Respiratory syncytial virus (RSV) can cause acute clinical findings that range from symptoms of upper respiratory infection, with or without otitis media, to severe lower respiratory tract disease. Virtually all children become infected with RSV within 2 years of birth, most commonly before 6 months of age, and 1% require hospitalization 1. RSV is the primary cause of hospitalization for acute respiratory tract illness in young children, and it may be responsible for 40–90% of cases of bronchiolitis, for 5–40% of cases of pneumonia, and for 10–30% of cases of tracheobronchitis in this age group 2.

RSV is transmitted most commonly by direct contact with surfaces or persons contaminated with infectious nasal secretions. After an incubation period of 2–8 days, RSV replicates in the nasopharyngeal epithelium and can spread to the lower respiratory tract within 1–3 days 3. Pneumonia or bronchiolitis occurs in 30–71% of infants and young children at the time of first RSV infection 4.

RSV bronchiolitis is often followed by recurrent episodes of wheezing, although the pathogenesis of this link is poorly understood. Bont et al.5 found that 47% of 130 infants hospitalized for RSV lower respiratory tract infection (LRTI) developed recurrent wheezing during a 1-year follow up. The occurrence of wheezing was significantly higher in infants with airflow limitation (61%) than for those without airflow limitation (21%; P < 0.001) during the acute infection. In a study by conducted by Stein et al.6, 207 children who had RSV LRTI before age 3 years also had a significantly increased risk for both infrequent wheezing and frequent wheezing by age 6 years (3.2 and 4.3 times greater incidence than in children who did not have RSV LRTI before age 3 years, respectively; P < 0.001). However, this risk decreased and was no longer significant by age 13 years, and none of the patients was hospitalized. Sigurs et al. 7 demonstrated that RSV bronchiolitis that was severe enough to require hospitalization in 47 infants was highly associated (P < 0.001) with development of asthma and recurrent wheeze up to age 7.5 years. The cumulative prevalence of asthma was 30% in the RSV group and 3% in the control group (P < 0.001), and the cumulative prevalence rates of any wheezing were 68% and 34%, respectively (P < 0.001).

The majority of children who experience postbronchiolitic wheezing have multiple (recurrent) episodes. Hall 3 cited subsequent episodes of wheezing in 40–50% of infants hospitalized with RSV bronchiolitis, imposing a significant burden on health care resources. During the 1980s, an estimated 100,000 children were hospitalized with RSV infection in the USA annually 38, at a cost of US$300 million. In the study conducted by Bont et al. 5 recurrent wheezing in the hospitalized infants was defined as two or more episodes; respiratory symptoms were recorded in a daily diary. Infants had a total of 241 episodes of wheezing, with a median number of two episodes.

It is difficult to predict which children will develop recurrent wheezing, although some clinical and immunologic parameters may be useful in prediction models in the future. Airflow limitation during RSV LRTI is the first useful clinical predictor of subsequent recurrent wheezing and physician diagnosed asthma in early childhood 5. Another predictor may be monocyte interleukin-10 responses in vitro to stimulation with nonspecific stimuli 9. In addition, a high (≥ 16 μg/l) serum eosinophil cationic protein concentration during the acute phase of bronchiolitis is a specific but insensitive predictor of wheezing after bronchiolitis 10. Thus, a high serum level of eosinophil cationic protein is strongly predictive of subsequent wheezing, but low values do not exclude wheezing episodes in the future.

The pathogenesis of recurrent wheezing after RSV LRTI is not completely understood. Prospective, randomized studies are needed to determine whether severe RSV LRTI causes long-term pulmonary sequelae and a predisposition to wheezing, or whether inherent genetic or structural abnormalities predispose a child to both severe LRTI and wheezing later in life. If severe RSV LRTI causes subsequent wheezing, then reducing the severity of RSV LRTI should reduce the risk for subsequent wheezing. This issue has been explored in several studies of RSV LRTI treatment or prevention; these studies are discussed below.

Antiviral therapy with aerosolized ribavirin and symptomatic therapy with bronchodilators and corticosteroids are the available treatment options for RSV infections. Unfortunately, they produce only a modest short-term improvement in respiratory outcome, or have no effect at all.

Ribavirin is a synthetic guanosine analog and broad-spectrum antiviral agent that is approved only for hospitalized infants and young children with severe RSV infection. Ribavirin inhibits RSV replication during the active replication phase. Use of aerosolized ribavirin has been associated with improved oxygenation and clinical scores 11 and with reduced levels of secretory mediators of inflammation associated with severe disease and wheezing 12. However, some investigations were criticized for their methodology and use of subjective end-points (e.g. clinical score) rather than objective end-points (e.g. mortality, arterial oxygen saturation, and need for or duration of mechanical ventilation) 13. Any beneficial effects of ribavirin, such as a reduction in duration of mechanical ventilation or hospitalization, are unproven 3, and routine use in high-risk children with RSV infections is no longer warranted 13.

Most available data do not support the use of corticosteroids in the treatment of acute RSV bronchiolitis. Intravenous hydrocortisone followed by oral prednisone 14, intramuscular or oral dexamethasone 1516, and oral prednisolone 17 have yielded little or no benefit, except possibly in a select subgroup of patients.

Several trials 18192021 have also shown that β₂-agonist bronchodilators, such as salbutamol and the anticholinergic agent ipratropium bromide, have no beneficial effect on acute RSV bronchiolitis. Although bronchodilators may produce a modest short-term improvement in clinical scores 13, Flores and Horwitz 22 concluded (on the basis of an extensive meta-analysis) that there is insufficient evidence to support the use of β₂-agonists to treat bronchiolitis.

Studies of the efficacy of vitamin A 23 and interferon 24 also had disappointing results. Oral administration of vitamin A did not decrease respiratory morbidity in children with acute RSV bronchiolitis 23. In a double-blind, placebo-controlled study 24, IFN-α-2a had a prophylactic effect but did not reduce the severity of signs and symptoms or duration of illness. There was a significant difference (P < 0.05) in the frequency of colds in the two groups: one out of 19 receiving IFN-α-2a and seven out of 19 receiving placebo had colds. Also, 14 out of 19 receiving placebo showed laboratory evidence of RSV infection, versus 10 of 19 receiving IFN-α-2a. Because the risk for a secondary bacterial infection in patients with RSV bronchiolitis is very low 25, routine use of antibiotics is not warranted.

The results of two therapeutic trials with RSV intravenous immune globulin (RSV-IGIV; RespiGam™, MedImmune, Inc., Gaithersburg, MD, USA) were also disappointing. RSV-IGIV was no more effective than placebo in previously healthy children hospitalized with RSV infection with regard to duration of stay either in hospital or on the intensive care unit 26, or was it beneficial in hospitalized children at high risk for severe RSV infection 27. However, RSV-IGIV has been shown to be effective in the prevention of RSV LRTI in these high-risk children.

Prevention of RSV bronchiolitis has met with greater success than has treatment. Although no vaccine is available to prevent RSV bronchiolitis, passive immunization can be conferred by RSV-IGIV, which contains high levels of RSV neutralizing antibody, or by intramuscular injections of the humanized monoclonal antibody palivizumab (Synagis^®; MedImmune, Inc.). Both products are costly, however.

If the recurrent wheezing episodes associated with severe RSV LRTIs in infants are in fact due to the initial RSV infection, then these sequelae might be prevented in one of two ways. One is treating the initial RSV bronchiolitis episode in order to lessen its severity; treatment options include ribavirin and corticosteroids. The other option is to prevent RSV bronchiolitis; effective options include RSV-IGIV and palivizumab 37.

Studies have shown that ribavirin therapy appears to have no significant effect on reducing the long-term respiratory outcomes associated with RSV LRTI. Inhaled corticosteroid or bronchodilator therapy administered at the time of acute RSV infection may improve respiratory outcomes only in the short term. RSV-IGIV and palivizumab are effective agents for prevention of RSV LRTI in children with BPD and/or prematurity, but their long-term effect on the development of asthma and recurrent wheezing is not clear. Further research is needed to elucidate the mechanisms involved and to evaluate the impact of available therapies on long-term respiratory outcomes of RSV LRTI.

BPD = bronchopulmonary dysplasia; IFN = interferon; LRTI = lower respiratory tract infection; RAD = reactive airway disease; RSV = respiratory syncytial virus; RSV-IGIV = respiratory syncytial virus immune globulin intravenous (human).