Who Shall Not Receive Palivizumab?

To the Editor. A respiratory syncytial virus (RSV)-specific monoclonal antibody, palivizumab, is now available. The clinical effect of the drug has so far been evaluated in only 1 randomized, blinded clinical study against a placebo—the IMpact-RSV study.1 In this study, palivizumab was given as an intramuscular injection every 30 days throughout the RSV season to premature children and children with bronchopulmonary dysplasia. The study demonstrated an overall 55% reduction in the hospitalization rate for RSV, while the overall length of stay in intensive care unit were significantly longer for the children treated with palivizumab compared with placebo: 12.7 and 13.3 days, respectively (P = .023). The IMpact-RSV study also demonstrated that palivizumab did not prevent RSV infection, but rather modulated its clinical course. Seven of the children with a RSV infection in the treatment group (n = 1002) were in need of assisted ventilation in contrast to 1 in the placebo group (n = 500). Two of the children in the treatment group died of an RSV infection; none died in the placebo group. Despite appropriate prophylactic treatment with palivizumab, these 2 infants developed RSV infections and did not survive.After the IMpact-RSV study, palivizumab has been accepted by the Food and Drug Administration for clinical use, and guidelines have been worked out.2 The question about possible harm palivizumab may do to subgroups of prematurely born children has not been raised, but is substantial after the IMpact-RSV study. Do we have enough scientific data from the IMpact-RSV study to set up guidelines for when not to give palivizumab?In Reply. The results of the IMpact-RSV study1 demonstrate significant efficacy (P = .00004) of palivizumab prophylaxis, with a 55% reduction in RSV hospitalization in high-risk children and a significant reduction in the need for intensive care unit admission (P = .026). No significant differences were observed in the number of patients receiving mechanical ventilation (P = .280) in the trial; 7 of 1002 (0.7%) children receiving palivizumab and 1 of 500 (0.2%) children receiving placebo required mechanical ventilation. It's important to note that the placebo rate for mechanical ventilation was considerably lower than the control group rates of mechanical ventilation (1.9%–2.8%) in previous RSV prophylaxis studies.1–4 Among children hospitalized for RSV (a nonrandomized subset) in the IMpact-RSV trial, the number of hospital days was not normally distributed. In the palivizumab group 3 children with severe underlying bronchopulmonary dysplasia and other complicating conditions accounted for 60% of intensive care unit days and 65% of mechanical ventilation days. These children's course was anticipated based on their extensive underlying disease unrelated to RSV and did not suggest “atypical” or “enhanced RSV disease.”As described in the IMpact paper, there were no statistically or medically significant differences in the number of deaths in this population. Among 2 children who died in the palivizumab group during a RSV hospitalization, 1 occurred after surgery following recovery from RSV and the other occurred in a very high-risk and complicated child. The children cited by Dr Brunvand and colleagues acquired RSV despite palivizumab prophylaxis. These children had severe RSV as would be expected based on their underlying conditions. There was no evidence that palivizumab contributed to this outcome.A wide and extensive body of preclinical and clinical data strongly suggest that RSV antibodies, and in particular palivizumab, do not enhance the severity of disease, but rather reduce RSV pulmonary replication and reduce the incidence of RSV hospitalization in children. First, passive antibody (in contrast to antibody and cellular immunity produced by vaccination with formalin-inactivated vaccines) is associated with reduction of pulmonary RSV and no enhancement of histopathology in cotton rats.5 Preclinical studies have shown that palivizumab does not induce antibody-dependent enhancement in a primary RSV infection in cotton rats nor does it enhance either virus replication or virus-induced pathology in a rechallenge of previously infected cotton rats. Second, palivizumab has been shown to have an antiviral effect and reduce RSV in the lower respiratory tract in children. In a placebo-controlled study6 of intubated children with RSV infection, palivizumab treatment (15 mg/kg IV) was associated with a significant (P = .004) reduction of RSV in tracheal secretions. Third, a Phase I/II placebo-controlled study7 of palivizumab treatment of RSV-infected children demonstrated no significant differences in mean days of RSV hospitalization (6.05 vs 4.39, for placebo and palivizumab, respectively), days of oxygen therapy (3.23 vs 2.47), or days of mechanical ventilation (7.91 vs 4.71). Thus, there is no evidence of enhancement in RSV-infected children with palivizumab treatment. Experience with polyclonal antibody (RSV-IGIV) also supports the benefits of RSV prophylaxis.8The efficacy of palivizumab in prevention of RSV hospitalization in high-risk children has been proven. Comprehensive clinical trials data on approximately 1100 children receiving more than 5000 doses of palivizumab demonstrated its safety. These data have been reviewed extensively by regulatory authorities throughout the world. There is no evidence to suggest that subgroups of premature children or children with bronchopulmonary dysplasia should not receive prophylaxis based on “harm.” The safety and efficacy of palivizumab in children with congenital heart disease is now being studied in a large multicenter, multinational, randomized, double-blind, placebo-controlled study.