Infections and Asthma

Respiratory infections can cause wheezing illnesses in children of all ages and also may influence the development and severity of asthma. Respiratory tract infections caused by viruses,1, 2, 3 chlamydia4, 5, 6, 7 or mycoplasma5, 8, 9, 10 have been implicated in the pathogenesis of asthma. Of these respiratory pathogens, viruses have been demonstrated to be epidemiologically associated with asthma in several ways (Figure 35-1 ). First, certain viruses associated with infantile wheezing have been implicated as potentially being responsible for the inception of the asthmatic phenotype.^{11 , 12} Second, in children with established asthma, viral upper respiratory tract infections (URIs) play a significant role in producing acute exacerbations that may result in healthcare utilization.13, 14, 15 Furthermore, children who develop severe viral respiratory infections in the first 3 years of life are more likely to have asthma later in childhood.3, 11, 16 Several host factors, including respiratory allergy^{13 , 17} and virus-induced interferon responses18, 19, 20 modify the risk of virus-induced wheezing. Treatment of virus-induced wheezing and exacerbations of asthma can be challenging and studies evaluating current treatment strategies are reviewed. For infections with other microbial agents, attention has focused on chlamydophila and mycoplasma,^{5 , 7} as potential contributors to both exacerbations and the severity of chronic asthma. Finally, colonization of the upper airways in infancy with common bacterial pathogens has been associated with increased risk of subsequent asthma. We review these various associations as they pertain to both the pathogenesis and treatment of childhood asthma.

Figure 35-1.

Infections and asthma. Infections can influence the pathophysiology of asthma in a number of ways. First, they may be involved in the inception of the asthmatic phenotype within the first decade of life. Second, once asthma is clinically recognized, viral infections may cause disease exacerbations in patients with both intermittent and persistent phenotypes. Third, if asthma goes into remission, it is possible that certain infections may contribute to disease relapse. Fourth, infections may contribute to disease chronicity and/or severity over time. Fifth, infections (based on their type, frequency, target organ involvement, and/or timing) may actually prevent the development of allergic sensitization and perhaps asthma as well. Finally, allergic sensitization and allergen exposures may act as important cofactors in the clinical expression of the asthmatic response to various infections.

Epidemiology

Relationship of Virus-Induced Wheezing in Infancy to Childhood Asthma

One of the most common viral illnesses that leads to lower respiratory tract infection (LRI) and wheezing in infancy is respiratory syncytial virus (RSV). Using multiple virus detection methods, including polymerase chain reaction (PCR), Jartti and colleagues²¹ investigated the etiology of wheezing illness in 293 hospitalized children. Of the 76 infants with virus detected, 54% had RSV, 42% had picornavirus (human rhinovirus [HRV] and enterovirus) and 1% had human metapneumovirus-1 (hMPV). In older children, respiratory picornaviruses dominated (65% of children aged 1 to 2 years and 82% of children aged ≥ 3 years).²¹ From 1980 to 1996, the rates of hospitalization of infants with bronchiolitis increased substantially²² and RSV was the etiology in about 70% of these episodes.

However, bronchiolitis is a severe form of RSV infection that occurs in a minority of children. By the age of 1 year, 50% to 65% of children will have been infected with this virus and by the age of 2 years, nearly 100%²³ Children aged 4 months and born close to the onset of the viral season are most prone to the development of lower respiratory tract symptoms,^{24 , 25} and this is likely to be due to a developmental component (e.g. airway, lung parenchyma, and/or immunologic maturation).²³ Furthermore, infant birth 4 months before the winter virus peak predicts an increased likelihood of developing childhood asthma.²⁴ Additional risk factors for bronchiolitis include antiviral immune responses (both innate²⁶ and adaptive²⁷), gender, lung size, and passive smoke exposure.¹⁶

Several large, long-term prospective studies of children have demonstrated that RSV bronchiolitis is a significant independent risk factor for recurrent wheezing and asthma, at least within the first decade of life.^{12 , 28} A longitudinal, population-based cohort study has demonstrated that the association between RSV LRIs and both frequent (>3 episodes) and infrequent wheezing (<3 episodes) decreased markedly with age and becomes nonsignificant by the age of 13 years.¹² A decrease in the frequency of wheezing with increasing age after documented RSV infections has been observed by other investigators as well.^{29 , 30} These data suggest that although RSV infections contribute substantially to the risk of recurrent wheezing and asthma in early childhood, other cofactors (e.g. genetic, environmental, developmental) also contribute to the initial expression of asthma or modification of the phenotype over time.

Although a bronchiolitis diagnosis during infancy is associated with an approximately 2-fold increased risk of early childhood asthma, this risk differs by season of bronchiolitis. Bronchiolitis occurring during HRV-predominant months (spring and fall) was associated with an estimated 25% increased risk of early childhood asthma compared with RSV-predominant (winter) months. However, the proportion of associated asthma after winter season bronchiolitis is greater than HRV-predominant months because of higher rates of bronchiolitis during the RSV season.³¹ Another study by Kuesel and coworkers demonstrated that although RSV was associated with more severe LRI requiring hospitalization, HRV was associated with more than three times the number of both wheezing and nonwheezing LRI in infancy. These findings support the concept that HRV is also an important cause of bronchiolitis and appears to be most indicative of the risk for developing asthma.¹¹

Host factors such as atopy or decreased lung function in infancy may also potentiate the risk of recurrent wheeze and/or asthma. Premorbid measurements of lung function indicate that children with reduced levels of lung function in infancy appear to be at an increased risk of the development of chronic lower respiratory tract sequelae after viral infections³² and an obstructive pattern of lung function into adulthood.³³ Whether reduced lung function alone is responsible for these developments is presently unknown. Children with early atopy (less than 2 years) were more likely to be diagnosed with current wheeze or asthma if they had an LRI with RSV or HRV in infancy.³ Thus, viral infections may interact with atopy and reduced lung function in infancy to promote later asthma.

Viral Respiratory Infections and Acute Exacerbations of Asthma

The relationship between viral infections and and exacerbations of asthma has been clarified by the advent of sensitive diagnostic tests, based on the polymerase chain reaction (PCR), for viruses that are difficult to culture, such as HRV, hMPV, and bocaviruses. With the advent of these more sensitive diagnostic tools, information linking common cold infections with exacerbations of asthma has come from a number of sources. Prospective studies of subjects with asthma have demonstrated that up to 85% of exacerbations of wheezing or asthma in children are caused by viral infections.¹⁵ Although many respiratory viruses can provoke acute asthma symptoms, HRVs are most often detected, especially during the spring and fall HRV seasons. In fact, the spring and fall peaks in hospitalizations because of asthma closely coincide with patterns of HRV isolation within the community.¹⁴ HRV infections are frequently detected in children older than 2 years who present to emergency departments with acute wheezing¹³ and in children hospitalized for acute asthma.³⁴ A newly discovered HRV species, HRV-C, is associated with asthma exacerbations in children during the fall and winter.35, 36, 37 Influenza and RSV are somewhat more likely to trigger acute asthma symptoms in the winter but appear to account for a smaller fraction of total asthma flares. Other viruses that are less frequently associated with exacerbations of asthma include bocavirus, metapneumonvirus, and coronaviruses.³⁸ Together, these studies provide evidence of a strong relationship between viral infections, particularly those because of HRV, and acute exacerbations of asthma.

It is interesting that individuals with asthma do not necessarily have more colds, and neither the severity nor the duration of virus-induced upper respiratory symptoms is enhanced by respiratory allergies or asthma.^{39 , 40} In contrast to findings in the upper airway, a prospective study of colds in couples consisting of one asthmatic and one normal individual demonstrated that colds cause greater duration and severity of lower respiratory symptoms in subjects with asthma.⁴⁰ These findings suggest that asthma is associated with fundamental differences in the lower airway, but not necessarily upper airway, manifestations of respiratory viral infections. In addition to provoking asthma, HRV infections can increase lower airway obstruction in individuals with other chronic airway diseases (e.g. chronic obstructive pulmonary disease and cystic fibrosis).^{41 , 42} Thus, common cold viruses that produce relatively mild illnesses in most people can cause severe pulmonary problems in selected individuals.

Viral Respiratory Infections and the Hygiene Hypothesis

The ‘hygiene hypothesis’ postulates that some viral or bacterial infections might actually protect against the subsequent development of allergies and asthma. David Strachan first noted that the risk of the development of allergies and asthma is inversely related to the number of children in the family,⁴³ an observation that has been duplicated in a number of subsequent studies.44, 45, 46 This finding has led to speculation that infectious diseases, which are more likely to be transmitted in large families or daycare centers,^{47 , 48} could modulate the development of the immune system in a manner to reduce the chances of developing allergies. This hypothesis implies that the immune system is skewed toward a T helper cell type 2 (Th2)-like response pattern at birth. In support of this concept, there is experimental evidence to show that Th1-like interferon responses are depressed at birth⁴⁹ and are more likely to be depressed in children who develop recurrent wheezing.²⁰ According to this hypothesis, each viral infection would provide a stimulus for the development and/or activation of Th1-like immune responses. The result of this repetitive stimulation would be to change the polarization of the Th system away from a Th2 overexpression and thus reduce the risk for developing allergies (Figure 35-2 ).

Figure 35-2.

The hygiene hypothesis. According to this hypothesis, children are born with an immature immune system that is skewed toward T helper cell type 2 (Th2) responses. Exposure to infections or microbial products soon after birth provides Th1-like stimuli that help the immune system to develop balanced T cell responses. In the absence of these stimuli, the Th2 skewing persists, and with exposure to allergens in the environment, allergy and atopic disorders are likely to develop.

(Modified from Gern JE, Busse WW. J Allergy Clin Immunol 2000; 106:201–212.)

However, there is no evidence that viral infections of the respiratory tract protect against either allergies or asthma, and in fact, as previously described, bronchiolitis and pneumonias in infancy indicate an increased risk of subsequent asthma. This has led to speculation that the site of infection might also be an important factor related to asthma risk, and it is possible the gastrointestinal infections are protective. Other epidemiologic and biologic factors that influence the risk of allergic sensitization and/or asthma include early exposure to pets, a farming lifestyle, alterations in bacterial flora of the gut, and increased use of antibiotics.⁵⁰ Furthermore, exposure to high levels of endotoxin in the home, such as occurs in farmhouses, is associated with reduced rates of allergy and an enhanced number of interferon-producing cells in peripheral blood.^{51 , 52} Collectively, these studies suggest that exposure to microbes may have a greater effect than actual infections on immune development and the risk of atopy and asthma. Other epidemiologic and biologic factors that have been considered to influence the development of allergic sensitization and/or asthma are reviewed in detail in Chapters 2 and 6.

Can Chronic Infections Cause Asthma?

It has been proposed that chronic viral and bacterial infections or colonization with pathogenic bacteria could initiate chronic lower airway inflammation, impaired mucociliary clearance, increased mucus production and ultimately in asthma.^{53 , 54} Organisms primarily implicated in this process include Adenovirus,⁵⁵ Chlamydophila pneumoniae,4, 5, 7 Mycoplasma pneumoniae, 8, 9, 10 S. pneumoniae, H. influenzae, and M. catarrhalis.⁵⁴ Studies of chronic mycobacteria or chlamydophila infection and asthma in children have yielded conflicting results, probably in part due to the limitations of current diagnostics. Findings of diagnostic tests in the upper and lower airways are not always concurrent, and diagnosis of infection by serology leads to inaccuracies.

Historically, the first potential association between asthma and C. pneumoniae was reported in 1991 in 19 wheezing adult asthmatic patients, of whom 9 were found to have serologic evidence of current or recent infection with this organism.⁶ In school-age children with wheezing, an unexpectedly high prevalence of low-grade C. pneumoniae infection in nasal aspirates has been reported.⁵⁶ The detection of C. pneumoniae infection by PCR and serology (secretory IgA) was similar during symptomatic and asymptomatic episodes (23% vs 28%, respectively). Children who reported multiple episodes also tended to remain PCR positive for C. pneumoniae, suggesting chronic infection. Further, C. pneumoniae-specific secretory IgA antibodies were more than 7 times greater in subjects who reported four or more exacerbations in the study compared with those who reported just one. In a study of 70 pediatric patients undergoing flexible fiberoptic bronchoscopy, 40% PCR C. pneumoniae-positive samples were from patients with asthma. Culture of the blood samples revealed that a significantly higher proportion of asthma subjects (34.3%) were positive for Chlamydia compared to matched nonrespiratory control subjects (11%).⁴ It is interesting to speculate that chronic chlamydophila infection promotes ongoing airway inflammation that increases susceptibility to other exacerbating stimuli such as viruses, allergens, or both.

Thus far, the most comprehensive evaluation of the role of both chlamydophila and mycoplasmal infections in chronic asthma was recently reported by Martin and colleagues.⁵³ This group of investigators evaluated 55 adult patients with chronic asthma (percent predicted forced expiratory volume in 1 second [FEV₁] = 69.3 [2.1%]) and 11 controls for infection with Mycoplasma, C. pneumoniae, and viruses. Bronchoalveolar lavage cell count and differential, as well as tissue morphometry, were also evaluated. Of the asthmatic patients, 56% had a positive PCR for M. pneumoniae (N = 25) or C. pneumoniae (N = 7), which was mainly found in lavage fluid or biopsy samples. Only 1 of 11 control subjects had a positive PCR for Mycoplasma. A distinguishing feature between patients with positive and negative PCR results was the significantly greater number of tissue mast cells in the group of patients who were positive on PCR. Cultures for both organisms were negative in all patients, and serologic confirmation correlated poorly with PCR results. In another study by Biscardi and colleagues, 119 children, aged 2 to 15 years, with a previous history of asthma and hospitalized for a severe asthma exacerbation were tested for acute infection due to M. pneumoniae or C. pneumoniae determined by positive results of serologic testing. Nasopharyngeal aspirate PCR was also performed. Acute M. pneumoniae infection by positive serology was found in 20% and C. pneumoniae infection was found in 3.4% of the patients during the current exacerbation. Of 51 patients experiencing their first asthma attack, acute M. pneumoniae infection was proven in 50% of the patients and C. pneumoniae in 8.3%. Of the children experiencing their first asthma attack and infected with M. pneumoniae or C. pneumoniae, 62% had asthma recurrences but only 27% without these infections had asthma recurrences.⁹ Similar to the previous study, serologic confirmation correlated poorly with PCR results. Chronic chlamydophila infection may possibly promote ongoing airway inflammation that increases susceptibility to other exacerbating stimuli such as viruses, allergens, or both.

To further substantiate the contribution of C. pneumoniae to asthma, the results of pharmacologic intervention trials are noteworthy. In one study, roxithromycin was administered for 6 weeks to a group of adult asthmatic patients who had serologic evidence of concurrent infection with C. pneumoniae and a small but significant improvement was observed in both morning and evening peak expiratory flow rates; however, these improvements were not sustained several months after the discontinuation of therapy and no control group was included.⁵⁷ In a pediatric trial, 71 children aged 2 to 14 years with an acute episode of wheezing and 80 age-matched healthy children were studied. Sera for specific antibody levels and nasopharyngeal aspirates for the PCR detection of M. pneumoniae and C. pneumoniae were obtained on admission and after 4 to 6 weeks. All children with wheezing received a standard therapy with inhaled corticosteroids and bronchodilators for 5 to 7 days and 30.9% received a 10-day course of clarithromycin irrespective of serological and PCR results, on the judgement of the pediatrician in charge. During the 3-month follow-up period, among children with evidence of acute M. pneumoniae and/or C. pneumoniae infection, significantly more (69.2%) nonantibiotic-treated subjects showed recurrence of wheezing; conversely, none of the clarithromycin-treated patients showed a new episode of wheezing.¹⁰ To date, the data are difficult to interpret because of the limited number of studies, difficulty in eradicating Chlamydia and Mycoplasma infection, and the fact that many of the macrolide antibiotics have antiinflammatory effects in addition to serving as antimicrobials.⁵⁸

If C. pneumoniae infection does indeed contribute to asthma chronicity, disease severity, and instability, what mechanisms may contribute to these effects? In this regard, some investigators have proposed that the development of C. pneumoniae-specific immunoglobulin E (IgE) antibody causes the release of mediators that lead to bronchospasm, airway inflammation, and airway reactivity.⁵⁹ Unless the organism was eradicated with antibiotic therapy, antigenic stimulation leading to specific IgE production would persist, thereby explaining the protracted course of asthma in some patients that is unresponsive to the aggressive use of bronchodilators and steroids.⁵⁹ In addition, as indicated previously, a major C. pneumoniae antigen is heat shock protein 60 (cHSP60). This protein has been implicated in the induction of deleterious immune responses in human chlamydial infections and has been found to colocalize with infiltrating macrophages in atheromatous lesions. Recently, cHSP60 was found to be a potent inducer of macrophage inflammatory responses mediated through the innate immune receptor complex TLR4-MD2 (Toll-like receptor 4).⁶⁰ These latter findings suggest that chronic asymptomatic chlamydial infections may perpetuate ongoing airway inflammatory responses through both innate and adaptive immune responses.

As briefly introduced previously, M. pneumoniae also has been associated with both acute and chronic asthma. Various investigators have not been able to uniformly establish the potential for mycoplasmal infections to induce acute exacerbations of asthma. Although some have reported infection in up to 25% of children with wheezing,⁶¹ others have not been able to substantiate these observations.⁵⁶ Indeed, when the same population of children was evaluated for the relative contributions of mycoplasmal (and chlamydial) infections to acute exacerbations, viral etiologies were by far the most frequently implicated.^{12 , 56} It is possible that these data may be altered in the future as more sensitive and specific serologic diagnostic tests become available and/or culture techniques improve.

In contrast to the effects of pathogenic Mycoplasma species on acute asthma exacerbations, associations of this microbe with chronic asthma have been more securely established. Using PCR techniques on bronchial biopsy specimens, Mycoplasma species have been detected in 25 of 55 adult asthmatic subjects and only 1 of 11 controls.²⁴ Case reports of chronic asthma beginning with M. pneumoniae infection suggest that this infection is potentially a causative agent in some patients.⁶² In this regard, possible causal mechanisms of Mycoplasma-induced airway inflammation have been investigated, including increased Th2 responses and inflammatory neuropeptides. Children with acute M. pneumonia have an elevated interleukin (IL)-4/interferon (IFN)-γ ratio compared with children with pneumococcal pneumonia or controls,⁶³ and mice experimentally infected with M. pneumoniae develop airway hyperresponsiveness (AHR), which is associated with decreased production of mRNA for IFN-γ.⁶⁴ In addition, asthmatic patients with M. pneumoniae infection detected by PCR have elevated levels of neurokinin 1, which responds to treatment with a macrolide antibiotic.⁶⁵

One additional mechanism implicated in the pathogenesis of chronic asthmatic symptoms is latent adenovirus infection.⁵⁵ A latent infection occurs when a virus incorporates itself into the host cell DNA and continues to periodically express viral genes. Respiratory disease caused by adenoviruses can be followed by latent infection that persists for many years.⁶⁶ A Slovenic study demonstrated that 94% of children with steroid-resistant asthma had detectable adenovirus antigens compared with 0% of controls.⁶⁷ In adults, both with and without asthma, evidence of adenoviral infection has been reported to be as high as 50% of the individuals tested.⁵³

A recent study by Bisgaard and coworkers found that neonates colonized in the hypopharyngeal region with S. pneumoniae, H. influenzae, or M. catarrhalis, or with a combination of these organisms, are at increased risk for recurrent wheeze early in life and the diagnosis of asthma at the age of 5 years.⁵⁴ Although these preliminary results are intriguing, additional studies are needed to establish causality and the specificity of these observations to asthma pathogenesis and to define immunoinflammatory mechanisms contributing to these associations in both adult and pediatric patients.

Sinus Infections and Asthma

The nature of the association between asthma and sinusitis in children (and adults) has been the subject of debate for many years. Much of the difficulty in defining this relationship results from the uncertainties in making the clinical diagnosis of sinusitis, because the signs and symptoms of sinusitis in children overlap with many common childhood respiratory disorders, including the common cold, allergic rhinitis, and asthma. As reviewed in Chapter 30, untreated sinus disease may contribute to unstable asthma control in some patients. Because bacterial infections are clearly involved in acute and chronic sinus disease, the mechanisms by which these microbes may promote AHR in the lower airway have been of great interest. These relationships are covered in depth elsewhere in this text and therefore are not further reviewed in this chapter.

Mechanisms of Virus-Induced Wheezing and Asthma

Several mechanisms have been proposed to explain how respiratory viruses cause wheezing illnesses and exacerbations of asthma (Box 35-1 ). First, viral infections damage airway epithelial cells and can cause airway edema and leakage of serum proteins into the airway. These effects, together with shedding of infected cells into the airway, can lead to obstruction and wheezing. In addition, virus-induced immune responses are necessary to clear the viral infection, but could also contribute to airway dysfunction and symptoms by causing influx of inflammatory cells that adversely affect lower airway physiology. Respiratory viruses can enhance airway inflammation by directly infecting lower airway tissues, or possibly by infecting the upper airway and then inducing a systemic immune response that potentiates lower airway inflammation. Environmental factors may be important influences on the outcome of viral infections, and viral infections and other known triggers for asthma exert synergistic effects to cause acute exacerbations. Allergy is a strong risk factor for the development of asthma after virus-induced wheezing episodes in infancy, and is also closely associated with virus-induced exacerbations of asthma in older children and adults with asthma. For example, effects of colds on asthma may be amplified by exposure to allergens¹⁷ and by exposure to greater levels of air pollutants.⁶⁸ Mechanisms underlying virus-induced wheezing episodes and asthma will be discussed in the following sections.

BOX 35-1. Key concepts.

Proposed Mechanisms of Virus-Induced Asthma and Wheezing

• •Virus-induced damage to airways.
• •Airway edema and transudation of serum proteins.
• •
  Respiratory viral infections may enhance underlying airway inflammation in asthma in at least two ways:

  • Directly through infection of lower airway epithelial cells
  • Indirectly after infection of the upper airway through the generation of systemic immune responses
• •A characteristic feature of respiratory viral infections is their ability to enhance airway responsiveness in both normal and asthmatic individuals.
• •Interactions between respiratory viral infections and allergic inflammation.

Viral Infections of the Lower Airway

Respiratory viruses such as RSV and influenza are well known to infect the lower airway, and both can cause bronchitis, bronchiolitis, and pneumonia. HRV has traditionally been considered to be an upper airway pathogen because of its association with common cold symptoms and the observation that HRV replicates best at 33–35°C, which approximates temperatures in the upper airway. In fact, lower airway temperatures have been directly mapped using a bronchoscope equipped with a small thermistor.⁶⁹ During quiet breathing at room temperature, airway temperatures are conducive to HRV replication down to fourth-generation bronchi and exceed 35°C only in the periphery of the lung. Moreover, HRV appears to replicate equally well in cultured epithelial cells derived from either upper or lower airway epithelium.⁷⁰ Finally, HRV has been detected in lower airway cells and secretions by several techniques after experimental inoculation.71, 72, 73 Titers of infectious virus in lower sputum reach or exceed those found in nasal secretions in some individuals.⁷³ In addition to evidence from experimental infection models, HRV is frequently detected in infants and children with lower respiratory signs and symptoms, including children hospitalized for pneumonia.⁷⁴ Collectively, these findings suggest that respiratory viruses, including HRV, are likely to cause wheezing illnesses and exacerbations of asthma mainly by infecting lower airways and causing or amplifying lower airway inflammation.

Role of Virus-Induced Inflammation

Epithelial Cells

Respiratory viruses replicate primarily in upper and lower airway epithelial cells (Figure 35-3 ). Virus-induced injury to the epithelium can disrupt airway physiology through a number of different pathways (Box 35-2 ). For example, epithelial edema and sloughing together with mucus production can lead to airway obstruction and wheezing. The resultant epithelial damage can also increase the permeability of the mucosal layer,⁷⁵ which may facilitate contact of irritants and allergens with immune cells, leave neural elements exposed, and enhance viral replication in less differentiated basal epithelial cells.⁷⁶

Figure 35-3.

Virus-induced inflammation. Airway epithelial cells are the principal host cells for viral replication and, through the release of cytokines and chemokines, help to initiate the immune response to viral infection. In turn, these factors recruit mononuclear cells into the airway, and after the initial round of viral replication, these cells are activated by virus. Virus-induced cytokines, together with unique viral products such as double-stranded RNA (dsRNA), are potent inducers of antiviral responses. In addition, many of these factors promote airway inflammation and dysfunction through a number of mechanisms, as shown in the figure.

BOX 35-2. Key concepts.

Components of the Immune Response to Viral Infections

• •Airway epithelial cells serve as hosts for viral replication and help to initiate the innate immune response to infection.
• •Innate and adaptive immune responses to viral infections promote viral clearance; however, both may augment ongoing local inflammatory responses as well.
• •There is evidence that the effectiveness of the antiviral response depends on factors related to the host (developmental and genetic), virus (strain, virulence), and environment (allergens, pollutants, nutrition).

The processes associated with viral replication trigger both innate and adaptive immune responses within the epithelial cell. For viruses such as HRV, which infect relatively few cells in the airway, this may be the primary mechanism for airway symptoms and lower airway dysfunction.⁷⁷ Virus attachment to cell surface receptors can initiate some immune responses. For example, RSV infection activates signaling pathways in airway epithelial cells through the innate immune system through Toll-like receptor-4.⁷⁸ Apart from receptor activation, the development of oxidative stress during viral infections can activate epithelial cell responses.⁷⁹ Viral RNA binds to cell surface receptors (Toll-like receptor-3)⁸⁰ and intracellular proteins, such as the dsRNA-dependent protein kinase and retinoic acid-inducible gene I, to activate the innate antiviral immune response.⁸¹ Through these pathways, viral replication stimulates the production of nitric oxide, activation of RNase L, and inhibition of protein synthesis within infected cells. In addition, innate antiviral responses induce chemokines that recruit inflammatory cells into the airway.⁸² HRV-infected epithelial cells secrete RANTES and IFN-γ–inducible protein (IP)–10, which induce T cell chemotaxis.⁸³ Notably, IP-10 expression is augmented in asthma exacerbations caused by HRV and other viruses, and the level of IP-10 expression has been reported to differentiate between virus-induced and nonvirus-induced asthma exacerbations.⁸³

Finally, viral respiratory infections can induce the synthesis of many of the factors that regulate airway and alveolar development and remodeling, including vascular endothelial growth factor (VEGF), nitric oxide (NO), and fibroblast growth factor (FGF).84, 85, 86, 87 How single or repeated bouts of virus-induced overexpression of these regulators of lung development and remodeling affects the ultimate lung structure and function are not known, but is of interest regarding the long-term effects on lung function and asthma.

Inflammatory Cells

Monocytes and macrophages can be activated by viruses to secrete proinflammatory cytokines such as IL-1, IL-8, IL-10, tumor necrosis factor (TNF)-α, and IFN-γ.88, 89, 90 In animal models, respiratory viral infections lead to a prominent expansion of mature dendritic cells in the lung.⁹¹ These lung dendritic cells have a strong facility to activate both naïve and memory T cells and to stimulate their proliferation. Increases in numbers of lung dendritic cells created from local precursors in the lung, survive past the resolution of disease in RSV infection.⁹² Significantly, pulmonary dendritic cells express high levels of Toll-like receptors, and secrete large amounts of interferons in response to viral infection.

Acute respiratory viral infections are often accompanied by neutrophilia of upper and lower respiratory secretions, and products of neutrophil activation are likely to be involved in obstructing the airways and causing lower airway symptoms. Importantly, there is evidence that activated neutrophils, through the release of the potent secretagogue elastase, can up-regulate goblet cell secretion of mucus.⁹³ Additionally, changes in IL-8 levels in nasal secretions have been related to respiratory symptoms and virus-induced increases in AHR.^{94 , 95}

P2X7 is a cation channel expressed by leukocytes and airway epithelial cells that is important to pathogen control and concomitant cellular inflammation. A recent study by Denlinger and coworkers demonstrated that attenuated P2X7 function is common in mild to moderate asthma.⁹⁶ This attenuated function is associated with reduced recruitment of neutrophils to the airway during HRV colds, and an increased risk of acute asthma symptoms, even after adjustment for inhaled corticosteroid treatment. Thus, attenuated P2X7 pore activity may be an important regulator of virus-induced neutrophilia, and potentially a novel biomarker for the loss of asthma control during HRV infections.

Lymphocytes are recruited into the upper and lower airways during the early stages of a viral respiratory infection, and it is presumed that these cells help to limit the extent of infection and to clear virus-infected epithelial cells. This is consistent with reports of severe viral LRIs in immunocompromised patients.⁹⁷ After virus inoculation, B cell responses to infection can be detected in the generation of mucosal IgA by day 3, followed by IgM, and finally IgG after 7 to 8 days.⁹⁸ Rapid induction of specific preformed neutralizing IgG to HRV serves to prevent or limit the degree of reinfection.

Relationship of Mononuclear Cell Responses to Outcome of Viral Infections

Several studies have tested the hypothesis that individual variations in cellular immune responses and patterns of cytokine production are related to the outcome of respiratory infections. In a study of children at high risk for the development of asthma based on parental history, reduced mitogen-induced production of IFN-γ from cord blood mononuclear cells ex vivo was associated with a significant increase in viral respiratory illnesses during infancy.¹⁸ Moreover, reduced peripheral blood mononuclear cell (PBMC) production of IFN-γ, both during and months after RSV, is a risk factor for subsequent asthma.⁹⁹ There is evidence in vitro that asthma is associated with impaired virus-induced secretion of interferons by airway and peripheral blood cells.100, 101, 102 Together, these experimental findings suggest that the cellular immune response to respiratory viruses, and interferon responses in particular, can influence the clinical and virologic outcomes of infection.

Interactions between Viral Infections and Allergy

The impact that allergic sensitization may have on the asthmatic airway response to viral infection has generated much interest and research. Interactions between these two factors appear to be bidirectional and dynamic in that the atopic state can influence the lower airway response to viral infections,^{16 , 103} viral infections can influence the development of allergen sensitization,^{104 , 105} and interactions can occur when individuals are exposed simultaneously to both allergens and viruses.11, 106, 107

Atopy is a risk factor for the development of childhood asthma after virus-induced wheezing illnesses, and defining the mechanisms of this relationship has been of interest to many investigative groups.¹⁰⁸ It has also been suggested that atopy could be a significant predisposing factor for the development of acute bronchiolitis during RSV epidemics.¹⁰⁹ Although some have found that those children most likely to have persistent wheezing were born to atopic parents,109, 110, 111 others have not found this,^{112 , 113} Similarly, there is debate as to whether personal atopy is more prevalent after bronchiolitis.12, 104, 113, 114 Despite these uncertainties, it is clear that children who wheeze in early life and have atopic features such as allergic sensitization, atopic dermatitis, and either blood eosinophilia or allergen-specific IgE are at the highest risk for subsequent asthma. These observations have led to the development of predictive indices to estimate the risk of asthma after wheezing in infancy (Table 35-1 ).

Table 35-1.

Active Predictive Indices

1The child must have a history of four or more wheezing episodes with at least one physician diagnosis. 2In addition, the child must have a history of four or more wheezing episodes with at least one confirmed by a physician.
mAPI: major criteria • Parental history of asthma • Physician-diagnosed atopic dermatitis • Allergic sensitization to ≥ 1 aeroallergen	Original API: major criteria • Parental history of asthma • Physician-diagnosed atopic dermatitis
mAPI: minor criteria • Allergic sensitization to milk, egg, or peanuts • Wheezing unrelated to colds • Blood eosinophils ≥ 4%	Original API: mcriteria • Physician-diagnosed allergic rhinitis • Wheezing unrelated to colds • Blood eosinophils ≥ 4%

Differences in indices are in bold

The original Asthma Predictive Index (API) was based on data from the Tucson Children's Respiratory Study and it had a positive predictive value for active asthma of 47.5% to 51.5% between the ages of 6 and 13 years.¹⁶³ Conversely, only 5% of children with a negative API result had active asthma between the ages of 6 and 13 years. The Prevention of Early Asthma in Kids trial¹³² modified the published API to include allergic sensitization to aeroallergens and to foods and was used in place of MD-diagnosed allergic rhinitis as this can be difficult to diagnose in young children. It is expected that this modified index would have a similar positive predictive value as the original API for asthma. The modified index has since been adopted by the National Asthma Education and Prevention Program (NAEPP) 2007 Guidelines¹³⁶ to identify children at high risk of developing asthma and who may benefit from asthma controller therapy.

From Guilbert et al.¹⁶²

There is convincing evidence to implicate respiratory allergy as a risk factor for wheezing with common cold infections later on in childhood. In studies conducted in an emergency department, risk factors for developing acute wheezing episodes were determined.¹³ Individual risk factors for developing wheezing included detection of a respiratory virus, most commonly HRV, positive allergen-specific IgE (RAST), and presence of eosinophilic inflammation. Notably, viral infections and allergic inflammation synergistically enhanced the risk of wheezing. Furthermore, experimental inoculation with HRV is more likely to increase airway responsiveness in allergic individuals compared with nonallergic individuals.¹¹⁵ Lastly, the risk of hospitalization among virus-infected individuals is increased in patients who are both sensitized and exposed to respiratory allergens.¹⁷ These findings suggest that individuals with respiratory allergies or eosinophilic airway inflammation are at increased risk for wheezing with virus. This concept has been difficult to model using experimentally-induced colds, however, as allergen administration before inoculation did not enhance symptoms of the cold.^{116 , 117}

Viral infections are postulated to interact with allergic inflammation leading to airway dysfunction through several mechanisms. For example, viral infections could damage the barrier function of the airway epithelium, leading to enhanced absorption of aeroallergens across the airway wall and enhanced inflammation.¹¹⁸ Additionally, production of various cytokines (tumor necrosis factor [TNF]-α, IL-1β, IL-6), chemokines (CCL3, CCL5, CCL2, CXCL8), leukotrienes, and adhesion molecules (ICAM-1) may further up-regulate cellular recruitment, cell activation, and the ongoing inflammatory response.¹¹⁹

Effects of Viral Infections on Airway Hyperresponsiveness

Information derived from animal models, as well as clinical studies of natural or experimentally induced viral infections, indicate that viruses can enhance airway hyperresponsiveness, which is one of the key features of asthma. Clinical studies of human volunteers inoculated with common cold viruses have generally shown that viral infections cause mild increases in airway responsiveness during the time of peak cold symptoms, and that these changes can last for several weeks.¹²⁰ A heightened sensitivity to inhaled irritants, as well as greater maximum bronchoconstriction in response to these stimuli have both been observed. The mechanism of virus-induced airway responsiveness is likely to be multifactorial, and contributing factors are likely to include impairment in the inactivation of tachykinins, virus effects on nitric oxide production, and virus-induced changes in neural control of the airways.¹²¹

Tachykinins, which are synthesized by sensory nerves, are potent bronchoconstrictors and vasodilators and, through these effects, have the potential to cause severe airway obstruction. Because airway epithelial cells help to regulate tachykinin levels through the production of the enzyme neutral endopeptidase, loss of this enzyme activity in epithelium that has been damaged by viral infection could lead to airway obstruction.¹²² Nitric oxide can regulate both vascular and bronchial tone and can interfere with the replication of some viruses.⁸⁶ Nitric oxide synthesis is enhanced by viral infections.¹²³ but because of the many potential effects of nitric oxide on the lower airways, it is uncertain as to whether this is beneficial to lower airway function in asthma.

Viruses can also affect airway tone and responsiveness by enhancing vagally mediated reflex bronchoconstriction. A potential mechanism for this effect is virus interference in the function of the M2 muscarinic receptor.¹²⁴ The M2 receptors are part of an important negative feedback loop that limits the release of acetylcholine from vagal nerve endings. When the M2 receptor is damaged by viral infection or virus-induced interferon¹²⁵ bronchoconstriction is enhanced, leading to increased airway obstruction. Further delineation of this pathway may lead to novel treatments for virus-induced asthma symptoms that are refractory to standard therapy.

Treatment

Virus-Induced Wheezing in Infancy

Virus-induced coughing and wheezing lead to significant morbidity, and can be particularly difficult to treat. Potential therapies include the use of bronchodilators, antiinflammatory agents, and strategies based on an antiviral approach to either prevention or treatment of acute wheezing. Conventional therapy for virus-induced wheezing in young children commonly includes a step-wise addition of medications, typically starting with a bronchodilator. If lower respiratory tract symptoms become increasingly severe or respiratory distress develops, oral corticosteroids are often added. Recent clinical trials in the management of these wheezing episodes also have included the use of high-dose inhaled corticosteroids (ICS) (both prophylactically and as an acute intervention) and leukotriene receptor antagonists (Box 35-3 ). These strategies are reviewed in the following sections.

BOX 35-3. Key concepts.

Treatment of Virus-Induced Asthma: Prevention and Intervention

• •Inhaled corticosteroid (ICS) treatment after respiratory syncytial virus bronchiolitis does not significantly decrease the development of chronic lower airway symptomatology.
• •Chronic treatment with ICS reduces the frequency and severity of intermittent virus-induced wheezing episodes in children with multi-trigger wheezing but does not completely prevent their occurrence. Conversely, in nonatopic children who wheeze only with viral infections, it has not been demonstrated that ICS given either prophylactically or as an acute intervention are effective in reducing the severity or frequency of virus-induced wheezing episodes.
• •Treatment of virus-induced asthma exacerbations with oral corticosteroids significantly improves a number of outcome measures.
• •The overall and comparative efficacy and the safety of the treatment of similar episodes with either high-dose ICS or leukotriene modifiers warrants further study.

The Role of Bronchodilators and Corticosteroids for Acute Respiratory Syncytial Virus-Induced Bronchiolitis

The efficacy of various therapeutic interventions for the acute symptoms of wheezing, tachypnea, retractions, and hypoxemia that occur as a result of bronchiolitis has been controversial because of variations in study design, the inability to rapidly and conveniently measure pulmonary physiologic variables, the confounding of results by the inclusion of children with a history of multiple wheezing episodes (i.e. asthmatic phenotypes), and the choice of outcome measures that have been evaluated. In a Cochrane meta-analysis of this subject¹²⁶ bronchodilators were found to generate modest short-term improvements in clinical features of mild or moderately severe bronchiolitis; no differences in the rate or duration of hospitalization were noted. However, given the high costs and uncertain benefit of this therapy, the authors concluded that bronchodilators could not be recommended for routine management of first-time wheezers. Similarly, the recent American Academy of Pediatrics (AAP) bronchiolitis guidelines suggest that many children with bronchiolitis do not show a response to bronchodilators. However, a carefully monitored trial of β-adrenergic medication is an option and inhaled bronchodilators could be continued if there is a documented positive clinical response to the trial using an objective means of evaluation.¹²⁷

The efficacy of therapy with either oral or parenteral corticosteroids was reviewed in a meta-analysis of studies that sought to evaluate this form of intervention.¹²⁸ A meta-analysis of 13 studies involving therapy with either oral or parenteral corticosteroids concluded that this approach demonstrated a pooled decrease in length of stay of 0.38 days. However, this decrease was not statistically significant. The review concluded: ‘No benefits were found in either LOS [length of stay] or clinical score in infants and young children treated with systemic glucocorticoids as compared with placebo’. Two additional studies that evaluated inhaled corticosteroids in bronchiolitis^{129 , 130} showed no benefit in the course of the acute disease. Thus, the AAP bronchiolitis guidelines recommend that corticosteroid medications should not be used routinely in the management of bronchiolitis as the safety of high-dose inhaled corticosteroids in infants is still not clear and an apparent benefit has not been demonstrated.¹²⁷ For the majority of cases, supportive treatment remains the standard of care for infants with bronchiolitis.

Effect of Corticosteroids for the Prophylactic Treatment of Recurrent Wheezing and Asthma after Bronchiolitis

Another controversial question is whether corticosteroid treatment can prevent respiratory sequelae after bronchiolitis. Several placebo-controlled trials that address the question of whether corticosteroid treatment can influence the degree of respiratory sequelae after bronchiolitis have been reviewed.^{30 , 128} The majority (7 of 10) of these trials did not show any long-term effects (follow-up time, 6 months to 5 years) on postbronchiolitic wheezing, the development of various wheezing phenotypes (transient, persistent, or late onset), or a subsequent diagnosis of asthma. In the trials that did show some benefit, the positive effects observed were mainly over shorter time intervals after infection. One study¹³¹ concluded that the greatest benefit was more likely to be seen in atopic children. This is similar to other studies of preschool children with recurrent, viral-induced wheezing which demonstrate that atopic children show response to inhaled corticosteroids (ICS).^{132 , 133} Additionally, there is new data that infants who wheeze with HRV are less likely to develop recurrent wheezing if systemic corticosteroid therapy is initiated during the acute infection.¹³⁴ This finding, if confirmed, suggests a distinct pathogenesis and therapeutic approach for infants diagnosed with HRV wheezing illnesses.

Role of Oral Corticosteroids in Acute Exacerbations of Asthma in Young Children

Numerous studies have been undertaken to assess the role of corticosteroid therapy in acute episodes of asthma in children and adults. A recent meta-analysis of six trials involving 374 subjects assessed the benefit of systemic corticosteroids for the treatment of asthmatic patients discharged from an acute care setting after assessment and treatment of an acute asthmatic exacerbation.¹³⁵ A short course of corticosteroids following assessment for an asthma exacerbation significantly reduces the number of relapses to additional care, hospitalizations and use of short-acting β₂ agonist without an apparent increase in side-effects. Intramuscular and oral corticosteroids are both effective. As a reflection of such information, the most recent National Heart, Lung, and Blood Institute Guidelines for the Diagnosis and Management of Asthma¹³⁶ recommends the addition of corticosteroids for asthma exacerbations unresponsive to bronchodilators. These guidelines suggest that the introduction of oral prednisone or prednisolone, for a short course may reduce the duration of the exacerbation and prevent hospitalization. However, only a few pediatric studies have examined whether systemic corticosteroids reduce the severity of exacerbations in children who have bronchospasm exclusively with viral infections. Brunette and colleagues¹³⁷ explored the role of early intervention with oral corticosteroid therapy in 32 children under the age of 6 years (mean age, 38.4 months) with asthma typically provoked by viral URI. During the first year of this 2-year study, acute exacerbations were treated with oral bronchodilators initially, with the addition of prednisone for more severe attacks. In the second year, oral prednisone was administered at the first sign of a URI to a group of patients whose parents and caretakers were unblinded to the treatment intervention. The group receiving prednisone during the second year experienced fewer attacks, a 65% reduction in the number of wheezing days, a 61% decrease in emergency department visits, and a 90% decrease in hospitalizations. The administration of prednisone at the first sign of URI was not associated with greater overall prednisone use. Although this study suggests that early intervention with oral corticosteroids has the potential to significantly affect the morbidity associated with acute virus-induced asthma episodes, the unblinded study design makes these results less convincing.

Tal and colleagues¹³⁸ conducted an emergency department-based, double-blind, placebo-controlled trial of administration of a single dose of methylprednisolone intramuscularly and demonstrated a statistically significant decrease in hospitalization rate (20% in the methylprednisolone group vs 43% in the control group, P < 0.05); this effect was most pronounced in the group less than 24 months old (18% in the methylprednisolone group vs 50% in the control group, P < 0.050). Taken together, the results of these two studies suggest that early corticosteroid therapy, ideally started at home, should have an impact on the progression of asthma episodes and decrease the rate of hospitalization for asthma.

Conversely, a recent study comparing oral prednisolone to placebo in 687 hospitalized preschool children with virus-induced wheezing demonstrated no benefit in length of hospitalization, symptom scores, or albuterol use.¹³⁹ This study suggests that non-atopic preschool children (only 8% with physician-diagnosed ‘hayfever’) with severe wheezing episodes severe enough to warrant evaluations in a hospital setting may not respond to corticosteroids; however, the systemic corticosteroids were given during initial evaluation in the hospital setting when the exacerbation was already well underway. In addition, more than one third of these children had no prior history of wheezing.

Young children who experience frequent exacerbations of asthma may receive several short courses of systemic corticosteroids during each viral season and the potential toxicity of repeated courses of oral corticosteroids is a significant clinical concern. Individual courses of oral corticosteroids may be associated with behavioral side-effects. In addition, Dolan and colleagues¹⁴⁰ reported that 20% of children who received four or more short courses of oral corticosteroids in the past year had impaired responses to insulin-induced hypoglycemia. The potential toxicity of repeated courses of oral corticosteroids is a significant clinical concern and likely influences the behaviors of primary care physicians faced with young children who wheeze after having URI symptoms.

Role of Inhaled Corticosteroids in the Treatment of Acute Asthma Exacerbations

Due to the concern of side-effects from repeated doses of oral corticosteroids, the efficacy of ICS intervention for exacerbations has been evaluated in several studies. First, Wilson and Silverman¹⁴¹ examined the use of beclomethasone dipropionate (750 μg 3 times daily for 5 days administered via metered-dose inhaler [MDI]) at the first sign of an asthma episode in children 1 to 5 years of age. Although failing to alter the need for additional therapy, ICS therapy was associated with improvement in asthma symptoms during the first week of the episode. Daugbjerg and colleagues¹⁴² conducted a double-blind, placebo-controlled trial comparing the effects of inhaled bronchodilator alone or in combination with either high-dose ICS (budesonide nebulization 0.5 mg every 4 hours until discharge) or systemic corticosteroid (prednisolone) in children younger than 18 months who were admitted to a hospital with acute wheezing. Their results demonstrated earlier discharge from the hospital in both the inhalation and systemic corticosteroid-treated groups, as well as a significantly accelerated rate of clinical improvement in the budesonide-treated group compared with the oral corticosteroid- and noncorticosteroid-treated groups. Connett and Lenney¹⁴³ compared the efficacy of two doses of budesonide (800 or 1600 μg twice daily) via MDI and a spacer device initiated at the onset of upper respiratory tract symptoms in preschool-aged children with recurrent wheezing with URIs. Therapy was continued for up to 7 days or until patients were asymptomatic for 24 hours. Budesonide therapy was associated with decreased symptom scores during the first week of infection. A double-blind, placebo-controlled crossover study by Svedmyr and colleagues¹⁴⁴ involved the administration of budesonide (200 μg 4 times daily for 3 days, 3 times daily for 3 days, and then twice daily for 3 days) via MDI and spacer or placebo to children 3 to 10 years of age with a history of URI-associated deterioration of asthma. Although budesonide therapy had no significant impact on symptom scores, it was associated with significantly higher peak expiratory flow rates. In an emergency department-based study, Volovitz and colleagues¹⁴⁵ compared the effects of inhaled budesonide and oral prednisolone in children aged 6 to 16 years with acute asthma exacerbations. Patients received either budesonide 1600 μg by Turbuhaler or 2 mg/kg of oral prednisolone in the emergency department followed by a tapering dose of medication over the next 6 days. Both treatment groups had similar rates of improvement in the emergency department in terms of symptom scores and peak expiratory flow. However, over the next week, the budesonide-treated group had a more rapid improvement in asthma symptoms. Serum cortisol levels and response to corticotropin were significantly decreased in the prednisolone-treated group at the end of the week of therapy compared with the budesonide-treated group but returned to the normal range 2 weeks later. This study suggests that high-dose therapy with a potent ICS may be as effective as oral prednisolone and avoids hypothalamic-pituitary-adrenal axis suppression. Another study comparing the effects of high-dose ICSs and oral corticosteroids in children seen in an emergency department for severe, acute asthma (mean FEV₁, <40% predicted on presentation) found oral corticosteroids to be superior in terms of improvement in lung function and hospitalization rate.¹⁴⁶ However, these patients were clearly in the middle of severe exacerbations, and ICSs were not used early in the course of the illness. Another recent study of 129 nonatopic preschool children with moderate-to-severe virus-induced wheezing demonstrated a 50% reduction in use of rescue oral corticosteroids during wheezing episodes when high-dose fluticasone was used intermittently at the onset of illness compared to placebo.¹⁴⁷ This suggests a potential benefit of inhaled corticosteroid use in nonatopic children with recurrent wheeze; however, the authors recommended further studies to be done before this treatment strategy was adopted as a small, but statistically significant decrease in height growth was observed.

In summary, ICSs appear to improve asthma symptoms when administered for acute exacerbations of asthma. Although all of these studies provide useful information, they are limited by small numbers of patients and do not delineate features predictive of patients who would be expected to respond to a given therapy. In addition, the ideal drug, dosage, delivery system, and duration of therapy remain unclear. Improved delivery of a potent drug to the lower airways may be associated with a more favorable clinical response.

Role of Leukotrienes in Virus-Induced Wheezing

The cysteinyl leukotrienes have been identified as important mediators in the complex pathophysiology of asthma. Leukotrienes are detectable in the blood, urine, nasal secretions, sputum, and bronchoalveolar lavage fluid of patients with chronic asthma. In addition, leukotrienes are released during acute asthma episodes. Volovitz and colleagues¹⁴⁸ demonstrated elevated levels of leukotriene C₄ (LTC₄) in nasopharyngeal secretions from infants with acute bronchiolitis because of RSV compared with children with upper respiratory illnesses alone. In another study, van Schaik and colleagues¹⁴⁹ also examined leukotriene levels in nasopharyngeal samples from infants and young children with URIs without wheezing, bronchiolitis (first-time wheezers), or acute episodes of wheezing in children with prior wheezing episodes. These investigators found elevated levels of leukotrienes in nasopharyngeal samples from both first-time and recurrent viral wheezers compared with children with nonwheezing URIs. Finally, bronchoalveolar lavage samples obtained from young children (median age, 14.9 months) with recurrent wheezing contain increased numbers of epithelial and inflammatory cells, and also increased levels of cyclooxygenase and lipoxygenase pathway mediators.¹⁵⁰ Interestingly, the levels of these cells and mediators were unaffected by concurrent treatment with ICSs. Studies in vitro or in animal models also suggested that leukotrienes contribute to virus-induced wheezing and asthma. For example, RSV induces 5-lipoxygenase activity in bronchial epithelial cell lines,¹⁵¹ and in a rat model, treatment with a leukotriene antagonist reduces RSV-induced airway edema in rats.¹⁵²

The effect of a leukotriene receptor antagonist (LTRA) in modulating virus-induced wheezing has been evaluated in clinical studies. Initially, a pilot study demonstrated a 28-day treatment course of montelukast significantly reduced lower respiratory tract symptoms in infants who were hospitalized for RSV bronchiolitis.¹⁵³ However, a larger double-blind, placebo-controlled study of 979 children, aged 3 to 24 months, who had been hospitalized for a first or second episode of physician-diagnosed RSV bronchiolitis, were randomized to placebo or to montelukast at 4 or 8 mg/day for 4 weeks and 20 weeks. In this more definitive study, no significant differences were seen between montelukast and placebo groups in the percentage of symptom-free days over either treatment period. This study suggests that this class of compounds are not useful in the prevention of postbronchiolitis respiratory symptoms. Many other mediators and cytokines have been found to be augmented during viral infection. Future studies will determine whether inhibition of specific components of virus-induced inflammation, such as proinflammatory cytokines (eg, IL-8) or mediators (leukotrienes, bradykinin), will be able to provide safe and effective relief from virus-induced wheezing and asthma.

The efficacy of LTRA in intermittent viral wheezing episodes in preschool children was studied in the Prevention of Viral Induced Asthma (PREVIA) trial.¹⁵⁴ PREVIA was a 1-year randomized double-blind placebo-controlled parallel group worldwide trial in 549 preschool children, aged 24 to 60 months, with intermittent asthma-like symptoms (15% with >2 days of symptoms/week and 16% >2 night awakening/month at baseline) that compared montelukast (4 mg daily) to matching placebo. Montelukast was better than placebo in reducing the rate of (−32%, p < 0.001) and time to first exacerbation/CSW episode (p = 0.024) and supplementary ICS courses (p = 0.027). However, because most exacerbations/CSW episodes were mild and did not require OCS, montelukast failed to reduce oral corticosteroid courses (p = 0.368). Post-hoc analyses did not demonstrate an effect of age or atopic status on response to therapy. In a more recent double-blind, placebo-controlled clinical trial, 220 children, aged 2 to 14 years with intermittent asthma, were randomized to receive a 12-month treatment with montelukast or placebo, initiated by parents at the onset of each upper respiratory tract infection or asthma symptoms for a minimum of 7 days. Emergency department visits were reduced by 45%, visits to all healthcare practitioners were reduced by 23%, and time of preschool/school and parental time off work was reduced by 33% for children who took montelukast for a median of 10 days.

Comparison of Role of ICS and Leukotrienes in Virus-Induced Wheezing

While both ICS and LTRA continuous treatment regimens have demonstrated efficacy in preschool children, comparisons between them have not been conducted with sufficient rigor in order to better clarify which treatment would be best suited for individual children based on various phenotypic or genotypic characteristics. In younger children (2 to 8 years of age) with mild asthma or recurrent wheezing, only one comparison trial of continuous treatment has been published.¹⁵⁵ In this study, the effects of ICS (once-daily budesonide inhalation suspension 0.5 mg) were compared to LTRA (once-daily oral montelukast 4 or 5 mg). No significant between-group differences were observed for the primary outcome (time to first additional asthma medication at 52 weeks); however, other secondary outcomes such as time to first additional asthma medication was longer and exacerbation rates were lower over a period of 52 weeks for budesonide versus montelukast. Time to first severe exacerbation (requiring oral corticosteroids) was similar in both groups. This study had some significant limitations, as ≈ 30% of children did not complete the study and one third of children had adherence rates less than 80%. In addition, a significant portion of children were ≥ 5 years of age and analyses were not stratified by age, making it difficult to extrapolate conclusions to the toddler wheezing age group. Finally, the study was not stratified by atopic status. A recent trial, Acute Intervention Management Strategies (AIMS), examined the effectiveness of episodic use of a high-dose inhaled corticosteroid, a leukotriene receptor antagonist, or placebo during respiratory tract illnesses in 238 preschool children with moderate-to-severe intermittent wheezing. Intermittent budesonide and montelukast modestly improved symptom scores during respiratory tract illnesses but did not improve episode-free days (EFDs) or decrease oral corticosteroid use. Children with positive asthma predictive indices or those who required oral corticosteroids for wheezing in the past year demonstrated the most benefit.¹⁵⁶

Antiviral Strategies

Influenza vaccine is used as a prevention strategy to reduce virus-induced exacerbations of asthma in the winter. For RSV and HRV, which are more frequently associated with wheezing illnesses, vaccines are not available, and considering that there are well over 100 strains of HRV³⁵ standard vaccination techniques are not technically feasible for this virus. Although limited by high cost to treatment of high-risk groups, passive prophylaxis with neutralizing antibody to RSV can reduce the influence of more severe respiratory disease. It is encouraging that a small case-control study of premature infants treated with RSV immune globulin reported better lung function and less atopy and asthma in the treated group 7 to 10 years later.¹⁵⁷ In addition, in a European case-control study, infants treated with palivizumab had lower rates of recurrent wheezing compared with untreated controls.¹⁵⁸ Although interpretation of these studies is limited by the lack of randomization, the findings provide reason for optimism and additional preventive studies. Several antiviral agents are in development, and a number of anti-HRV compounds have been tested in clinical trials. These include molecules such as soluble ICAM and capsid-binding agents (e.g. pleconaril), which either hinder HRV binding to cellular receptors or inhibit uncoating of the virus to release RNA inside the cell159, 160, 161 and inhibitors of HRV 3C protease. It is not clear whether these antiviral agents can prevent asthma exacerbations if given at the first sign of a cold.

Conclusions

Viral infections are important causes of wheezing illnesses in children of all ages, and progress is being made toward understanding the mechanisms by which viruses can cause acute wheezing, and perhaps even more importantly, how severe viral infections influence the pathophysiology of asthma in a number of ways (see Figure 35-1). Once these mechanisms are established, it may be possible to identify with greater certainty children who are at the greatest risk for wheezing with viral infections, or those children whose virus-induced wheezing is a preface to asthma. This would represent an important step forward in that preventive therapy could be focused to the groups with the greatest need. Of course, the other rationale for identifying pathogenic mechanisms of virus-induced wheeze is to identify targets for novel therapeutic strategies. Standard therapy for asthma is not satisfactory in that efficacy is low during respiratory infections, and in the case of systemic corticosteroids, side-effects can be significant. Given the close relationship between viral infections and wheezing illnesses in children, it would be attractive to apply antiviral strategies to the prevention and treatment of asthma, and both HRV and RSV are obvious targets. Unfortunately, attempts at developing an RSV vaccine have so far been unsuccessful, and vaccination to prevent HRV infection does not seem to be feasible because of the large number of serotypes. As an alternative, several types of antiviral agents are in development, and several compounds with activity against HRV have been tested in clinical trials.

The other potential therapeutic approach for respiratory viral infections would be to inhibit proinflammatory immune responses induced by the virus. This approach has proved to be effective because the systemic administration of glucocorticoids can reduce acute airway obstruction and the risk of hospitalization for virus-induced exacerbations of asthma. It remains to be demonstrated whether more focused inhibition of specific components of virus-induced inflammation, such as proinflammatory cytokines (e.g. IL-8) or mediators (leukotrienes, bradykinin), will be successful in reducing the severity of viral respiratory infections or exacerbations of asthma.

The evidence that asthma may be associated with a defective immune response to viruses and allergens also could lead to novel therapeutic strategies. Infancy seems to be a time during which the immune response is rapidly developing, and this process appears to be responsive to environmental stimuli, and perhaps dietary factors and lifestyle. It is intriguing that children exposed to rich microbial environments (exposure to pets, farm animals) are less likely to develop acute and chronic wheezing, suggesting that there are environmental factors that can positively modify immune development to strengthen antiviral responses in childhood. Future goals include the development of new treatments to enhance or supplement antiviral responses in infancy to treat acute wheezing episodes, and perhaps reduce the risk of subsequent asthma.

Acknowledgments

This work was supported by National Institutes of Health grants HL070831, AI070503, HL080072, RR025011.

Helpful Websites

The National Heart, Lung and Blood Institute website (www.nhlbi.nih.gov)

The American Academy of Allergy Asthma and Immunology website (www.aaaai.org)

The Childhood Asthma Research and Education Network website (www.asthma-carenet.org)

The Asthma Clinical Research Network website (www.acrn.org)