Compared with its course in otherwise healthy children, respiratory syncytial virus (RSV) infections lead to higher mortality and morbidity measured by hospital duration, transfer to intensive care, and ventilation in children with underlying heart or lung disease.^1,2 Recently, a polyclonal RSV immune globulin preparation, containing high titers of RSV neutralizing antibodies, was approved in the United States for use as a prophylactic agent against severe RSV infections. Licensure followed the demonstration of efficacy in terms of reduced frequency and duration of hospitalizations for RSV lower respiratory tract infection (LRI) among children with underlying lung disease and premature infants.³ Such prophylaxis, however, is expensive and requires monthly intravenous infusions during the RSV season. Given the expense, time commitment, and difficulty gaining intravenous access in premature infants, RSV immune globulin may be more appropriately reserved for those children with the highest risk for complicated disease.

Studies in otherwise healthy children have shown that the frequency of primary and recurrent RSV infection is inversely correlated with the titer of RSV neutralizing antibodies measured before the onset of the RSV season.⁶ Information on illness or hospitalization frequency obtained in this population, however, is likely to underestimate disease in patients with underlying cardiac or pulmonary conditions.

This study was conducted to determine whether preseason RSV neutralizing antibody titers reduced the frequency of RSV infection in children with underlying heart or lung disease. In addition, current information was obtained regarding hospitalization risk in this population. Such data may be helpful in determining the population who would be most likely to benefit from receipt of prophylactic RSV immune globulin.

PATIENTS AND METHODS

After enrollment, demographic data including details about the underlying illness and gestational age, and a serum sample were obtained. Weekly telephone follow-up inquired about respiratory illnesses using a previously described questionnaire.¹⁰ Subjects with a new respiratory illness identified by new respiratory symptoms on the questionnaire were seen by the study nurse to collect nasopharyngeal secretions by aspiration with a syringe and infant feeding catheter. Because of financial constraints, such home visits to collect nasopharyngeal aspirates were made only after the onset of RSV season at each center. Each new illness was classified as an upper or lower respiratory infection with the latter distinguished by radiographic evidence of pneumonia or the new onset of wheezing or exacerbation of preexisting wheezing. Any hospitalizations were noted. Patients continued to have weekly follow-up until an RSV infection was identified or the RSV season ended, defined as the month of May at all sites. Once a nasopharyngeal aspirate had been positive for RSV for a particular patient, no further specimens were obtained in that season.

Nasopharyngeal aspirates were processed in the virology laboratory at each site using immunofluorescence microscopy or enzyme immunoassay as previously described.² Sera were stored at 70°C until sent on dry ice to the study central laboratory in Winnipeg, Manitoba. RSV neutralizing antibody was performed using previously described methods.¹¹ Briefly, sera were heat-inactivated and tested in duplicate without exogenous complement. A 60% plaque reduction assay was performed on microtiter plates lined with HEP2 cells. The RSV test strains A2 (RSV subgroup A) and 18537 (RSV subgroup B), immunoreagents and control sera were provided by Lederle Praxis Biologicals Inc (Rochester, NY). A RSV neutralizing antibody was considered high if the assay was positive at a dilution of 1:100. This approximated the titer of 128 used as a cut-off for high antibody in a study of RSV antibody in healthy children.⁶

A Fisher's exact test was used to compare the proportion of patients with RSV LRI or RSV-associated hospitalization in different age groups. Analysis of covariance was used to determine the effect of age and prematurity on antibody concentrations. Prematurity was defined as a gestational age of less than 33 weeks in this analysis, because one would predict less maternal transfer of RSV antibody in more premature neonates. ² analyses were used to compare RSV neutralizing antibody concentrations with frequency of RSV infection, RSV LRI, RSV hospitalization, and all hospitalizations. A stratified analysis was used to assess the effect of antibody after controlling for the effect due to age.

RESULTS

Table 1. Demographic Characteristics of Enrolled Patients [View Table]

Eleven percent and 12% of lung and heart disease groups, respectively, experienced an RSV LRI. Six percent and 3% of lung and heart groups were hospitalized with RSV infection. There was a reduction in frequency of RSV LRI and RSV hospitalization with increasing age in both heart and lung disease subgroups (Table 2). The subgroup of 114 patients with bronchopulmonary dysplasia was examined separately because their premature birth may lead to their having narrower airways and lower RSV neutralizing antibodies predisposing them to more severe disease. Their RSV LRI and RSV-associated hospitalization rates were 11% and 6%, respectively, with similar age specific rates to those observed in the overall group of children with chronic lung disease of any kind. In the entire group, RSV LRI rates were approximately threefold higher and RSV-associated hospitalizations were over fivefold higher in those in the first year of life compared with those rates in older children.

Table 2. Frequency of Respiratory Syncytial Virus (RSV) Lower Respiratory Infection and RSV Hospitalization by Age [View Table]

Preseason sera was obtained from 422 patients. Antibody titers varied by age (P = .0001) with trends to lower titers in premature versus term infants that did not reach statistical significance (Figure). There was a U-shaped distribution with an initial fall to a nadir at 6 to 9 months followed by a rise in antibody titers. The trends to lower antibody titers in subgroup B patients in the younger age group as compared with subgroup A did not reach statistical significance. In this analysis, prematurity was defined as gestational age less than 33 weeks. When this analysis was performed again using gestational age less than 37 weeks as the definition of prematurity, the above observations remained the same.

When baseline antibody concentrations were at least 100, a significant reduction was observed in the frequency of RSV infections and LRIs. The reduction in frequency of RSV hospitalizations did not reach statistical significance (Table 3). The significant differences were maintained after age stratification. That the effect was specific for RSV infection was confirmed by the lack of difference in overall LRIs and hospitalizations when children with high and low antibody titers were compared.

Table 3. Antibody Status and Frequency of Respiratory Syncytial Virus (RSV) Infection and Hospitalization [View Table]

DISCUSSION

The rates of RSV LRI rates were 18.2% and 20.4% in infants with underlying lung or heart disease. Corresponding hospitalization rates in these groups were 14.5% and 6.9%, respectively. One can use the `number needed to treat' to help in making a decision on the children who should receive prophylaxis. The number needed to treat to prevent one hospitalization can be calculated using the risk reduction of 67% observed with RSV immune globulin in the randomized trial^3,4 and an estimate of baseline event rate.¹⁴ Using a baseline event rate of 20% observed in the trial, approximately eight subjects would need to receive prophylaxis to prevent one hospitalization. Using a baseline event rate of 15% as observed in infants with lung disease in this study, 10% in all infants in this study, or 1.4% in 1- to 3-year-old children in this study, then 10, 15, or 100 subjects, respectively, would require prophylaxis to achieve the same benefit. From these calculations, children older than 12 months are less likely to benefit from RSV immune globulin and a cost-benefit analysis may not support its use in this population. Other factors such as prematurity in addition to cardiac or pulmonary compromise should be considered in selecting infants who could most benefit from prophylaxis if the main purpose is the avoidance of hospitalization. Other important benefits of this product are avoidance of the need for intensive care or ventilation. However, these are much rarer events.

Why was there a higher hospitalization rate in patients with underlying pulmonary vs cardiac disease? The bulk of the former group are made up of premature infants. The nadir of endogenous, presumably maternally derived, antibody occurred in both preterm and term infants at about 6 to 9 months. Although the difference did not reach statistical significance, the antibody concentrations in preterm infants are lower throughout the first year of life in the preterm infants. Premature infants have two features contributing to more severe illness: the abnormal lung structure with reduced surface area for gas exchange and the relative lack of maternally derived RSV antibody. As their lung function normalizes, their antibody levels decline during their first year. One would, therefore, predict that the maximum benefit from exogenous immune globulin in preventing RSV infection would occur early in the first year of life in this group when the airways have not had a chance to grow and there is little RSV neutralizing antibody.

Randomized trials provide the highest quality of evidence about the efficacy of interventions.¹⁵ However, the generalizability of findings from such trials may be limited by differences in trial participants and compliance with the regimen compared with that in the usual clinical setting. This observational study provides additional data to estimate the effectiveness of interventions in the usual setting. The expected reductions in effects compared with those observed in a trial are particularly relevant to decisions regarding implementation of costly interventions.