AMERICAN ACADEMY OF PEDIATRICS Committee on Infectious Diseases and Committee on Fetus and Newborn

Prevention of Respiratory Syncytial : Indications for the Use of Palivizumab and Update on the Use of RSV-IGIV

ABSTRACT. The Food and Drug Administration re- rophylaxis to prevent respiratory syncytial vi- cently approved the use of palivizumab (pale¯-vizhu¯- rus (RSV) in infants and children at ma¨b), an intramuscularly administered monoclonal anti- increased risk for severe disease, particularly body preparation. Recommendations for its use are based P those with chronic lung disease (CLD) receiving med- on a large, randomized study demonstrating a 55% re- ical management on a long-term basis, is now available duction in the risk of hospitalization attributable to re- using either an intravenous or an intramuscular prep- spiratory syncytial virus (RSV) infections in high-risk pediatric patients. Infants and children with chronic lung aration. Choosing which product to use in individual disease (CLD), formerly designated bronchopulmonary patients will depend on age, availability of intravenous dysplasia, as well as prematurely born infants without access, cost, and other factors. Neither preparation is CLD experienced a reduced number of hospitalizations approved by the Food and Drug Administration (FDA) while receiving palivizumab compared with a placebo. for infants or children with congenital heart disease Both palivizumab and respiratory syncytial virus im- (CHD). Unlike respiratory syncytial virus immune mune globulin intravenous (RSV-IGIV) are available for globulin intravenous (RSV-IGIV), recipients of palivi- protecting high-risk children against serious complica- zumab do not require delaying measles-containing tions from RSV infections. Palivizumab is preferred for vaccine or varicella vaccine. most high-risk children because of ease of administra- tion (intramuscular), lack of interference with measles– –rubella vaccine and varicella vaccine, and lack of BACKGROUND complications associated with intravenous administra- RSV-IGIV (RespiGam, Massachusetts Public Health tion of human immune globulin products. RSV-IGIV, Biologic Laboratories, and MedImmune, Inc, Gaithers- however, provides additional protection against other burg, MD) was licensed by the FDA in January 1996 for respiratory viral illnesses and may be preferred for prevention of severe RSV lower respiratory tract dis- selected high-risk children including those receiving ease in infants and children younger than 24 months replacement intravenous immune globulin because of with CLD or a history of premature birth (Յ35 weeks underlying immune deficiency or human immuno- of gestation). Recommendations for the use of this deficiency virus infection. For premature infants about to product have been summarized previously by the be discharged from hospitals during the RSV season, 1 physicians could consider administering RSV-IGIV for American Academy of Pediatrics (AAP). Randomized, the first month of prophylaxis. controlled clinical trials demonstrated the efficacy and Most of the guidelines from the American Academy of safety of monthly RSV-IGIV infusions in selected in- Pediatrics for the selection of infants and children to fants.2,3 Although RSV-IGIV was the first agent with receive RSV-prophylaxis remain unchanged. Palivi- demonstrated efficacy for prophylaxis against RSV in- zumab has been shown to provide benefit for infants fections, and did provide a 41% reduction in RSV hos- who were 32 to 35 weeks of gestation at birth. RSV-IGIV pitalizations, several disadvantages are associated with is contraindicated and palivizumab is not recommended this product. On the basis of available clinical trials, the for children with cyanotic congenital heart disease. The safety and efficacy of RSV-IGIV in children with CHD number of patients with adverse events judged to be related to palivizumab was similar to that of the placebo has not been established. Children with cyanotic CHD group (11% vs 10%, respectively); discontinuation of in- who received RSV-IGIV and underwent cardiac sur- jections for adverse events related to palivizumab was gery appeared to experience an increased surgical mor- rare. tality rate.4 RSV-IGIV prophylaxis requires monthly intravenous infusion throughout the RSV season, and like palivizumab is costly.5 Also, a widespread shortage ABBREVIATIONS. RSV, respiratory syncytial virus; CLD, chronic lung disease; FDA, Food and Drug Administration; CHD, congen- of RSV-IGIV during the past two winter seasons made ital heart disease; RSV-IGIV, respiratory syncytial virus immune supplies unreliable. The need for alternative ap- globulin intravenous; AAP, American Academy of Pediatrics; proaches to the prophylaxis of RSV infection in high- ICU, intensive care unit; MMR, measles–mumps–rubella; IPV, risk infants is apparent. inactivated poliovirus vaccine; OPV, oral poliovirus vaccine; IGIV, immune globulin intravenous. A recent study using a RSV intramuscular monoclo- nal , palivizumab, (Synagis, MedImmune, Inc, Gaithersburg, MD) provided an alternative ap- proach to the prevention of RSV infections in high-risk The recommendations in this statement do not indicate an exclusive course infants. Palivizumab is a humanized monoclonal anti- of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate. body directed against the F glycoprotein of RSV—a PEDIATRICS (ISSN 0031 4005). Copyright © 1998 by the American Acad- surface that is highly conserved among RSV emy of Pediatrics. isolates.6 Because the monoclonal antibody is not de-

Downloaded from www.aappublications.org/newsPEDIATRICS by guest on October Vol. 1021, 2021 No. 5 November 1998 1211 rived from human immune globulin, it is free of poten- and RSV infection risk factors (ie, prematurity, neonatal tial contamination by infectious agents and can be pro- CLD). Prophylaxis resulted in a 55% overall reduction duced readily in batch lots; thus, shortages are not in RSV-related hospitalizations (11% to 5% in placebo anticipated. The recently completed IMpact-RSV clini- vs palivizumab recipients, respectively, P Ͻ .001). cal trial defines the usefulness of this product for pre- Small differences in rates of hospitalizations were vention of RSV disease in high-risk infants.7 Palivi- noted between placebo and prophylaxis groups in dif- zumab was approved by the FDA in June 1998 based ferent geographic regions. These rates were 10% pro- on the results of this trial. This statement summarizes phylaxis compared with 5% placebo for the United existing data on palivizumab and provides recommen- States, 15% prophylaxis compared with 9% placebo for dations concerning its appropriate use in clinical prac- Canada, and 10% prophylaxis compared with 4% pla- tice. Previous policy from the AAP has described other cebo for the United Kingdom. aspects of RSV disease: epidemiologic characteristics, The number of days of hospitalization for RSV infec- risk factors for serious illness, laboratory diagnosis, and tion per 100 children was decreased from 62 in patients treatment with ribavirin8 as well as use of RSV-IGIV.1 receiving a placebo to 36 in those receiving palivi- zumab (P Ͻ .001). Clinical benefit could be ascribed for CLINICAL STUDIES additional secondary endpoints (Table 1), including Clinical Efficacy of Palivizumab decreased requirement for supplemental oxygen, a de- During the winter of 1996 and 1997, 1502 infants crease in the number of days of moderate or severe were enrolled in a multicenter, double-blind, ran- lower respiratory tract illness per 100 children (illness domized clinical trial of palivizumab (2:1 enrollment, severity score), or a reduction in the requirement for treated vs placebo group). At 30-day intervals, start- hospitalization in an ICU. No statistically significant ing at the onset of the RSV season, 5 intramuscular differences were identified for the requirement of me- 7 doses (15 mg/kg) of either palivizumab or a placebo chanical ventilation or in the incidence of otitis media. were administered. Children eligible for participa- The mortality rate was low in both study populations. tion in the clinical trial were younger than 2 years Among placebo recipients, 5 children died (1%) com- with CLD who required continuing medical therapy pared with 4 children who received palivizumab (supplemental oxygen, bronchodilator, and diuretic (0.4%). Hospital deaths during the study occurred in 2 or corticosteroid therapy) and children 35 weeks of of the palivizumab recipients, 1 attributed to aspiration gestation or less who were younger than 6 months at and the other to complications of liquid ventilation in a the start of the RSV season. The primary endpoint child with RSV pneumonia. was efficacy of prophylaxis in reducing the incidence Adverse events were not significant. Overall, the of hospitalization for RSV infections. Secondary end- development of erythema, pain, and induration at points included the total number of hospital days the site of resulted in adverse attributable to RSV as well as other respiratory vi- events in 2% of the placebo recipients and in 3% of 7 ruses, days of supplemental oxygen therapy, days of infants receiving palivizumab. There were no signif- altered respiratory illness score (the respiratory ill- icant differences in adverse event rates or the appear- 9 ness score included work of breathing, respiratory ance of antibody to the monoclonal antibody. No rate, retractions, and oxygen requirements [greater data are available regarding the potential for adverse than 3 days]), days of intensive care unit (ICU) man- events or therapeutic efficacy in a second year of agement, days of mechanical ventilation use, and administration. incidence of otitis media. One hundred thirty-nine sites in the United States, Subgroup Analyses Canada, and the United Kingdom participated in this Palivizumab reduced the severity of clinical illness clinical trial. Placebo and prophylaxis groups were bal- in all subgroups evaluated (Table 2). Premature in- anced at the beginning of the study for demographics fants without CLD had an overall 78% reduction in

TABLE 1. Prevention of Respiratory Syncytial Virus Infections: Indications for the Use of Palivizumab and Update on the Use of RSV-IGIV Summary of Clinical Efficacy for Palivizumab* Parameter Rates % Reduction P Value Placebo Palivizumab Incidence of RSV hospitalization, % 10.6 4.8 55 Ͻ.001 RSV hospitalizations/100 children, day 62.4 36.4 42 Ͻ.001 Ͻ O2 requirement/100 children, day 50.6 30.3 40 .001 Incidence RSV ICU care, % 3.0 1.3 57 .026 ICU/100 children, day 12.7 13.3 — NS Mechanical ventilation, % .2 .7† — NS Mechanical ventilation, total number of days 1.7 8.4 — .210 All respiratory hospitalizations, % 22 16 27 .008 Respiratory hospitalizations/100 children, day (including RSV) 180 124 31 .004 Otitis media, % 40 42 — NS Deaths, % 1 .4 — * RSV-IVIG indicates respiratory syncytial virus immune globulin intravenous; ICU, intensive care unit. † Includes 2 infants who required prolonged ventilatory support.

1212 PREVENTION OF RESPIRATORYDownloaded from www.aappublications.org/news SYNCYTIAL VIRUS INFECTIONS by guest on October 1, 2021 hospitalization (8% in the placebo group vs 2% in the and transmission of RSV. Preventive measures in- palivizumab group, P Ͻ .001). Premature infants clude eliminating exposure to cigarette smoke and with CLD showed a 39% reduction (13% in the pla- limiting exposure to contagious settings (eg, child cebo group vs 8% in the palivizumab group, P ϭ care centers). Emphasis on hand-washing in all set- .038). Although the overall number of children in the tings, including the home, especially during periods clinical trial allowed for comparisons of smaller when contacts of high-risk children have respiratory groups, these assessments should be considered ret- infections or are at high risk for exposure to respira- rospective and exploratory. tory infections from siblings who are in child care or In a retrospective subgroup analysis, reduction in attend school, is also important. the rate of RSV-associated hospitalizations from 10% in the placebo group to 1.8% in the palivizumab group was noted for children born between 32 and Clinical Selection of RSV-IGIV Over Palivizumab 35 weeks of gestation who did not have CLD. How- Although palivizumab provides effective protec- ever, lower rates of hospitalization have been docu- tion against RSV for eligible infants, and has greater mented for children of similar ages who received no ease of administration and fewer adverse effects than therapy.10 RSV-IGIV, there may be certain considerations that might favor the use of RSV-IGIV. Specifically, in the Overall Considerations RSV-IGIV trial, immunoprophylaxis decreased the As noted earlier, palivizumab decreases risk of overall rate of hospitalizations for non-RSV respira- severe RSV disease, as does RSV-IGIV. No direct tory infections, whereas palivizumab did not. This studies were done to compare relative efficacy of the may be of value in those infants younger than 6 two products. Palivizumab is not a human blood months who are not eligible for vaccina- product and, therefore, is not associated with risks of tion as well as for those infants and children with acquisition of blood-borne pathogens, a potential severe pulmonary disease for whom respiratory in- risk with RSV-IGIV. Because of its ease of adminis- fections other than those caused by RSV may be tration, palivizumab is favored over RSV-IGIV medically important. Similarly, there was a statisti- (1 intramuscular injection vs a 4-hour intravenous cally significant reduction in the overall frequency of infusion). Furthermore, the availability of palivi- otitis media, although this latter point alone is un- zumab is not contingent on the blood donor pool. likely to justify use of RSV-IGIV. Palivizumab has Currently, palivizumab is only available in an intra- not been tested in the treatment of children with muscular formulation; however, an intravenous for- CHD. Neither product is licensed by the FDA for use mulation will likely be available in the near future. in children with CHD, and RSV-IGIV should not be The only rationale for such a formulation is to pro- administered to children with cyanotic CHD. vide the capability of administering this product in- travenously if the infant has an intravenous line in place for other reasons. Administration Escape mutants (ie, resistant ) to palivi- Palivizumab is administered intramuscularly in a zumab have not been identified after the administra- dose of 15 mg/kg once a month during the RSV tion of this product; however, the administration of season. Palivizumab is packaged in 100-mg vials, other monoclonal has been associated and opened vials must be used within 6 hours. To with development of such resistant mutants. Surveil- minimize wastage, physicians should arrange for ad- lance will be required to identify the risk for such ministration so that 2 or more eligible patients can events. receive the vaccine within the 6-hour period after A critical aspect of RSV prevention in high-risk opening a vial. RSV-IGIV is administered intrave- infants is the education of parents and other caregiv- nously in a dose of 750 mg/kg once a month during ers about the importance of reducing exposure to the RSV season.

TABLE 2. Prevention of Respiratory Syncytial Virus Infections: Indications for the Use of Palivizumab and Update on the Use of RSV-IGIV Subgroup Analyses of RSV Hospitalization by Treatment Group* Group Rate, % % Reduction P Value Placebo Palivizumab All infants 10.6 4.8 55 .00004 Premature infants with CLD 12.8 7.9 39 .038 Premature infants without CLD 8.1 1.8 78 Ͻ.001 Neonatal weight Ͼ5 kg 10.7 5.2 51 .014 Ͻ5 kg 10.5 4.5 57 .001 Neonatal gestational age Ͻ32 wk 11.0 5.8 47 .0026 32–35 wk† 9.8 2.0 80 Ͻ.001 * CLD indicates chronic lung disease. † Rates for infants (N ϭ 355 total) born at 32 to 35 weeks of gestation, but without CLD, were 10% and 1.8% for placebo and palivizumab recipients, respectively.

Downloaded from www.aappublications.org/newsAMERICAN by guest on October ACADEMY 1, 2021 OF PEDIATRICS 1213 Vaccination who require medical therapy. Decisions regard- Palivizumab does not interfere with vaccine admin- ing individual patients may need additional con- istration. Infants and children receiving RSV-IGIV pro- sultation from neonatologists, intensivists, or pul- phylaxis (750-mg/kg dose) with mea- monologists. There are limited data on the sles–mumps–rubella (MMR) and varicella vaccines efficacy of palivizumab during the second year of should be deferred for 9 months after the last dose. (See age; risk of severe RSV disease exists for children Table 3.37 on page 353 of the 1997 Red Book.11) There are with CLD who require medical therapy. Al- no data on the use of RSV-IGIV and the response to though those with less severe underlying disease vaccine, but there is no reason to anticipate may receive some benefit for the second season, interference because RSV-IGIV does not contain anti- immunoprophylaxis may not be necessary. bodies to hepatitis B surface antigen. RSV-IGIV use 2. Infants born at 32 weeks of gestation or earlier should not alter the primary immunization schedule without CLD or who do not meet the criteria in for diphtheria and tetanus toxoids, whole-cell or acel- recommendation 1 also may benefit from RSV lular pertussis, Haemophilus influenzae type b, and po- prophylaxis. In these infants, major risk factors to liovirus vaccines (inactivated poliovirus vaccine [IPV] consider are gestational age and chronologic age or oral poliovirus vaccine [OPV]). The manufacturer of at the start of the RSV season. Infants born at 28 RSV-IGIV has suggested that an additional dose of weeks of gestation or earlier may benefit from vaccine might be needed to assure an adequate im- prophylaxis up to 12 months of age. Infants born mune response to diphtheria and tetanus toxoids, at 29 to 32 weeks of gestation may benefit most whole-cell or acellular pertussis, Haemophilus influenzae from prophylaxis up to 6 months of age. Deci- type b, and OPV (refer to the RespiGam package in- sions regarding duration of prophylaxis should sert), but more information is needed before changes in be individualized, according to the duration of the current immunization recommendations can be made. RSV season. Practitioners may wish to use RSV Currently, the available data do not support the need rehospitalization data from their own region to for supplemental doses of routinely administered vac- assist in the decision-making process. cines. Parenterally administered immunoglobulin 3. Given the large number of patients born be- preparations have little, if any, effect on the replication tween 32 to 35 weeks and the cost of the drug, of OPV in the intestinal tract. the use of palivizumab in this population should be reserved for those infants with addi- Cost-benefit Analyses tional risk factors (see “Cost-benefit Analyses” Only limited cost-benefit analysis data are avail- section) until more data are available. able for RSV-IGIV, and no peer-reviewed data are 4. Palivizumab and RSV-IGIV are not licensed by available at this time for palivizumab. Cost-benefit the FDA for patients with CHD. Available data indicate that RSV-IGIV is contraindicated in pa- analyses of RSV-IGIV did not demonstrate an overall 4 savings in hospitalization considering the costs of tients with cyanotic CHD. However, patients therapy for all at-risk children.12,13 Although results with CLD, who are premature, or both, who of another study were more favorable, different meet the criteria in recommendations 1 and 2 methods were used.5 and who also have acyanotic Factors other than CLD influence the decision CHD (eg, patent ductus arteriosus or ventricu- about use of prophylaxis, particularly in children lar septal defect) may benefit from prophylaxis. with a gestational age of 32 to 35 weeks, including 5. Palivizumab or RSV-IGIV prophylaxis has not other underlying conditions that predispose to respi- been evaluated in randomized trials in immuno- ratory complications (eg, neurologic disease in very compromised children. Although specific recom- low birth weight infants), number of young siblings, mendations for immunocompromised patients child care center attendance, exposure to tobacco cannot be made, children with severe immunode- smoke in the home, anticipated cardiac surgery, and ficiencies (eg, severe combined immunodefi- distance to and availability of hospital care for severe ciency or severe acquired immunodeficiency syn- respiratory illness. For many infants qualifying for drome) may benefit from prophylaxis. If these the approved indications, risk of rehospitalization infants and children are receiving standard im- for serious respiratory illness will be low, and the mune globulin intravenous (IGIV) monthly, phy- cost and logistical difficulties associated with pro- sicians may consider substituting RSV-IGIV dur- phylaxis may outweigh the potential benefits. ing the RSV season. 6. RSV prophylaxis should be initiated at the onset RECOMMENDATIONS of the RSV season and terminated at the end of the RSV season. In most areas of the United States, the 1. Palivizumab or RSV-IGIV prophylaxis should be usual time for the beginning of RSV outbreaks is considered for infants and children younger than October to December, and termination is March to 2 years of age with CLD who have required med- May, but regional differences occur.15 The onset of ical therapy for their CLD within 6 months before RSV infection occurs earlier in southern states the anticipated RSV season. Palivizumab is pre- than in northern states.16 Practitioners should con- ferred for most high-risk children because of its tact their health departments and/or diagnostic ease of administration, safety, and effectiveness. laboratories in their geographic areas to Patients with more severe CLD14 may benefit from determine the optimal time to begin administra- prophylaxis for two RSV seasons, especially those tion.

1214 PREVENTION OF RESPIRATORYDownloaded from www.aappublications.org/news SYNCYTIAL VIRUS INFECTIONS by guest on October 1, 2021 7. RSV is known to be transmitted in the hospital Solomon Iyasu, MBBS, MPH setting17 and to cause serious disease in high- Centers for Disease Control and Prevention risk infants.18–20 In high-risk hospitalized infants, Patricia Johnson, RN, MS, NNP the major means to prevent RSV disease is strict American Nurses Association, Association of Women’s Health, Obstetric & Neonatal Nurses, observance of infection control practices, includ- National Association of Neonatal Nurses ing the use of rapid means to identify and cohort Douglas D. McMillan, MD RSV-infected infants.21 If an RSV outbreak is doc- Canadian Paediatric Society umented in a high-risk unit (eg, pediatric inten- Linda L. Wright, MD sive care unit), primary emphasis should be National Institutes of Health placed on proper infection control practices. The Section Liaisons need for and efficacy of prophylaxis in these sit- Jacob C. Langer, MD uations has not been evaluated. Section on Surgery 8. The guidelines for modification of immuniza- David K. Stevenson, MD tions after RSV-IGIV have not changed. Palivi- Section on Perinatal Pediatrics zumab does not interfere with the response to vaccines. REFERENCES 1. American Academy of Pediatrics, Committee on Infectious Diseases. Committee on Infectious Diseases, 1998–1999 Respiratory syncytial virus immune globulin intravenous: indications Neal A. Halsey, MD, Chairperson for use. Pediatrics. 1997;99:645–650 Jon S. Abramson, MD 2. Groothuis JR, Simoes EA, Levin MJ, RSVIG Study Group. Prophy- P. Joan Chesney, MD lactic administration of respiratory syncytial virus immune globulin Margaret C. Fisher, MD to high-risk infants and young children. N Engl J Med. 1993;329: Michael A. Gerber, MD 1524–1530 3. Connor E, PREVENT Study Group. Reduction of respiratory syncytial S. 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Downloaded from www.aappublications.org/newsAMERICAN by guest on October ACADEMY 1, 2021 OF PEDIATRICS 1215 1990–1996. Presented at RSV After 40 Years: An Anniversary infection in children with compromised immune function. N Engl J Med. Symposium; November 9–12, 1996; Charleston, SC. Abstract 1986;315:77–81 17. Hall CB, Geiman JM, Douglas RG, Meagher MP. Control of nosocomial 20. MacDonald NE, Hall CB, Suffin SC, Alexson C, Harris PJ, Manning JA. respiratory syncytial virus infections. Pediatrics. 1978;62:728–732 Respiratory syncytial viral infection in infants with congenital heart 18. Groothuis JR, Gutierrez KM, Lauer BA. Respiratory syncytial virus disease. N Engl J Med. 1982;307:397–400 infection in children with bronchopulmonary dysplasia. Pediatrics. 1988; 21. Madge P, Paton JY, McColl JH, Mackie PK. Prospective controlled study 82:199–203 of four infection control procedures to prevent nosocomial infection 19. Hall CB, Powell KR, MacDonald NE, et al. Respiratory syncytial viral with respiratory syncytial virus. Lancet. 1992;340:1079–1083

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Downloaded from www.aappublications.org/news by guest on October 1, 2021 Prevention of Respiratory Syncytial Virus Infections: Indications for the Use of Palivizumab and Update on the Use of RSV-IGIV Committee on Infectious Diseases and Committee on Fetus and Newborn Pediatrics 1998;102;1211 DOI: 10.1542/peds.102.5.1211

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1998 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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