Viruses

Viral respiratory illnesses leading to wheezing are one of the most common causes of hospitalization during infancy. Using multiple virus detection methods, including polymerase chain reaction (PCR), Jartti and colleagues investigated the etiology of wheezing illness in 293 hospitalized children. Of the 76 infants with virus detected, 54% had respiratory syncytial virus (RSV), 42% had picornaviruses (human rhinovirus [RV] and enterovirus) and 1% had human metapneumovirus (hMPV). In older children, respiratory picornaviruses, most commonly RV, dominated (65% of children aged 1 to 2 years and 82% of children aged ≥ 3 years). Outpatient wheezing illnesses are also extremely common in young children, and viruses have been implicated in 67% to 90% of these episodes in different populations.

Wheezing with viruses during infancy is often an early manifestation of asthma. 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. A recent clinical trial comparing palivizumab (anti-RSV monoclonal antibody) to placebo in near preterm infants demonstrated reductions in recurrent wheezing during the first year of life in the children treated with palivizumab. This is the strongest level of evidence to date in support of a causal role for RSV in recurrent wheezing. However, a longitudinal, population-based cohort study has demonstrated that the association between RSV lower respiratory infections during early life and both frequent (more than three episodes) and infrequent wheezing (less than three episodes) decreases with age and becomes nonsignificant by the age of 13 years. These data suggest that although RSV infections contribute substantially to the risk of recurrent wheezing and asthma in early childhood, other co-factors (e.g. genetic, environmental, developmental) also contribute to the expression of asthma or modification of phenotypes over time. Interestingly, a 2013 study identified unique immune response profiles during and after RSV bronchiolitis in comparison with bronchiolitis caused by other viruses.

With the development of molecular diagnostics, significant evidence has emerged to suggest that wheezing illnesses caused by RV identify children at highest risk for childhood asthma. The Childhood Origins of ASThma (COAST) birth cohort study confirmed prior associations between RSV wheezing in the first 3 years of life and childhood asthma, but demonstrated that RV wheezing during this time is associated with a greater, 10-fold increased risk of childhood asthma. Mechanisms by which recurrent RV infections may lead to wheezing and airway remodeling, particularly in susceptible hosts, have been described. A new species of RV, RV-C, was recently discovered, and has been shown to be an important cause of lower respiratory illnesses and wheezing in children. A longitudinal analysis within the COAST study demonstrated that both RV-A and RV-C were more likely than RV-B to cause moderate-to-severe respiratory illnesses in infants. Whether RV-C wheezing illnesses confer a greater risk of childhood asthma development is currently unknown.

Molecular diagnostics are not universally available to clinicians, so the question of whether season of wheezing is helpful in delineating risk is an important one. Bronchiolitis during infancy is associated with an approximately 2-fold increased risk of early childhood asthma; however, this risk differs by season of bronchiolitis. Bronchiolitis occurring during RV-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 RV-predominant months because of higher rates of bronchiolitis during the RSV season. Season of birth also appears relevant: children born close to the onset of the winter virus season are most prone to the development of lower respiratory tract symptoms, and this is likely due to a developmental component in relationship to the timing of the winter virus peak.

Bacteria

It has been proposed that chronic bacterial infections or colonization with pathogenic bacteria could initiate chronic lower airway inflammation, impaired mucociliary clearance, increased mucus production and ultimately asthma. Organisms primarily implicated in this process include Chlamydophila pneumoniae , Mycoplasma pneumoniae, Streptococcus pneu­moniae, Haemophilus influenzae and Moraxella catarrhalis . Studies of chronic mycobacterial or Chlamydophila infection and asthma in children have yielded conflicting results, potentially 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. The role of these bacteria in acute wheezing in young children is also unclear.

Recent publications have suggested that pathogenic bacteria may play a role in both acute wheezing episodes and asthma inception in preschool children. First, Bisgaard and colleagues found that neonates with S. pneumoniae, H. influenzae or M. catarrhalis , or with a combination of these organisms, in their hypopharynx are at increased risk for recurrent wheeze early in life and the diagnosis of asthma at the age of 5 years. This original observation was made in infants of mothers with asthma, but the researchers were able to replicate some of these findings in an unselected cohort. Further, these pathogens have been detected at higher rates in preschool children during acute wheezing episodes. Interestingly, a similar predominance of Proteobacteria has been identified in the airways of older children and adults with established asthma. Furthermore, in both human and animal studies, environmental exposure to ‘protective’ bacteria appears to have the capacity to prevent the development of wheezing and/or asthma in young children. These studies of the role of microbial exposures and the microbiome in asthma inception are intriguing, and additional studies are a high priority to establish causality/protection and the specificity of these observations to asthma pathogenesis, and to define immunoinflammatory mechanisms contributing to these associations in both pediatric and adult patients.

Spread of Infection from the Upper to the Lower Airways

Respiratory viruses such as RSV and influenza are well known to infect the lower airway, and both can cause bronchitis, bronchiolitis and pneumonia. RV has traditionally been considered to be an upper airway pathogen because of its association with common cold symptoms and the observation that it replicates best at 33–35°C, which approximates to temperatures in the upper airway. In fact, lower airway temperatures are conducive to RV replication down to fourth-generation bronchi and exceed 35°C only in the periphery of the lung. Moreover, some RV types, including RV-C isolates, replicate equally well at 33 and 37°C. RV appears to replicate equally well in cultured epithelial cells derived from either upper or lower airway epithelium. Finally, RV has been detected in lower airway cells and secretions by several techniques after experimental inoculation. Titers of infectious virus in lower sputum reach or exceed those found in nasal secretions in some individuals. In addition to evidence from experimental infection models, RV is frequently detected in infants and children with lower respiratory signs and symptoms, including children hospitalized for pneumonia. Collectively, these findings suggest that respiratory viruses, including RV, can cause wheezing illnesses and exacerbations of asthma mainly by infecting lower airways and causing or amplifying lower airway inflammation.

Virus-Induced Cytopathic Effects

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, viral infections stimulate mucus secretion and can also promote the formation of additional goblet cells (mucoid metaplasia) that can enhance mucus secretion that can persist even after the acute infection has resolved. Virus-induced injury to the epithelium can disrupt airway physiology through a number of different pathways ( Box 31-2 ). For example, viral infections can increase the permeability of the epithelium, which may facilitate contact of irritants and allergens with immune cells, leave neural elements exposed and promote secondary infection with bacterial pathogens. In addition, the combination of epithelial edema and sloughing together with mucus production can lead to airway obstruction and wheezing.

As reviewed under ‘Viruses’, there is clinical evidence that the RV-B species may be less virulent than other RVs. Moreover, there is corresponding evidence from in vitro studies that RV-B viruses replicate more slowly, produce less cytopathic effect and induce lower interferon and inflammatory responses compared to other RVs. Overall, these viruses appear to be attenuated.

Role of Antiviral Immune Responses

Virus-induced immune responses are necessary to clear the viral infection but they can also contribute to airway dysfunction and symptoms by causing an influx of inflammatory cells that adversely affect lower airway physiology. Antiviral immune responses are initiated within the epithelial cell and amplified by resident and recruited leukocytes in the airway. For viruses such as RV that infect relatively few cells in the airway, virus-induced inflammation may be the primary mechanism for the pathogenesis of respiratory symptoms and lower airway dysfunction. Viral respiratory infections can also 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), metalloproteinases and fibroblast growth factor (FGF). How single or repeated bouts of virus-induced overexpression of these regulators of lung development and remodeling affect the ultimate lung structure and function is not known, but they could exert long-term effects on lung function and asthma following viral infection in infancy.

Relationship of Cellular Antiviral 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 clinical studies, reduced IFN-γ responses of blood mononuclear cells ex vivo are associated with a significant increase in viral respiratory illnesses during infancy. In addition, several studies have found that asthma is associated with impaired virus-induced secretion of interferons by airway and peripheral blood cells. Together, these experimental findings suggest that individual variability in the cellular immune response to respiratory viruses, and interferon responses in particular, can influence the clinical and virologic outcomes of infection.

Interactions with Bacteria

It is well established that viral illnesses of the middle ear, sinuses and lungs can promote secondary infections with bacterial pathogens such as S. pneumoniae , M. catarrhalis , and H. influenzae . As reviewed under ‘Bacteria’, colonization with these bacteria in early childhood is also a risk factor for acute wheezing episodes and asthma. In school-aged children, these pathogens are more likely to be detected in association with a viral infection or just after a viral infection. Furthermore, the risk of illness vs asymptomatic infection was greater in children who had both viruses and bacteria detected. Similarly, for children with asthma, moderate exacerbations were most likely to occur in viral infections in which S. pneumoniae or M. catarrhalis were also detected. These findings suggest that viruses and bacteria may work together to promote airway pathology and respiratory symptoms.

Environmental Factors and Viral Illnesses

Environmental factors strongly influence the probability of exacerbations and appear to act together with viral infections in an additive fashion. As discussed in the next section, 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. Accordingly, the combination of allergy and exposure to a relevant allergen contributes to virus-induced exacerbations of asthma. Similarly, exposure to greater levels of air pollutants such as NO ₂ and SO ₂ also enhances the risk of virus-induced exacerbation.

Virus-Induced Wheezing in Infancy

Acute lower respiratory tract illnesses during the first one to two years of life are usually termed ‘bronchiolitis’ and are most likely due to infection with viral respiratory pathogens. The efficacy of various interventions for the treatment of the acute lower airway symptoms of wheezing, tachypnea, retractions and hypoxemia that occur as a result of these infections has been controversial due to 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 recent series of meta-analyses evaluating various therapies, the routine use of bronchodilators, steam or nebulized normal saline, anticholinergics and steroids has not been shown to be of consistent benefit.

A more recent study suggests that the timing of the administration of epinephrine may influence the observed benefit. In an eight-center randomized, double-blind trial with a two-by-two factorial design, investigators compared inhaled racemic epinephrine with inhaled saline and on-demand inhalation with fixed-schedule inhalation (up to every 2 hours) in infants (> 12 months of age) with moderate-to-severe acute bronchiolitis. Length of stay, use of oxygen supplementation, nasogastric tube feeding, ventilatory support and relative improvement in the clinical score from baseline (preinhalation) were similar in the infants treated with inhaled racemic epinephrine and those treated with inhaled saline. However, the strategy of inhalation on demand was superior to that of inhalation on a fixed schedule for many of the outcome measures evaluated.

The atopic background of the patient (eczema or asthma in a first-degree relative) may influence the response to oral corticosteroid administration. Infants aged ≤ 18 months presenting to a care facility for treatment of moderate-to-severe bronchiolitis and who had a positive history of eczema or were known to have a parent or a full sibling with a prior physician diagnosis of asthma were treated with oral dexamethasone, 1 mg/kg, then 0.6 mg/kg for 4 more days, or matching placebo. All patients received albuterol nebulization delivered through a tight-fitting face mask with pressurized oxygen. Dexamethasone plus albuterol treatment shortened time to readiness for discharge from the unit. However, there was no difference between the treatment groups in terms of infirmary and clinic visits during the week following discharge.

Virus-Induced Wheezing in Preschool Children

Therapeutic approaches for virus-induced wheezing in preschool children (ages 2–5 years) are challenging due to the fact that many children only wheeze with the ‘common cold’ and are totally asymptomatic in between these episodes, while others may have symptoms more or less on a daily basis as well. In addition, these episodes may range in severity from mild wheezing and coughing to severe respiratory distress that requires prompt medical intervention. Standard therapy for virus-induced wheezing in young children generally includes a stepwise addition of medications, typically commencing 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 (both prophylactically and/or as an acute intervention) and leukotriene receptor antagonists.

The 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. Meta-analyses of these studies support the early use of systemic corticosteroids in acute exacerbations based upon a reduction in the admission rate for asthma and prevention of relapse in the outpatient treatment of exacerbations. As a reflection of such information, the most recent National Heart, Lung, and Blood Institute (NHLBI) Guidelines for the Diagnosis and Management of Asthma recommend the addition of corticosteroids for asthma exacerbations unresponsive to bronchodilators; in contrast to previous versions of these guidelines, doubling the dose of inhaled corticosteroids to prevent further progression of the airway obstruction is not recommended.

Unfortunately, the applicability of these recommendations to young children and infants whose acute wheezing episode is primarily related to viral respiratory tract infections has not been as thoroughly examined. Moreover, in studies that have been conducted in this age group, the results are conflicting. Limitations of these studies include inclusion of multiple wheezing phenotypes, relatively small sample sizes, poor adherence to study medication and protocol in the outpatient studies, and episodes of relatively mild severity in both outpatient and inpatient studies. A recent randomized, double-blind, placebo-controlled trial compared a 5-day course of oral prednisolone (10 mg once a day for children 10–24 months of age and 20 mg once a day for older children for a total of 5 days) with placebo in over 650 children between the ages of 10 months and 60 months. The primary outcome, the duration of hospitalization, was no different between the treatment groups. An accompanying editorial for this published study challenged the clinical research community to conduct additional prospective trials to clearly establish the efficacy of oral corticosteroid treatment of these ‘asthma-like’ episodes in preschool children.

To address these concerns further, the Childhood Asthma Research and Education (CARE) network investigated whether oral corticosteroids reduced symptom scores during acute lower respiratory tract illnesses (LRTIs) in preschool children with recurrent wheeze. The investigators performed post hoc and replication analyses in two outpatient cohorts of children aged 1 to 5 years with episodic wheezing that had participated in previous CARE-conducted studies. Comparisons were made of symptom scores during LRTIs that were or were not treated with oral corticosteroids, adjusting for differences in disease and episode severity. The primary outcome was the area under the curve of total symptom scores among the more severe episodes. In both of the two cohorts studied independently, oral corticosteroid treatment did not reduce symptom severity during acute LRTIs. Moreover, subgroups of children who might have been more likely to experience benefit, such as those with asthma risk factors (positive modified asthma predictive index, personal eczema and/or family history of asthma), did not appear to have a greater benefit than those without such characteristics. The investigators emphasized, however, that these results were hypothesis generating and needed to be confirmed in randomized prospective studies. Taken together, however, these studies indicate that acute asthma-like episodes of airway obstruction in preschool children appear to respond less well to oral corticosteroid administration than do similar episodes in older children and adults.

The Role of Inhaled Corticosteroids in the Prevention and Treatment of Acute Wheezing Exacerbations

The CARE network conducted a 3-year prospective trial in preschool children, all of whom had a modified positive asthma predictive index. The overall goal of the study was to determine if early recognition and treatment of children who were at increased risk of developing childhood asthma could prevent the disease process from expressing itself and, further, if it could reduce losses of lung function that have been described during the first six years of life in children who develop persistent wheezing by age 3 years. Children, 2 to 4 years of age, were randomized to receive either fluticasone propionate 88 µg twice daily or matching placebo using a valved spacer with mask. Treatment was for 2 years followed by a 1-year observation period off all study medication. The primary outcome measure was episode-free days. During the active treatment phase, children receiving inhaled corticosteroid (ICS) had a significantly increased number of episode-free days. In addition, they had significant reductions in oral corticosteroid-requiring exacerbations (37% reduction) and less use of a prespecified step-up plan. Pulmonary function was also significantly better at the end of the treatment period in those children who had received ICS for the previous two years. Unfortunately, about three months into the observation period, there was no longer any significant difference in any of these outcome measures and at the end of the observation period (1 year later), pulmonary function was also no different between the two groups. These data indicate that continuous therapy with ICS in preschool children at high risk of developing asthma reduces lower respiratory tract exacerbations that are most frequently caused by respiratory pathogens in this age group.

Many preschool children wheeze only with respiratory tract pathogens and are asymptomatic between these episodes. Therefore, a 1-year randomized, double-blind comparison among intermittent treatment with high-dose ICS, a leuko­triene receptor antagonist (montelukast) and scheduled albuterol (so-called ‘standard of care’) was conducted in preschool children with histories consistent with this type of respiratory pattern. Therapy was initiated by the family, based on the participant achieving a symptom profile threshold that the child had exhibited in the past that would usually foreshadow the development of more significant lower airway involvement. After 1 year of treatment, the three groups did not differ in proportions of episode-free days (primary outcome), oral corticosteroid use, healthcare utilization, quality of life or linear growth. However, during respiratory tract illnesses, both ICS and montelukast therapy led to modest reductions in trouble breathing and interference with activity scores compared to those children only treated with albuterol. These differences were significant only in those children with a positive asthma predictive index prior to enrollment. In a post hoc analysis, similar findings were obtained when the cohort was stratified by oral corticosteroid use (0 vs ≥ 1 course) during the year preceding participation in the trial.

The observations that both the continuous and intermittent use of ICS had an effect on both the frequency and severity of exacerbations that were most likely related to a concomitant viral or bacterial respiratory tract illness provided the impetus for a third CARE network-initiated trial. This trial studied 278 children between the ages of 12 and 53 months who all had positive modified asthma predictive indices, recurrent wheezing episodes with a low grade of interval impairment, and at least one exacerbation in the previous year. Children were randomly assigned to receive nebulized budesonide suspensions for 1 year as either an intermittent high-dose regimen (1.0 mg twice daily for 7 days starting at the onset of predefined respiratory tract illness symptoms) or a daily low-dose regimen (0.5 mg nightly) with corresponding placebos in both treatment arms. The two regimens were similar with respect to exacerbation frequency (primary outcome) and other measures of asthma severity including the time to first exacerbation. The mean exposure to budesonide was 104 mg less with the intermittent regimen.

Although the results of this trial indicate that, in preschool children with this type of pre-asthma phenotype, intermittent therapy versus continuous therapy would be a therapeutic consideration, the lack of a placebo group in this study does not permit more exact interpretations of these findings. Inclusion of a placebo group was not permitted by the various human subjects committees of the clinical centers participating in this trial. This was due to the intensity of the symptom severity pattern present in the children prior to enrollment in the trial.

Role of Leukotrienes Modifiers in Viral-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. As a result of the potential for these mediators to influence airway tone, inflammatory cascades and mucus secretion, antagonists for their receptors have been developed and extensively studied. The cysteinyl leukotriene receptor antagonist, montelukast, has been the most frequently studied in both preschool and school-aged children.

In one of the initial clinical trials designed to primarily evaluate safety, patients aged 2 to 5 years were treated for over 12 weeks with montelukast administered as a 4-mg chewable tablet. Efficacy outcomes were also evaluated secondarily. Compared with placebo, montelukast produced significant improvements in multiple parameters of asthma control including: daytime asthma symptoms (cough, wheeze, trouble breathing and activity limitation); overnight asthma symptoms (cough); the percentage of days with asthma symptoms; the percentage of days without asthma; the need for beta-agonist or oral corticosteroids; physician global evaluations; and peripheral blood eosinophils. The clinical benefit of montelukast was evident within 1 day of starting therapy. Improvements in asthma control were consistent across age, sex, race and study center, and whether or not patients had a positive in vitro allergen-specific IgE test.

Robertson et al evaluated the intermittent use of montelukast in 2- to 14-year-old children with histories of intermittent asthma. The family was instructed to begin a 7-day treatment with montelukast (age-appropriate dose) at the onset of asthma symptoms or the first sign of an upper respiratory tract illness that had previously been associated with the subsequent development of lower airway asthma symptoms. Compared to placebo, montelukast treatment resulted in a modest reduction in acute healthcare resource utilization, symptoms, time off from school and parental time off work in children with intermittent asthma.

Bisgaard et al evaluated the efficacy of 1-year daily treatment with montelukast in children with intermittent asthma in reducing exacerbations. The primary efficacy endpoint was the number of asthma exacerbation episodes defined as any three consecutive days with daytime symptoms (average score of four daily daytime symptom questions of at least 1.0 on each day) and at least two treatments of beta-agonist per day, or rescue use of oral/inhaled corticosteroids during 1 or more days, or a hospitalization because of asthma. Over 12 months of therapy, montelukast significantly reduced the rate of asthma exacerbations by 31.9% compared with placebo. The average rate of exacerbation episodes per patient was 1.60 episodes per year on montelukast compared with 2.34 episodes on placebo. Montelukast also delayed the median time to first exacerbation by approximately 2 months and the rate of inhaled corticosteroid courses compared with placebo. Unfortunately, treatment did not reduce the necessity for oral corticosteroid administration. One of the remarkable aspects of this trial was the marked seasonal variation in exacerbation rates, with the summer months having less frequent exacerbations and no observed treatment effects. These data are an excellent documentation of the ‘honeymoon’ period from asthma symptoms that many clinicians observe in their patients during the summer months, most likely related to reduced numbers of respiratory tract illnesses.

Because infections with RSV in early life have been associated with an increased risk of developing recurrent wheezing and later asthma, two studies have evaluated the effects of montelukast treatment on the development of subsequent reactive airway disease symptoms. In the first ‘pilot study’, children without a diagnosis of asthma (3–36 months old), hospitalized with acute RSV bronchiolitis, were randomized into a double-blind, parallel comparison of 5 mg montelukast or placebo given for 28 days starting within 7 days of the onset of symptoms. Infants on montelukast were free of any symptoms on 22% of the days and nights compared with 4% of the days and nights in infants on placebo. Daytime cough was significantly reduced, as were exacerbations in those children on active treatment. In contrast, in a follow-up study in children 3 to 24 months of age conducted over a period of 24 weeks, montelukast treatment did not alleviate post RSV-induced respiratory tract symptoms.

In school-aged children, montelukast has been shown to be less effective compared to inhaled corticosteroid treatment in reducing the need for oral corticosteroid use and time to treatment failure over a 1-year time period. Both of these outcomes could be considered surrogates for respiratory pathogen-induced asthma exacerbations or worsening of overall asthma control.

Anti-Infection Therapy

Therapy for infection-induced asthma could potentially include one or more of the following approaches: avoidance, non-medicinal interventions, vaccination, antimicrobial drug therapy and/or immunotherapy (monoclonal antibodies directed against the relevant pathogens). The ubiquitous nature of respiratory pathogens in the environment and the social nature of interactions in childhood (daycare, school, older siblings, etc.) make avoidance strategies unfeasible. Indeed, on average, children experience 2 to 8 or more ‘colds’ per year during their preschool years.

The cure for the common cold remains elusive; as such, a number of non-medicinal interventions have been tried. Vitamin C has long been touted for common cold treatment; however, a meta-analysis of common cold treatment studies found no significant effects on either prevention or treatment. A Cochrane review of clinical studies found evidence that zinc lozenges reduce common cold duration but have significant side-effects including bad taste and nausea. Large-scale trials of Echinacea have provided no evidence of efficacy. There is evidence that warm drinks, as recommended for generations, can provide symptomatic relief from malaise and nasal symptoms without troublesome side-effects. These approaches obviously are aimed at symptom reduction of the common cold but their effects on asthma control or exacerbations have not been directly evaluated.

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 RV and RSV are obvious targets. Attempts at developing an RSV vaccine have so far been unsuccessful; however, recent data have provided renewed encouragement. Unfortunately, vaccination to prevent RV infection is even more challenging due to the large number of serotypes. As an alternative, several types of antiviral agents are in development, and several compounds with activity against RV have been tested in clinical trials.

Improved knowledge of RV molecular virology has led to several attempts to develop antiviral agents. Interferon-α has antiviral effects in vitro and shortens the duration and severity of colds, but topical application led to nasal irritation and bleeding. Anti-ICAM-1 and soluble ICAM-1 were developed to prevent binding of major group viruses to their receptor. Capsid binding agents that bind to the VP1 pocket and inhibit viral binding and/or uncoating have shown modest antiviral effects and efficacy in clinical trials. An inhibitor to the 3C protease (rupintrivir) also showed broad anti-HRV activity in vitro and efficacy in clinical trials. Unfortunately, these antiviral approaches have not so far led to development of a clinically useful medication. The molecules tested to date have been limited by combinations of modest efficacy, side-effects and/or drug interactions.

Another new approach has been to boost antiviral defenses in the lung with inhaled IFN-β. In a randomized study, subjects with persistent asthma and a history of exacerbations with colds were treated with either nebulized IFN-β or placebo within 24 hours of the onset of cold symptoms. In the intent-to-treat population, there were no significant effects on the asthma symptoms scores (which was the primary outcome) but IFN-β treatment improved recovery of peak expiratory flow. Notably, IFN-β was well tolerated and also induced expression of innate antiviral effectors in the blood and sputum. In a subgroup analysis of study subjects with more severe asthma (British Thoracic Society Step 4 and 5), colds were associated with increased symptoms in the placebo group but not in IFN-β-treated subjects. These exciting new findings, if confirmed, suggest that inhaled IFN-β used at the first sign of a cold could be a useful adjunct to standard therapy in patients with more severe asthma.

Two recent trials evaluating the efficacy of monoclonal antibody therapy directed specifically against RSV and the allergic antibody, IgE, have yielded interesting results. The first trial studied the anti-RSV monoclonal antibody, palivizumab, in a double-blind, placebo-controlled trial: 429 otherwise healthy preterm (33–35 weeks’ gestational age) infants were randomly assigned to receive either monthly palivizumab injections or placebo during the RSV season. The prespecified primary outcome was the total number of parent-reported wheezing days in the first year of life. Nasopharyngeal swabs were taken during respiratory episodes for viral analysis. Palivizumab treatment resulted in a relative reduction of 61% in the total number of wheezing days during the first year of life (1.8% vs 4.5% in the placebo group). During this time, the proportion of infants with recurrent wheeze was 10 percentage points lower in patients treated with palivizumab (11% vs 21%). As discussed above, the data generated thus far cannot ascertain what effect such treatment may have on the subsequent development of asthma in later childhood.

The second trial evaluated the anti-IgE monoclonal antibody, omalizumab, which specifically targets the Fc portion of IgE to prevent binding to the surface of cells and is therefore a narrowly focussed intervention for type I hypersensitivity. In a placebo-controlled trial of guidelines-based asthma treatment compared to omalizumab added to standard therapy, omalizumab prevented the seasonal increases in exacerbations during the fall and spring, which are peak times for viral exacerbations ( Figure 31-1 ). Analysis of viruses in nasal secretions during a subset of exacerbations confirmed that the treatment group had fewer viral and nonviral exacerbations. This study provides direct evidence that IgE-mediated inflammation contributes to the risk of virus-induced exacerbations of asthma. These observations indicate that interactions between allergic sensitization (antigen-specific IgE antibody formation) and viral respiratory illnesses play an important role in asthma control. Finally, it will be of interest to determine whether other drugs targeting specific type-2 cytokines (e.g. mepolizumab and IL-5) can also reduce the risk of virus-induced exacerbations.

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