Respiratory syncytial virus (RSV), a major cause of lower respiratory tract infections in infants and children, causes seasonal epidemics in most communities each year. Those at greatest morbidity and mortality risk are children with underlying heart or lung disease, premature infants, and the immunocompromised. There is currently no safe and effective vaccine for the prevention of RSV infection. Use of the antiviral agent ribavirin, (Virazole7), is controversial and may not be cost effective in some cases. RSV-immune globulin, (RSV-IG), was approved by the FDA in January of 1996 for the prevention of serious lower respiratory tract infections caused by RSV in children under age two with bronchopulmonary dysplasia or infants under age one with a history of prematurity (specifically, those whose gestational age is less than or equal to 35 weeks). Although RSV-IG does not directly prevent RSV infection, it is safe and effective in reducing the frequency and severity of infection with the virus.
RespiGam7, (RSV-IG), is a polyclonal hyper-immune antibody product derived from human plasma that contains high titers of neutralizing antibody to RSV. The concentration of RSV-neutralizing antibodies is greater in RSV-IG than in other intravenous immune globulin products. Administration of RSV-IG to children at high risk for complications from RSV may help prevent infection with the virus or reduce the severity of illness by passively supplementing the natural immune system. The mean half life of serum RSV-neutralizing antibodies after RSV-IG infusion is 22-28 days.
A limited review of the medical literature identified two large, placebo controlled trials in which the use of RSV-IG in infants and children at increased risk of RSV was evaluated during RSV season. The pivotal study, Prophylaxis of Respiratory Syncytial Virus in Elevated-risk Neonates, or the PREVENT trial, evaluated the efficacy of RSV-IG in preventing RSV infection in 510 high-risk children. In a 54 center, double-blind study, children under 24 months of age with bronchopulmonary dysplasia (n=220) or under six months of age that had experienced premature birth (<35 weeks gestation; n="290)" were randomly allocated to treatment with either 750 mg/kg of RSV-IG or placebo administered monthly for six months during RSV season (November 1994 through April 1995). Follow-up continued for two months after the last infusion. Significant reductions were seen in RSV-associated hospitalizations (41%), RSV hospital days (53%), and the incidence of moderate to severe RSV lower respiratory tract infection (54%). In the treatment group, RSV-IG showed significant benefit in non-RSV disease, reducing non-RSV hospitalization by 49% and acute otitis media rates by 38%.
The attenuation or prevention of RSV infection in high risk children was evaluated in the National Institute of Allergy and Infectious Diseases (NIAID) trial. Two hundred forty nine infants (102 with bronchodysplasia, 87 with heart disease, and 60 born prematurely) were randomized to receive high-dose RSV-IG (750 mg/kg; n=81), low-dose RSV-IG (150 mg/kg; n=79), or no drug (control; n=89) monthly through RSV season. Compared with controls, children who received high-dose RSV-IG showed significant reductions in the incidence of RSV lower respiratory tract infection (9 versus 22% of patients) and the occurrence of such infection that was moderate or severe (6 versus 19%). Similar reductions were also observed in hospitalizations for RSV (63%), number of hospital days (63%), and number of days spent in the ICU (97%). The low-dose group exhibited a trend toward fewer RSV lower respiratory tract infections (a 27% reduction compared with controls) and fewer that were moderate or severe (a 53% reduction versus controls). Although three deaths occurred in each of the two treatment groups, no death was attributable to RSV-IG or to RSV illness.
In clinical trials, RSV-IG was generally well tolerated, with an incidence of most side effects of less than three percent. The most frequent side effects included fever, nausea, vomiting, and wheezing. Excluding hypersensitivity reaction, adverse reactions similar to those reported with other intravenous immune globulins, such as dizziness, flushing, blood pressure changes, anxiety, palpitations, chest tightness, dyspnea, abdominal cramps, pruritus, myalgia, and arthralgia, are often related to the rate of infusion. Loop diuretics should be available for the management of patients who are at risk of fluid overload (i.e., those with underlying pulmonary disease).
Administration of RSV-IG, like other plasma products, carries a risk of transmission of blood-borne pathogens. However, the risk of viral transmission is considered low because of plasma donor screening and the addition of a solvent detergent that inactivates most known blood-borne viruses.
Antibodies present in immune globulin preparations may interfere with the immune response to live virus vaccines, such as mumps, rubella, and particularly measles. The Committee on Infectious Diseases of the American Academy of Pediatrics recommends that MMR vaccination be delayed for at least three months after a patient has received it. If such vaccines are given during or within three months of RSV-IG infusion, re-vaccination is recommended.
Patients qualifying for RSV prophylaxis should receive a monthly infusion of RSV-IG prior to and continuing throughout the RSV season. In the Northern Hemisphere, the RSV season typically begins in November and continues through April. The manufacturer recommends that children infected with RSV also continue to receive monthly doses of RSV-IG for the duration of the RSV season. The maximum recommended total dosage per monthly infusion is 750 mg/kg. The following table is a guideline for administration. Actual infusion rates should be based on cautious monitoring of the patient.
RSV is an expensive illness, often requiring prolonged hospitalization and mechanical ventilation in high risk children. In a randomized double-blinded study of ribavirin therapy versus placebo that was published in 1991, the mean hospital bill for infants with RSV at Stanford Medical Center was $68,067 versus $77,666, respectively (not statistically significant). The pivotal PREVENT study that was the basis for FDA approval of Respi-Gam7 lowered the RSV hospitalization rate from 13.5% to 8%. Estimated pediatric patient charge for a 6 month course of Respi-Gam7 therapy is between $5,000 and $ 10,000.
As a result of the cost associated with RSV-IG therapy, many institutions have established guidelines for the use of RSV-IG in patients who are at risk for severe RSV infection. Such patients include children under 24 months of age who are premature at birth (<35 weeks gestation), have bronchopulmonary dysplasia, or moderate to severe congenital heart disease. Immunocompromised patients may also benefit from RSV-IG during community or nosocomial outbreak of RSV infection.
Respiratory syncytial virus immune globulin has been proven safe and effective in preventing severe RSV lower respiratory tract infections in high-risk children under age two with bronchopulmonary dysplasia and a history of prematurity (less than or equal to 35 weeks gestation). Use of Respi-Gam7 must be determined on an individualized basis.
