Role of viruses in wheezing and asthma: An overview

INTRODUCTION — Viral respiratory tract infections are the most common cause of wheezing illnesses and asthma exacerbations in both children and adults [1-4]. In young children, infection with viral respiratory infections can induce symptoms of acute bronchiolitis, croup, and recurrent wheezing. Wheezing with viral infections, particularly respiratory syncytial virus (RSV) and human rhinovirus (RV), may predispose infants and young children to develop asthma later in life [5-11]. RV and RSV are the most common viruses detected in wheezing illnesses and asthma exacerbations, although multiple viruses including enteroviruses, bocaviruses, coronaviruses, parainfluenza, influenza, human metapneumoviruses (hMPV), and adenoviruses can trigger acute exacerbations in both children and adults with asthma (table 1) [12].

The mechanisms by which viral respiratory infections trigger wheezing and asthma exacerbations are reviewed here. The influence of viral infection on both the development and perpetuation of asthma is also discussed. Other issues relating to the pathogenesis of asthma are reviewed elsewhere. Treatment of virus-induced wheezing and asthma is also discussed separately. (See "Pathogenesis of asthma" and "Risk factors for asthma" and "Natural history of asthma" and "Treatment of recurrent virus-induced wheezing in young children".)

The differential diagnosis of wheezing in children includes a variety of congenital and acquired conditions (table 2). Other conditions that involve a variety of anatomic airway locations can produce obstruction and expiratory or inspiratory wheezing in adults. The evaluation of patients with wheezing is reviewed in greater detail separately. (See "Evaluation of wheezing in infants and children" and "Evaluation of wheezing illnesses other than asthma in adults".)

Control of environmental triggers of asthma, risk factors for asthma, and the genetics of asthma are discussed in detail separately. (See "Trigger control to enhance asthma management" and "Risk factors for asthma" and "Genetics of asthma" and "Pathogenesis of asthma".)

ROLE OF VIRUSES IN WHEEZING IN INFANTS AND YOUNG CHILDREN — Viruses are a common trigger of wheezing illness in children, and virus-induced wheezing represents a heterogeneous group of illnesses including bronchiolitis, asthma exacerbations, and croup. Bronchiolitis, or inflammation of the bronchioles, is a clinical syndrome characterized by wheezing, tachypnea, and hyperinflation of the lungs [13]. It is of primary importance in infants and young children less than two years of age. A first episode of wheezing in association with a viral respiratory infection leads to an outpatient visit for approximately 15 percent of all infants in the United States, and 3 percent are hospitalized with this presentation [14,15]. Bronchiolitis is covered in greater detail separately. (See "Bronchiolitis in infants and children: Clinical features and diagnosis" and "Bronchiolitis in infants and children: Treatment, outcome, and prevention".)

Specific viruses — A number of respiratory viruses are known to cause acute wheezing illnesses in children less than two years of age. These are covered briefly here and reviewed in detail separately. (See "Bronchiolitis in infants and children: Clinical features and diagnosis", section on 'Viral etiology'.)

●Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and wheezing in this age group, with most infections occurring in winter and spring months. One study examining the causative factors for acute wheezing in infants and children presenting to the emergency department (ED) found that RSV was the most common infectious agent found in children less than two years of age [16]. (See "Respiratory syncytial virus infection: Clinical features and diagnosis in infants and children".)

●Human metapneumovirus (hMPV), a member of the Paramyxoviridae family, is a frequent cause upper and lower respiratory tract infection in infants and children [17]. (See "Human metapneumovirus infections", section on 'Children'.)

●Rhinovirus (RV) is also a common cause of wheezing and bronchiolitis in infancy [18]. (See "The common cold in children: Clinical features and diagnosis", section on 'Virology' and "Epidemiology, clinical manifestations, and pathogenesis of rhinovirus infections".)

●Coronaviruses, enterovirus, adenoviruses, bocaviruses, parainfluenza, and influenza can also provoke wheezing in this age group, as well as in older children and adults [19-23]. (See "Coronaviruses" and "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection" and "Parainfluenza viruses in children" and "Seasonal influenza in children: Clinical features and diagnosis", section on 'Clinical features'.)

Risk factors for acute wheezing — The two major risk factors for acute wheezing with viral infection during the first two years of life include exposure to cigarette smoke, particularly maternal smoking, and persistently reduced lung function [24-29]. In predisposed children, postnatal exposures, such as allergic sensitizations and virus-induced wheezing illnesses, may further influence the future development of asthma [5,10,11,26,30-33].

The data can be summarized as follows:

●A prospective analysis of 1246 children assessing the relationship between initial lung function and the development of a wheezing illness during the first year of life reported that infants with reduced lung function were more likely to develop asthma in childhood. These data are further supported by studies showing that children with prematurity and lower lung function in infancy are at increased risk of RSV-induced lower respiratory illness, recurrent virus-induced wheezing, and asthma [24,25,27,34].

●The Copenhagen Prospective Studies on Asthma in Childhood conducted a prospective trial 411 children at risk for the development of asthma and followed lung function with spirometry and methacholine bronchoprovocation tests as neonates and compared with spirometry conducted in children at age seven years. In this study, children who developed asthma at age seven years had reduced lung function and increased bronchial reactivity as neonates, which then progressed during childhood, with children at age seven years showing progression of the airflow deficits. These findings suggest that children who develop asthma not only exhibit reduced lung function at birth but that wheezing illnesses may worsen lung function in these children [29]. In addition, responses to bacterial and viral pathogens during infancy may further modulate future asthma risk [35].

●Data from the Perth Infant Asthma Follow-up Study showed that bronchial hyperreactivity to histamine during infancy and maternal smoking were associated with an increased risk of wheezing in childhood. However, in subsequent studies, investigators reported that these effects may diminish over time and that postnatal exposures within the environment, such as allergic sensitization and viral infections, play a greater role in lung function and the development of asthma in later childhood and adult life. These findings suggest that a critical window may exist where future asthma risk in predisposed children may be mitigated with interventions that preserve lung function in infancy and early childhood [32,33].

Risk factors for recurrent wheezing — Risk factors associated with recurrent wheezing in children aged 12 to 15 months in a cross-sectional study included parental history of asthma, maternal smoking during pregnancy, patient history of bronchopneumonia, daycare attendance, and early exposure to pets [36]. Children over two years of age with wheezing episodes triggered by viral infection are more likely than those without virus-induced wheezing to have features that are associated with a predisposition to asthma including elevated plasma immunoglobulin E (IgE) levels, sensitization to inhalant allergens, eosinophilic inflammation, and maternal history of asthma [16,37-39].

In addition, the Tucson Children's Respiratory Study described different phenotypes for children who wheeze in early childhood. These phenotypes include the "transient early" phenotype where children primarily wheeze with viral illnesses, with symptoms often resolving by age six years. Children with the "persistent wheezing" and "late-onset wheezing" phenotypes are associated with a higher risk of allergic sensitization and the subsequent development of asthma [25]. Subsequent birth cohort studies have further established the link between recurrent wheezing with viral illnesses, allergic sensitization, and future asthma risk [5,9,40]. (See "Wheezing phenotypes and prediction of asthma in young children".)

ROLE OF VIRUSES IN ASTHMA — Viral respiratory infections infect airway epithelium and interact with host factors to promote an inflammatory response that can trigger wheezing illnesses [5,10,40,41]. In susceptible individuals, the virus-induced immune response may mediate host responses to other microbes, infections, allergens, stress, and pollutants, resulting in wheezing and asthma exacerbations.

Host factors — Although patients with asthma may not be more susceptible to contracting viral illnesses compared with healthy controls, they do suffer a longer duration of symptoms and experience a more severe viral-induced respiratory illness [42]. Host factors likely play a role in this exaggerated immune response to viral infections in patients with asthma.

Respiratory viruses, such as influenza and respiratory syncytial virus (RSV), infect and cause cytopathic damage to airway epithelium, which in turn induces the release of proinflammatory cytokine and chemokines such as thymic stromal lymphopoietin (TSLP), interleukin (IL) 25, and IL-33. In turn, this proinflammatory response propagates eosinophilia and stimulates the release of cytokines that promote asthma and atopic disease (IL-4, IL-5, IL-13) [43-46]. Other viruses, such as rhinovirus (RV), may not damage the epithelium directly but rather interact with macrophages, T cells, or mast cells to stimulate allergic airway inflammation and modulate the host response to allergens, irritants, and the environment [43-46].

Viral factors — Respiratory viral infection and replication activate innate and adaptive antiviral immune responses, resulting in proinflammatory cytokine and chemokine production and the recruitment of inflammatory cells to the airway. Many viruses, including RV, RSV, influenza, coronavirus, human metapneumovirus (hMPV), parainfluenza, adenovirus, and human bocavirus, can trigger wheezing and exacerbations in patients with asthma (table 1). In infants and younger children, wheezing with RSV and RV infection may induce an inflammatory response in a predisposed host that influences the later development of asthma [5-7,9-11,41,47]. (See 'Development of asthma' below.)

Viruses and the microbiome — Studies have suggested that the interaction between viruses and bacteria may increase the risk of wheezing and symptoms of asthma [35,48]. RV infection has been shown to alter the airway microbiome, with increased detection of Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae in children with and without asthma [49,50]. This coalescing of antimicrobial immune responses was associated with increased respiratory symptoms.

Development of asthma — Viral respiratory tract infections in infancy, particularly with RSV and human RV, are predictive of the development of asthma in later childhood to young adulthood [5-8,40,41,51-56]. Factors including the timing of birth and the subsequent exposure to peak bronchiolitis and viral seasons for RSV and potentially hMPV may influence the future development of asthma in a predisposed host [57,58]. However, it remains unclear whether certain viral respiratory infections cause asthma or if wheezing with viral infections in general are predictors for the subsequent development of asthma [59]. (See 'Role of viruses in asthma' above and "Risk factors for asthma", section on 'Respiratory infections'.)

Specific viruses associated with the development of asthma include the following:

●Respiratory syncytial virus – RSV is a frequent cause of wheezing and bronchiolitis in infants and young children. RSV is a single-stranded enveloped RNA virus separated into two antigenic subgroups, A and B. Subtype A is associated with more virulent illness. RSV binds to airway epithelial cells and then replicates, damaging the airway epithelium and inducing the production of proinflammatory cytokines and chemokines, resulting in the recruitment of granulocytes, monocytes, and dendritic cells. The resulting cytopathic injury to the airway epithelium and airway inflammation causes acute respiratory illness, including acute bronchiolitis and wheezing, particularly in children younger than two years (figure 1) [30,60-66].

The causal effect of early-life RSV infections on the subsequent development of asthma is unclear. Observational studies have clearly demonstrated that RSV infections early in life are associated with an increased risk of developing asthma [6,7,67-69]. However, children that have persistent symptoms of asthma or that develop asthma after RSV infection also have asthma risk factors, such as a maternal history of asthma and elevated IgE levels [13,24,25,37,70-75]. In addition, studies investigating whether palivizumab, a monoclonal antibody directed against RSV antigens, prevents the development of recurrent wheeze have yielded mixed results [69,76,77]:

•In findings from a prospective cohort study of premature infants, 146 treated with palivizumab and 171 untreated, RSV prophylaxis decreased the risk of recurrent wheezing in children without a family history of atopy but had no effect in children from atopic families [69]. The data suggest that prevention of RSV infection is an important factor if you are not at risk for atopy but that family history of atopy overrides any influence of RSV prophylaxis when it comes to the risk of developing asthma (ie, prevention of RSV infection is a dependent variable of atopic predisposition).

•In a randomized trial of 429 high-risk infants, treatment of otherwise healthy preterm infants with palivizumab to prevent severe RSV infection was associated with a decreased rate of recurrent wheeze compared with the placebo group (11 versus 21 percent, respectively) [76]. However, a published six-year follow-up of this trial reported that there was no difference between the groups in physician-diagnosed current asthma or lung function [77]. This follow-up trial suggests that further long-term studies are needed to determine if RSV interacts with specific host factors to induce the development of asthma.

●Rhinovirus – RV refers to a genetically diverse species of nonenveloped, positive-stranded RNA viruses that are grouped into RV-A, RV-B, and RV-C serotypes [78]. RV, in contrast to RSV and other respiratory viruses, has few cytopathic effects on airway epithelium or other tissues but does induce a significant airway inflammatory immune response and, in patients with asthma, may impair the antiviral interferon (IFN) response during infections with RV.

Wheezing in the setting of RV infection may influence the development of asthma [5,13,51]. Studies have shown that infants who wheeze with RV infection have increased risk of recurrent wheeze and asthma at ages three, five, and six years [9,40,52]. Findings from a high-risk birth cohort, the Childhood Origins of Asthma Study (COAST), have shown that wheezing with RV infection during the first three years of life was a much stronger risk factor for asthma at six years of age than wheezing with RSV infection or the presence of aeroallergen sensitization [5].

Several studies have shown that RV interacts with host factors, particularly in atopic children, to influence the development of asthma:

•Studies suggest that allergic sensitization in the first year of life is the initial event that interacts with viral infections, particularly RV, to promote the development of asthma in children [5,9,10,31,51,79] (see "Risk factors for asthma"). Several studies implicate plasmacytoid airway mucosa dendritic cells as the antigen-presenting cell that mediates this synergistic inflammation induced by the presence of atopy and viral infections [80-82]. Specifically, upregulation and crosslinking of the Fc epsilon receptor that binds IgE on lung dendritic cells may promote T helper cell type 2 (Th2) inflammation and modulate type I and type III IFN antiviral responses (figure 2) [80-87].

•These findings are further supported by clinical studies in urban children with asthma showing that omalizumab, an anti-IgE monoclonal antibody, decreases the duration of RV infection and the frequency of RV illnesses [88]. Mechanistically, omalizumab was shown to increase IFN-alpha from RV stimulated peripheral blood mononuclear cells, which was associated with fewer asthma exacerbations [89].

•Genotypic variants at the 17q21 locus are associated with both RV wheezing illnesses in early childhood and the development of asthma in these children [90]. Strong interactions with respect to subsequent risk of asthma were demonstrated between 17q21 genotypes and RV-induced wheezing. In addition, variants in the gene encoding cadherin-related family member 3 (CDHR3) may be linked to increasing wheezing illnesses in children by mediating increased RV-C entry into host cells [78,91]. (See "Genetics of asthma" and "Risk factors for asthma".)

●Human metapneumovirus (hMPV) – hMPV is an RNA paramyxovirus with phylogenetic similarity to RSV. hMPV is a frequent cause of acute respiratory illness in children and adults, accounting for approximately 5 percent of acute respiratory illnesses in hospitalized children [19]. The virus typically peaks between December and April in the Northern Hemisphere and January to May in the Southern Hemisphere. The severity of illness is often greater in premature infants. The following studies are illustrative:

•Surveillance data have shown that hMPV detection in hospitalized children younger than five years of age is associated with an increased risk of intensive care unit (ICU) stays and need for supplemental oxygen during hospitalization [92].

•Retrospective data suggest that young children hospitalized with hMPV lower respiratory tract infections have an increased risk of developing asthma at age five years [17]. This increased risk of asthma development was similar to RSV-associated risk in this small study.

•Prospective data for one small study suggest that hMPV is associated with a higher risk of recurrent wheezing and potentially subsequent asthma diagnoses, although an increased risk of asthma development at age six years was not established [93].

●Influenza – Children and adults with asthma are at an increased risk of hospitalizations and respiratory morbidity during acute influenza respiratory infections [94,95]. Children with asthma were particularly prone to increased ICU stays and pneumonia during the 2009 to 2010 H1N1 pandemic. Influenza, along with RSV and parainfluenza, is also associated with a higher risk of emergency department (ED) treatment failure for acute respiratory illness (c) [95].

●Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – Asthma does not appear to be a strong risk factor for acquiring coronavirus disease 2019 (COVID-19; SARS-CoV-2) or to increase the risk of more severe disease or death for the majority of patients [96-99]. Neither the use of inhaled glucocorticoids nor the diagnosis of asthma conferred an increased risk of hospitalization in a large, single-center, electronic health records-based study of a mostly adult population [100]. Patients hospitalized with COVID-19 infection and a history of asthma do not suffer an increased rate of SARS-CoV-2 pneumonia, acute respiratory distress syndrome (ARDS), or death, although one US case series reported a link between asthma and prolonged intubation time in adults aged 18 to 65 years with asthma who were hospitalized with COVID-19 [101,102]. Molecular analyses have shown that two airway epithelial proteins that are in part modulated by asthma and allergic disease (angiotensin-converting enzyme 2 [ACE2] and the transmembrane protease serine 2 [TMPRSS2]) also mediate cell entry of the SARS-CoV-2 virus. Preliminary studies suggested that some patients with asthma may express lower levels of ACE2 in airway epithelium [103-105]. However, the regulation of ACE2 and TMPRSS2 is poorly understood and known to be mediated by other chronic diseases. Further study is needed to determine the role of these proteins in SARS-COV-2 infection. (See "An overview of asthma management", section on 'Advice related to COVID-19 pandemic'.)

Additional information about COVID-19 is provided separately. (See "COVID-19: Vaccines" and "COVID-19: Management in children" and "COVID-19: Evaluation of adults with acute illness in the outpatient setting" and "COVID-19: Management in hospitalized adults".)

Asthma exacerbations — Viral respiratory infections are an important cause of increased pulmonary symptoms in children and adults with preexisting asthma [13,38,39,51,106-108]. Studies have shown that viral infections trigger up to 85 percent of asthma exacerbations in school-aged children and up to 50 percent of exacerbations in adults [109,110]. RV is the predominant pathogen identified in school-aged children and adult patients with acute asthma exacerbations [5,9,40,51,52]. Infection with RV-C is associated with more severe disease in children admitted for asthma exacerbations [111-113].

Viral upper respiratory infections (URIs or colds) are the most frequent cause of asthma exacerbations. RV is the most frequent viral trigger for asthma exacerbations and may contribute to seasonal asthma morbidity. In adults and children, the presence of allergic sensitization is associated with a higher risk of wheezing and asthma exacerbations [114] and worsening asthma control during RV-triggered asthma exacerbations compared with individuals with asthma but no allergies [10].

One community study, for example, was conducted to identify the role of viral infections in asthma exacerbations in 9- to 11-year-old children [109]. In this study, 108 children were followed for 13 months, during which episodes of wheezing were documented and nasal specimens obtained for culture and polymerase chain reaction (PCR) analysis for viruses. The following results were observed:

●Viruses were detected in over 80 percent of the episodes of reduced peak flow and wheezing.

●Increased symptoms of asthma usually occurred within 48 hours of developing a URI and persisted for at least two weeks.

●The most commonly identified virus was RV (increasingly RV-C), accounting for approximately 60 percent of infections and wheezing episodes. RV-C was associated with more severe asthma exacerbations.

In another study, one-third to one-half of weekly respiratory isolates obtained from six- to eight-year-old children with asthma contained detectable virus, with 72 to 99 percent of the viruses identified as RV [11]. A subsequent weekly surveillance study during the H1N1 pandemic reported that samples from children with asthma were twice as likely to detect influenza as compared with children without asthma [115].

A more subjective study of 138 adult patients with asthma found that colds were reported during 80 percent (223 of 280) of episodes of wheezing, chest tightness, or breathlessness, and 89 percent (223 of 250) of colds were associated with asthma symptoms [109].

Asthma hospitalizations — Viral infections, especially with RV, are the leading cause of increased rates of hospitalization for asthma that are consistently observed in late summer and early fall in many countries, including the United States, Canada, Mexico, and Israel [116-118]. As an example, a Canadian study documented that asthma hospitalizations among school-aged children increased predictably after return to school following summer vacation and other breaks [119]. Specifically, a September (or fall/autumnal) asthma epidemic is observed in this age group during the third week of the month, with lesser increases in asthma admissions two days later in preschool children and six days later in adults, consistent with transmission of viral infections (figure 3).

A similar peak in asthma hospitalization caused by RV infection is seen in the Southern Hemisphere in mid-February, which also coincides with their fall and the onset of the school year [120]. A winter peak is primarily due to RSV, and a spring peak is caused by both RSV and RV. hMPV peaks in the winter season and extends through spring season [19].

The association between acetaminophen use and the development of asthma is discussed in greater detail separately. (See "Risk factors for asthma", section on 'Acetaminophen'.)

SUMMARY

●Viral respiratory infections, particularly with respiratory syncytial virus (RSV) and rhinovirus (RV), are the most common causes of wheezing in infants and young children, and they have important influences on the development of asthma (table 1). In addition, viral infections, most often with RV, are the most common causes of wheezing and asthma exacerbations in children and adults with pre-existing asthma. (See 'Introduction' above.)

●RSV is the most common cause of bronchiolitis and wheezing in children less than two years of age. Exposure to tobacco smoke and reduced lung function are risk factors associated with virus-induced wheezing in this age group. Respiratory viruses other than RSV are more common triggers in young children greater than two years of age. Human metapneumovirus (hMPV) is frequently associated with acute respiratory illnesses in infants and children younger than five years of age. Risk factors associated with recurrent virus-induced wheezing in this age group are associated with a predisposition to asthma, including allergic sensitization. (See 'Role of viruses in wheezing in infants and young children' above.)

●Respiratory viruses interact with allergic sensitization and other microbes to promote recurrent virus-induced wheezing and the development of asthma via a number of mechanisms including increased recruitment of inflammatory cells, promotion of cytokine production, enhancement of allergic inflammation, and augmented airways hyperresponsiveness. (See 'Role of viruses in asthma' above.)

●Wheezing with viral respiratory infections, particularly with RSV and RV, are important predictors of the subsequent development of asthma. However, it is unclear whether certain viral respiratory infections play a role in asthma inception or if wheezing with these infections is a predictor of childhood asthma. (See 'Development of asthma' above.)

●Viral respiratory infections are the most common cause of wheezing in children and adults with preexisting asthma. RV is the predominant pathogen and the most frequent trigger of virus-induced exacerbations in patients with preexisting asthma. Patients with asthma do not appear to be more susceptible to RV infection than healthy controls. However, they are at greater risk of developing more severe and prolonged lower respiratory tract symptoms with infection. (See 'Asthma exacerbations' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Sujani Kakumanu, MD, who contributed to earlier versions of this topic review.