Immunoprophylaxis and the control of respiratory syncytial virus disease.

Abstract

Respiratory syncytial virus (RSV) remains one of the most important infectious causes of hospitalization in infants and children. This enveloped, RNA virus produces predictable yearly outbreaks of disease that typically peak between January and February in countries in the northern hemisphere.1 The outcome of RSV infection varies from mild upper respiratory tract infection in approximately 75% of infected infants and young children to severe life-threatening disease in a small percent of infected patients.2 In the United States, RSV lower respiratory tract infection accounts for nearly 50% of hospitalizations due to bronchiolitis and 25% of hospitalizations due to pneumonia.1 Serologic surveys suggest that by 2 years of age, more than 90% of all children have been infected by RSV.3 Whether RSV infection early in life predisposes to subsequent reactive airway disease remains an unanswered question. Reinfection is common, indicating that immunity to RSV following natural infection is less than complete.4-6RSV lower respiratory tract disease occurs primarily in infants under 2 years of age; most infants who require hospitalization are previously healthy infants less than 6 months of age. Premature infants, infants born with congenital heart disease, and those with chronic lung disease (such as bronchopulmonary dysplasia [BPD]) constitute additional high-risk groups with high rates of hospitalization due to RSV infection.7-13 A recent report describes RSV mortality rates among such hospitalized infants of 4% to 5%.14Pre-engraftment bone marrow transplant recipients, solid organ transplant recipients, and lymphopenic children receiving chemotherapy appear to suffer even higher mortality rates, although prospective data are not available.15 Morbidity in these groups is also great; the average hospital stay and intensity of care for such children may be several times that of previously healthy infants.Despite the importance of RSV as a pathogen in the pediatric age group, options for treatment and prevention of RSV disease are limited. Aerosolized ribavirin was licensed in 1986 for treatment of children hospitalized with severe RSV lower respiratory tract infection. The efficacy of ribavirin therapy remains controversial despite the growing number of carefully conducted trials.16 Factors that complicate evaluation of antiviral therapy include the self-limited nature of most viral respiratory tract illness, and variation in the natural history of RSV disease from patient to patient. These variables make it difficult to select and define distinct endpoints that can be used to evaluate differences between treatment and control groups.Active immunization to prevent severe RSV disease has not yet been successful. Persistent concern regarding vaccine safety in the young infant is the result of an unanticipated reaction to a formalin inactivated RSV vaccine used in trials conducted in the early 1960s.17-19 Recipients (less than 12 months of age) of the inactivated RSV vaccine experienced higher mortality and morbidity rates upon subsequent RSV infection than did infants who received the control vaccine. The immunologic mechanism for this reaction remains unclear although there appears to have been an aberration in both the cellular and humoral response to the vaccine. Vaccine development is also complicated by the limited ability of infants to mount an immune response to RSV glycoprotein antigens. Furthermore, the presence of maternal neutralizing antibodies may attenuate an active immune response in a vaccinated infant. Despite current efforts to develop subunit vaccines, peptide vaccines, or live attenuated RSV vaccines, it is unlikely that active immunization for infants will be available in the near future.20As an alternative to active immunization against RSV, several approaches to passive immunization in high-risk infants have been evaluated. Clinical trials were first conducted using standard intravenous immune globulin (IGIV). Two randomized controlled trials involving monthly infusions of standard IGIV to high-risk infants failed to demonstrate a reduction in hospitalization rates due to RSV.2122 This lack of efficacy was most likely due to a failure to attain adequate peak and trough RSV neutralizing antibody titers. With the development of an RSV-enriched immune globulin in the late 1980s (RSV-IGIV), it became possible to achieve sufficiently high neutralizing antibody levels in the outpatient setting with infusion of a reasonable fluid volume (15 mL/kg). The first RSV-IGIV prophylaxis trial (National Institute of Allergy and Infectious Disease [NIAID] trial) published in 1993 was conducted over three respiratory virus seasons and included 249 children with prematurity, chronic lung disease or congenital heart disease.23 Children who received 750 mg/kg/dose of RSV-IGIV had a 63% reduction in RSV hospitalizations and a 63% reduction in RSV hospital days relative to control patients receiving no RSV-IGIV. A second prophylaxis trial using RSV-IGIV (PREVENT trial), was conducted over one respiratory virus season and included 510 premature infants with and without BPD.24 This trial demonstrated a 41% reduction in RSV hospitalizations and a 53% reduction in RSV hospital days. A third multicenter RSV-IGIV prophylaxis trial involving 416 infants and children (Cardiac trial) failed to show an overall reduction in RSV disease severity in children with congenital heart disease (unpublished data). A meta-analysis of children less than 6 months of age from all three prophylaxis trials demonstrated a 47% reduction in RSV-induced hospitalization (95% confidence interval of .28–.82) (P = .006) (Table). However, caution must be observed in interpreting these data. Although there is considerable interest in the evaluation of hospitalization rates in subgroups of infants, none of the three trials were prospectively designed for subgroup analysis.Two additional clinical benefits of polyclonal immune globulin administration were observed in recipients of RSV-IGIV prophylaxis. The PREVENT trial demonstrated a 38% reduction in hospitalization due to respiratory tract infection by any respiratory virus and a 46% reduction in total hospital days due to all respiratory illnesses.24 Further, both the NIAID trial and the PREVENT trial demonstrated a reduction in the incidence of acute otitis media in high-dose RSV-IGIV recipients (750 mg/kg/dose) relative to low-dose or control patients.2425RSV-IGIV use in patients with congenital heart disease has been evaluated in two trials (the NIAID trial and the Cardiac trial) and has involved a total of 516 children. The safety of RSV-IGIV, particularly in children with cyanotic heart disease, is uncertain. There appeared to be an increased incidence in both morbidity and mortality, particularly in association with cardiac surgery in RSV-IGIV recipients with cyanotic heart disease as compared with placebo recipients. The deaths occurred at variable times, up to 3 months following an RSV-IGIV infusion. No explanation has yet been found. At the present time, use of RSV-IGIV should be avoided in children with cyanotic heart disease. Among children with left to right shunts who received RSV-IGIV there was not a statistically significant reduction in the overall incidence of RSV hospitalization relative to the control group. Therefore, based on the currently available data, RSV-IGIV does not appear to be indicated for most children with noncyanotic congenital heart disease. It may be that immunoprophylaxis will be beneficial in those infants with noncyanotic heart disease who also satisfy immunoprophylaxis criteria based on prematurity or the presence of BPD. The role of RSV-IGIV in infants with large left to right shunts with pulmonary hypertension remains uncertain.RSV-neutralizing antibodies are directed mainly against two surface glycoproteins. The G glycoprotein mediates RSV attachment to a cell that will support RSV replication by binding with cellular receptors containing sialic acid. The F glycoprotein mediates fusion of the viral lipid envelope with the plasma membrane of the cell. Although there may be considerable sequence divergence in the G glycoprotein between RSV subgroups, the important neutralizing epitopes of the F glycoprotein appear to be faithfully conserved between RSV strains and over time. There has been interest in the use of monoclonal antibodies for prophylaxis against RSV disease because of the possibility of intramuscular (rather than intravenous) administration. One immunoprophylaxis trial using a humanized immunoglobulin G (IgG) monoclonal antibody was conducted during the 1995–1996 respiratory season. In this large, multicenter, double-blind, randomized, placebo-controlled trial, monoclonal antibody or placebo was administered intramuscularly once a month to preterm infants during the respiratory virus season. The results proved disappointing (unpublished data). Although safe, this monoclonal antibody preparation did not reduce RSV hospitalization rates at the dose administered. A second multicenter prophylaxis trial using a higher dose of a somewhat different humanized murine IgG monoclonal antibody and involving over 1500 patients is currently underway.RSV transmission occurs primarily by direct introduction of virus contaminated secretions onto mucous membranes of the upper airway. Bronchiolitis and pneumonia develop when RSV from the upper airway is aspirated into the lungs. The presence of RSV immunoglobulin A (IgA) nasal antibody may protect infants against the low titer of RSV that initiates infection. Studies in experimental animals demonstrate that intranasal administration of a murine monoclonal IgA directed against the RSV F glycoprotein significantly reduced viral replication in the nasal turbinates and the lungs.2627 Phase III prophylaxis trials to evaluate topical daily instillation of IgA antibody as nose drops are currently in progress in high-risk infants.The severity of RSV infection appears to be a function of both a direct viral cytopathic effect and the immune response of the host. Evidence supporting the concept that antiviral activity alone may not be sufficient to attenuate RSV disease expression comes from the unpublished trial demonstrating little if any benefit from prophylaxis with monoclonal IgG antibody, and from the clinical trials that show little beneficial effect from RSV-IGIV in the treatment of established RSV disease in infants.28 The beneficial effect on RSV disease severity that is derived from immunoprophylaxis with a hyperimmune polyclonal product may not be due to RSV neutralizing antibody alone.29 What other critical functions might be present in RSV-IGIV that are not present in a preparation of monoclonal antibodies? Recognized immunomodulatory functions of standard IGIV include: alteration of cytokine production,30 inhibition of T-cell proliferation in vitro,31 increase in natural killer cell activity,32 increase in antibody dependent cell cytotoxicity,32 and neutralization of superantigen activity.33 How important these or other as yet unrecognized immunomodulatory functions are in the attenuation of RSV disease expression remains to be determined.The cost of immunoprophylaxis with RSV-IGIV (licensed in 1996 by the Food and Drug Administration and sold under the trade name RespiGam) over one respiratory season is approximately $5000.34Therefore, it is important that prophylaxis be reserved for carefully selected infants. A recently published consensus statement reviewed the existing literature on RSV disease in various high-risk groups and offered the following guidelines for selection of RSV-IGIV eligible patients15:It must be remembered that the majority of children hospitalized due to RSV disease are previously healthy, young infants. During the 1995–1996 respiratory virus season, 69% of 95 children hospitalized at the New England Medical Center with RSV infection were full-term infants with normal cardiac and pulmonary status. Therefore, use of RSV-IGIV in appropriately selected, high-risk infants is unlikely to dramatically reduce the overall number of RSV induced admissions. However, high-risk children have a disproportionately high economic impact on RSV-associated health care costs because of the greater disease severity and the complexity of care required for these groups. In appropriately selected infants for whom the risk of hospitalization due to RSV and other respiratory viruses is greatest, passive immunoprophylaxis should have an important medical impact and improve their quality of life.