genetic variability among cohorts, parameters used to select the cohort, how wheezing/asthma is evaluated, and differences in the relative pathogenicity of circulating RSV strains.

Palivizumab Prophylaxis Treatment and the Development of Recurrent Wheezing

An alternative approach to determining if RSV contributes to the development of asthma is to limit RSV-induced disease. Although there is currently no licensed vaccine, passive immunization has shown some promise. ^24,69 In the mid-1990s, a monoclonal antibody specific for the fusion protein of RSV, palivizumab, was evaluated across the United States, United Kingdom, and Canada for efficacy in the prophylactic treatment of RSV infection. ¹ Palivizumab prophylaxis reduced RSV-associated hospitalization rates by 55% (10.6% placebo vs 4.8% palivizumab). Due to cost considerations, palivizumab prophylaxis is administered only to children at high risk of developing severe RSV-induced disease, such as preterm infants. In a study by Simoes et al, ⁸² preterm infants who either had received or had never been administered palivizumab prophylaxis were followed for development of wheezing symptoms.

This study indicated there were long-term benefits to lessening the severity of RSV infection. The rates of recurrent wheezing were compared between infants with prophylactic treatment who were not hospitalized for severe RSV infection and children who were hospitalized for RSV-induced bronchiolitis without prior palivizumab treatment. Children from the prophylaxis group were significantly less likely to develop physician-diagnosed recurrent wheezing (8% vs 16% of no prophylaxis group) by 3.5 years of age. ⁸² These data further support the notion that severe RSV infection may contribute to the development of asthma.

Lung Function

Infants younger than 6 months are highly susceptible to RSV-induced bronchiolitis. ^21,59 This is likely due to their reduced pulmonary function since lung development continues for several years. ^49,100 Length of hospital stay often correlates with the degree of lung dysfunction, and a significant number of infants with severe RSV-induced disease require mechanical ventilation. ⁹⁰ If severe RSV infection increases an individual’s risk of asthma inception, there may be long-term alterations to the lung environment. In agreement, children evaluated approximately 6 years after a severe RSV infection exhibited significantly reduced respiratory capacity compared with infants who were not hospitalized for RSV infection. ⁶³ A study by Korppi et al ³⁷ also demonstrated reduced lung function in young adults 20 years after a severe RSV infection. Similar results were observed in a number of other studies in which children exhibited reduced lung function 7 or more years after a severe RSV infection. ^{11,41,50,55,81,85} These studies indicate that severe RSV infection may alter the lung environment and lead to prolonged lung dysfunction long after the infection is resolved.

Immune Response

Infection with RSV results in a significant increase in proinflammatory cytokines and chemokines such as interleukin (IL)–1α, IL-1β, IL-6, IL-8, interferon (IFN)–γ, tumor necrosis factor (TNF)–α, monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein (MIP)–1α, and MIP-1β. Since asthma is a chronic inflammatory disease, severe RSV infection may promote a prolonged inflammatory environment within the lung that leads to the development of asthma. Nasopharyngeal aspirates obtained from asthmatic infants infected with RSV by age 2 years revealed significantly elevated IL-6 protein levels compared with controls. ⁵⁶ Furthermore, in murine models of allergic inflammatory disease, protein levels of proinflammatory chemokines MIP-1α and CCL5 (RANTES) were elevated and significantly contributed to allergic airway inflammation. ^36,71 Increased levels of RANTES protein also have been correlated with increased RSV disease severity. Studies also suggest that an imbalance in the type of CD4 T-cell response further exacerbates allergic responses. Infection by RSV at an early age tends to induce a type 2 helper T-cell response (Th2) that produces IL-4, IL-5, and IL-13. ^6,14 A Th2-biased immune response is known to contribute to disease in murine models of allergic airway inflammation and is strongly associated with asthmatic patients. ^{13,17,32,73,78} Therefore, infection by RSV at an early age may induce a Th2-biased immune response that promotes asthma inception.

Recent work also suggests a role for IL-17–induced pathogenesis in a subset of asthmatic patients. IL-17 is secreted by type 17 helper T cells (Th17) and can induce the chemotaxis of granulocytes such as neutrophils or directly signal through cells such as fibroblasts and macrophages to produce proinflammatory cytokines IL-1β, IL-6, and TNF-α. ⁵¹ Levels of IL-17 are elevated in the sputum and bronchoalveolar lavage (BAL) of asthmatic human patients. ^15,51 A Th17-biased immune response and subsequent neutrophilia is also observed in mice following allergic sensitization to ovalbumin (OVA). ⁹⁷ Furthermore, both IL-17 secretion and neutrophil influx were necessary to mediate granulocytic chemotaxis, mucus hypersecretion, and airway hypersensitivity following allergic sensitization. ^51,97 These studies indicate that Th17 responses play a critical role in mediating particular forms of asthma. In addition, levels of IL-17 are elevated in both humans and mice with severe RSV infection. ⁵² Neutralization of IL-17 signaling during RSV infection significantly reduced granulocytic infiltrate, airway resistance, and mucus hypersecretion. ⁵² These data suggest that elevated Th17 responses following RSV infection may increase an individual’s susceptibility to developing asthma.

Two-Hit Hypothesis

It is possible that children who are genetically predisposed to developing asthma will eventually develop chronic lung inflammation and are more likely to experience greater morbidity from RSV infection. Children who exhibit bronchiolitis prior to 1 year of age show signs of reduced lung function at 5 weeks old. ¹⁰⁰ However, as discussed, a number of studies suggest that severe RSV infection may increase an individual’s risk of developing asthma later in life. Children younger than 6 months exhibit the greatest risk of severe morbidity from an RSV infection. ^21,59 It is unclear how RSV infection would promote asthma, a chronic lung disease, years after the primary infection has been resolved.

It has been proposed that the development of asthma may require a “2-hit” scenario as illustrated in Fig. 1. ^31,42 This hypothesis suggests that asthma inception depends on the interaction of at least 2 genetic, developmental, or environmental factors. An example may be a polymorphism in a cytokine that predisposes an individual to develop allergic responses. If an individual with this polymorphism experiences a severe RSV infection, he or she is more likely to exhibit either long-term symptoms or chronic inflammation such as asthma. The 2-hit hypothesis also predicts that if only one factor is present, then either disease or allergic responses would be transient. This may explain why not all children who experience severe RSV-induced bronchiolitis develop asthma as well as why some children with early childhood wheezing exhibit resolution of their illness by their adolescence. ^46,65,87,88 A number of gene polymorphisms are associated with both asthma and susceptibility to severe RSV-induced disease, as discussed below.

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Figure 1.

Proposed model of severe respiratory syncytial virus (RSV) infection and asthma inception based on the “2-hit” hypothesis. A young infant must have a combination of 1 or more genetic factor(s) and RSV-related immunological factor(s) to develop asthma as suggested by the 2-hit hypothesis. An infant with a genetic predisposition to allergen sensitization can develop asthma following a severe RSV infection. For example, an infant with a gain-of-function gene polymorphism for the cytokine interleukin (IL)–4 may exhibit a Th2-biased immune response following a severe RSV infection. In the absence of either a genetic factor or a severe RSV infection, thus not fulfilling a 2-hit scenario, the infant will likely experience either transient pulmonary dysfunction or no disease at all. A child with a gain-of-function CCL5 polymorphism who experiences a mild RSV infection is an example of this, likely having either short-term pulmonary dysfunction or no long-term disease. Last, an infant who experiences a mild or asymptomatic RSV infection with no genetic predisposition toward allergic sensitization will exhibit no long-term disease.

Cytokines

Cytokines play a significant role in influencing the type of immune response that develops following infection. Cytokines such as IL-4 and IL-13 are primarily produced by Th2 CD4 T cells and play a crucial role in the induction of some allergic immune responses. Children with gain-of-function polymorphisms in both IL4RA and IL13 are almost 5 times as likely to develop asthma compared to individuals without polymorphisms in either gene. ³² Gain-of-function polymorphisms in IL-4 and IL-13 cytokine genes have also been reported to be increased in children hospitalized for RSV infection. ^30,66 A study by Ermers et al ¹⁷ also determined that following a severe RSV infection, children with the IL13-R130Q polymorphism were significantly more likely to experience wheezing at age 6 years. In addition, children with low IFN-γ, a type 1 helper CD4 T-cell (Th1)–associated cytokine, also exhibited an increased risk in developing recurrent wheezing during infancy. ^20,89 Taken together, these studies indicate that an imbalanced immune system, Th2 biased over Th1, may contribute to severe RSV infection and subsequent asthma inception.

Chemokines

Chemokines are critical for the recruitment and adhesion of leukocytes during infection. Polymorphisms in either chemokines or their receptors may predispose an individual toward chronic pulmonary inflammation and increase disease severity following respiratory viral infection. The chemokine CCL5, also known as RANTES, is an important chemotactic agent for Th2-associated immune cells, including Th2 cells, eosinophils, and basophils. Gain-of-function polymorphisms in the promoter region of the CCL5 gene have been associated with asthma and severe airway dysfunction. ⁴⁰ These promoter region polymorphisms have also been correlated with severe cases of RSV-induced bronchiolitis. ³ A study of 320 Chinese children with RSV-induced bronchiolitis revealed an increased risk of infants with CCL5 promoter region polymorphisms to exhibit severe morbidity during RSV infection and an increased likelihood to develop recurrent wheezing. ⁹⁴ Furthermore, children with elevated CCL5 levels from nasal epithelium at the time of RSV-induced bronchiolitis exhibit an increased risk of developing asthma by age 7 years. ⁵

Attachment of the RSV virion to the host epithelial cell is mediated through the G protein of RSV, which is necessary for optimal infection. ^43,92 While the G protein of RSV typically binds to highly sulfated heparin-like glucosaminoglycans, it also contains a chemokine motif similar to CX3CL1 or fractalkine. ^19,96 The CX3CL1 mimicry function of RSV likely allows the virus to alter the host immune response. ^12,96 A T280M mutation in CX3CR1, which encodes for the receptor that binds CX3CL1, has also been associated with increased morbidity following RSV infection and an increased risk of developing asthma. ^4,95 These studies suggest that excessive CX3CL1-CX3CR1 signaling following RSV infection in children with CX3CR1 polymorphisms further predisposes those infants to asthma inception.

IL-8 is a chemokine secreted by epithelial cells and macrophages that recruits primarily neutrophils but also targets macrophages, mast cells, endothelial cells, and keratinocytes. Therefore, IL-8 is an important mediator of the innate immune system to initiate inflammation. Two separate studies by Hull et al ^33,34 demonstrate that gain-of-function polymorphisms in the promoter region of IL8 lead to increased disease severity in infants following RSV infection. Polymorphisms in IL-8 are also associated with an increased risk of developing asthma. ⁶⁷ Furthermore, a study of 164 children in the United Kingdom revealed that children with a IL-8 polymorphism were significantly more likely to have episodes of wheezing following RSV-related bronchiolitis. ²³ Taken together, these studies suggest that genetic predispositions to allergic illness can alter the disease severity of RSV infection and the subsequent development of asthma.

Immune Tolerance

RSV infection may also increase the susceptibility to develop allergic immune responses by breaking immune tolerance to allergens early in life. Regulatory T cells (Tregs) play an essential role in mediating immune tolerance and prevention of immune responses to allergens. ⁴⁴ Tregs can regulate the immunogenicity of dendritic cells (DCs) by reducing DC expression of the costimulatory molecules CD80 and CD86 as well as expression of major histocompatibility complex (MHC) class II. ⁴⁴ However, infection of mice with RSV following OVA sensitization significantly inhibits the suppressive capacity of Tregs. ³⁸ The impaired Treg response correlates with increased DC expression of the costimulatory molecules CD40 and CD86 as well as MHC class II. This suggests that if immune tolerance is broken by RSV infection, infants may be more susceptible to the development of chronic inflammation to allergens and subsequent asthma. Furthermore, RSV infection may differentially affect the function of various DC subsets. RSV infection of myeloid DCs, but not plasmacytoid DCs, leads to the upregulation of maturation markers and an increased capacity to induce the proliferation of OVA-specific T cells in vitro. ⁷ Previous work has indicated that immunogenic myeloid DCs are important for promoting allergic sensitization, whereas plasmacytoid DCs are tolerogenic. ⁵⁷ Together, these studies suggest that impaired regulation of allergic immune responses following RSV infection can contribute to the development of asthma.