Revised Indications for the Use of Palivizumab and Respiratory

AMERICAN ACADEMY OF PEDIATRICS

POLICY STATEMENT Organizational Principles to Guide and Define the Child Health Care System and/or Improve the Health of All Children

Committee on Infectious Diseases and Committee on Fetus and Newborn

Revised Indications for the Use of Palivizumab and Respiratory Syncytial Virus Immune Globulin Intravenous for the Prevention of Respiratory Syncytial Virus Infections

ABSTRACT. Palivizumab and Respiratory Syncytial neutralizing and fusion inhibitory activity against Virus Immune Globulin Intravenous (RSV-IGIV) are li- RSV. Both preparations have been licensed for pre- censed by the Food and Drug Administration for use in vention of RSV disease in selected infants and chil- preventing severe lower respiratory tract infections dren younger than 24 months with chronic lung caused by respiratory syncytial virus (RSV) in high-risk disease (CLD [formerly called bronchopulmonary infants, children younger than 24 months with chronic dysplasia]) or with a history of preterm birth (Յ35 lung disease (formerly called bronchopulmonary dysplasia), and certain preterm infants. This statement provides weeks’ gestation). Only palivizumab is indicated for revised recommendations for administering RSV pro- use in children with hemodynamically significant phylaxis to infants and children with congenital heart congenital heart disease (CHD). Choosing which disease, for identifying infants with a history of preterm product to use in a patient will depend on the nature birth and chronic lung disease who are most likely to of the underlying disease, the preferred route of benefit from immunoprophylaxis, and for reducing the administration, and other factors. However, in all risk of RSV exposure and infection in high-risk children. instances immunoprophylaxis should be reserved On the basis of results of a recently completed clinical for use in infants and children at greatest risk of RSV trial, prophylaxis with palivizumab is appropriate for infection because of the high cost of this intervention. infants and young children with hemodynamically sig- Recommendations for use of both products have nificant congenital heart disease. RSV-IGIV should not be used in children with hemodynamically significant been summarized by the American Academy of Pe- 1,2 heart disease. Palivizumab is preferred for most high- diatrics. The purpose of this statement is to update risk infants and children because of ease of intramuscu- clinicians on the appropriate use of RSV-IGIV and lar administration. Monthly administration of palivi- palivizumab on the basis of data from 5 clinical trials. zumab during the RSV season results in a 45% to 55% Details regarding the results of clinical trials with decrease in the rate of hospitalization attributable to RSV-IGIV and palivizumab are available in the ac- RSV. Because of the large number of infants born after 32 companying technical report3 (also available online). to 35 weeks’ gestation and because of the high cost, immunoprophylaxis should be considered for this cate- OVERALL CONSIDERATIONS gory of preterm infants only if 2 or more risk factors are A critical aspect of RSV prevention in high-risk present. High-risk infants should not attend child care infants is the education of parents and other caregiv- during the RSV season when feasible, and exposure to tobacco smoke should be eliminated. ers about the importance of decreasing infants’ exposure to and acquisition of RSV. Preventive measures include eliminating exposure to cigarette ABBREVIATIONS. RSV, respiratory syncytial virus; RSV-IGIV, smoke and settings where RSV or other respiratory Respiratory Syncytial Virus Immune Globulin Intravenous; CLD, viruses may be transmitted (eg, child care centers). chronic lung disease; CHD, congenital heart disease. Emphasis on hand hygiene also is important in all settings including the home, especially during peri- urrently, there are 2 options for immunopro- ods when contacts of high-risk children have respi- phylaxis for preventing respiratory syncytial ratory tract infections or when infants are at risk of Cvirus (RSV) infection in high-risk infants. Re- exposure to respiratory infections from siblings who spiratory Syncytial Virus Immune Globulin Intrave- are in child care or who attend school. nous (RSV-IGIV) is a polyclonal hyperimmune glob- Both palivizumab and RSV-IGIV have been shown ulin prepared from donors selected for having high to decrease the risk of severe RSV disease in high- serum titers of RSV neutralizing antibody. Palivi- risk infants and children. No direct studies have been zumab is a humanized murine monoclonal anti-F conducted to compare the relative efficacy of the 2 glycoprotein immunoglobulin G1 antibody with interventions. Because of its ease of administration, monthly palivizumab, an intramuscular injection, PEDIATRICS (ISSN 0031 4005). Copyright © 2003 by the American Acad- generally is favored over RSV-IGIV, a 4-hour intra- emy of Pediatrics. venous infusion.

1442 PEDIATRICS Vol.Downloaded 112 No. 6 from December www.aappublications.org/news 2003 by guest on September 29, 2021 Limited data are available regarding the use of Either RSV-IGIV or palivizumab is administered palivizumab for 2 consecutive seasons. No difference once per month (eg, every 30 days) beginning just was noted between incidence of adverse events before the onset of the RSV season, which typically among children who received palivizumab prophy- occurs in November but may vary by region. In laxis for a second season and children receiving pro- general, 4 subsequent monthly doses (for a total of 5 phylaxis for only 1 season. In addition, limited expe- doses) are sufficient to provide protection during the rience from postmarketing data suggests that entire RSV season. Hospitalized infants determined adverse events occurring after more than 5 doses in to be at risk of severe RSV disease should receive a single season are no different from adverse events RSV-IGIV or palivizumab 48 to 72 hours before dis- occurring after the initial 5 doses. charge home from the hospital during the respira- Postmarketing surveys indicate that the effect of tory virus season and then every 30 days until the palivizumab prophylaxis on the rate of hospitaliza- end of the season. tion for RSV is similar to that found in controlled clinical trials. Rare cases of severe hypersensitivity RSV IMMUNOPROPHYLAXIS AND VACCINE reactions (Ͻ1 case per 100 000 recipients) have been ADMINISTRATION described after an initial dose as well as after reex- Palivizumab does not interfere with vaccine ad- posure to palivizumab. ministration. For infants and children receiving RSV- Palivizumab attaches to a well-conserved epitope IGIV prophylaxis, immunization with measles- in the A-antigenic site of the F protein of RSV. Al- mumps-rubella and varicella vaccines should be though resistant RSV strains can be generated in deferred for 9 months after the last dose. (see table laboratory experiments, naturally occurring escape 3.33 on p. 423 of the 2003 Red Book4). No data exist on mutants (ie, resistant viruses) to palivizumab have the use of RSV-IGIV and the response to hepatitis B not been identified after the administration of this vaccine, but there is no reason to anticipate interfer- product. Ongoing surveillance of RSV isolates has ence. RSV-IGIV use should not alter the primary failed to identify any decrease in sensitivity to palivi- immunization schedule for inactivated vaccines (eg, zumab. diphtheria and tetanus toxoids and acellular pertussis, Haemophilus influenzae type b conjugate, and in- CLINICAL SELECTION OF PALIVIZUMAB OVER activated poliovirus vaccines). The manufacturer of RSV-IGIV RSV-IGIV has suggested that an additional dose of Although palivizumab provides effective protec- vaccine might be needed to ensure an adequate im- tion against RSV for eligible infants and has greater mune response to diphtheria and tetanus toxoids ease of administration and fewer adverse effects than and acellular pertussis, H influenzae type b, and oral RSV-IGIV, there are other minor differences between poliovirus vaccines (refer to the RespiGam package the 2 products to be considered. In the RSV-IGIV insert), but available data do not support the need for trial, immunoprophylaxis decreased the overall rate supplemental doses of routinely administered vac- of hospitalization for non-RSV respiratory infections. cines. This may be of value for infants younger than 6 months who are not eligible for influenza immuni- COST-BENEFIT ANALYSES zation and for infants and children with severe pul- Several economic analyses of RSV immunopro- monary disease for whom respiratory tract infections phylaxis have been published and reviewed. The in addition to RSV may be important. However, the primary benefit of immunoprophylaxis with either concentration of antibodies against viruses other agent is a decrease in the rate of RSV-associated than RSV is not monitored in RSV-IGIV lots and is hospitalization. None of the 5 randomized, con- likely to vary from lot to lot, making this an unreli- trolled clinical trials have demonstrated a significant able basis for selecting RSV-IGIV. In addition, in the decrease in rate of mortality attributable to RSV in- RSV-IGIV trial, immunoprophylaxis significantly de- fection in infants who receive prophylaxis. Most of creased the frequency of otitis media, although this the economic analyses fail to demonstrate overall benefit alone does not justify its use. Palivizumab savings in health care dollars because of the high cost does not affect the rate of hospitalization for non- if all at-risk children were to receive prophylaxis. RSV respiratory disease or the incidence of otitis Estimates of cost per hospitalization prevented have media. RSV-IGIV should not be administered to chil- been inconsistent because of considerable variation dren with hemodynamically significant CHD. in the baseline rate of hospitalization attributable to RSV in different high-risk groups. Other consider- ADMINISTRATION ations that will influence results include the effect of Palivizumab is administered intramuscularly at a prophylaxis on outpatient costs and a resolution of dosage of 15 mg/kg. Palivizumab is packaged in the question of whether prevention of RSV infection 100- and 50-mg vials, and opened vials must be used in infancy decreases wheezing and lower respiratory within 6 hours. Currently, palivizumab for intramus- tract problems later in childhood. cular injection is available only as a lyophilized pow- Factors other than degree of prematurity, CHD, der that is reconstituted with sterile water (that does and CLD that may influence the decision regarding not contain a preservative); a liquid formulation of prophylaxis include presence of other underlying palivizumab for intramuscular injection may be conditions that predispose to respiratory complica- available in the future. RSV-IGIV is administered tions (eg, neurologic disease in very low birth weight intravenously at a dosage of 750 mg/kg (15 mL/kg). infants), number of young siblings, child care center

Downloaded from www.aappublications.org/news byAMERICAN guest on September ACADEMY 29, 2021 OF PEDIATRICS 1443 attendance, anticipation of cardiac surgery, and dis- tion for infants born between 32 and 35 weeks of tance to and availability of hospital care for severe gestation (ie, between 32 weeks, 1 day, and 35 respiratory illness. For many infants who qualify for weeks, 0 days) (Evidence grade I), the cost of the approved indications, risk of hospitalization for administering prophylaxis to this large group of serious respiratory illness will be low, and the cost infants must be considered carefully. and logistic difficulties associated with prophylaxis • Most experts recommend that prophylaxis be may outweigh potential benefits. reserved for infants in this group who are at greatest risk of severe infection and who are UPDATED RECOMMENDATIONS FOR RSV younger than 6 months at the start of the RSV PROPHYLAXIS season. Epidemiologic data suggest that RSV 1. Palivizumab or RSV-IGIV prophylaxis should be infection is more likely to lead to hospitaliza- considered for infants and children younger than tion for these infants when the following risk 2 years with CLD who have required medical factors are present: child care attendance, therapy (supplemental oxygen, bronchodilator, school-aged siblings, exposure to environmen- diuretic or corticosteroid therapy) for CLD tal air pollutants, congenital abnormalities of within 6 months before the anticipated start of the airways, or severe neuromuscular disease. the RSV season. Palivizumab is preferred over However, no single risk factor causes a very RSV-IGIV for most high-risk children because of large increase in the rate of hospitalization, its ease of administration, safety, and effective- and the risk is additive as the number of risk ness. (Evidence grade I*.) factors for an individual infant increases. • Patients with more severe CLD may benefit Therefore, prophylaxis should be considered from prophylaxis during a second RSV season for infants between 32 and 35 weeks’ gestation if they continue to require medical therapy for only if 2 or more of these risk factors are pulmonary or cardiac dysfunction. Individual present. patients may benefit from decisions made in • Exposure to tobacco smoke is a risk factor that consultation with neonatologists, pediatric in- can be controlled by the family of an infant at tensivists, pulmonologists, or infectious dis- increased risk of RSV disease, and tobacco ease specialists. There are limited data regard- smoke control measures will be far less costly ing the effectiveness of palivizumab during than palivizumab prophylaxis. High-risk in- the second year of life, although children with fants never should be exposed to tobacco CLD or CHD who require ongoing medical smoke. High-risk infants should be kept away therapy may experience severe RSV infections. from crowds and from situations where expo- 2. Infants born at 32 weeks’ gestation or earlier may sure to infected individuals cannot be con- benefit from RSV prophylaxis even if they do not trolled. have CLD. For these infants, major risk factors to • Participation in child care should be restricted consider include their gestational age and chro- during the RSV season for high-risk infants nologic age at the start of the RSV season. (Evi- whenever feasible. Parents should be in- dence grade I.) structed on the importance of careful hand • Infants born at 28 weeks’ gestation or earlier hygiene. may benefit from prophylaxis during their • All high-risk infants and their contacts should first RSV season whenever that occurs during be immunized against influenza beginning at the first 12 months of life. Infants born at 29 to 6 months of age. 32 weeks’ gestation may benefit most from 4. Prophylaxis against RSV should be initiated just prophylaxis up to 6 months of age. For the before the onset of the RSV season and termi- purpose of this recommendation, 32 weeks’ nated at the end of the RSV season. In most gestation refers to an infant born on or before seasons and in most regions of the Northern the 32nd week of gestation (ie, 32 weeks, 0 Hemisphere, the first dose of palivizumab days). Once a child qualifies for initiation of should be administered at the beginning of No- prophylaxis at the start of the RSV season, vember, and the last dose should be adminis- administration should continue throughout tered at the beginning of March, which will pro- the season and not stop at the point an infant vide protection into April.5 (Evidence grade III.) reaches either 6 or 12 months of age. • To understand the epidemiology of RSV in 3. Although palivizumab and RSV-IGIV have been their area, physicians should consult with lo- shown to decrease the likelihood of hospitaliza- cal health departments or diagnostic virology laboratories or the Centers for Disease Control * Evidence grade I: evidence obtained from at least one properly designed, and Prevention if such information is not randomized, controlled trial. available locally. Decisions about the specific Evidence grade II-1: evidence obtained from well-designed controlled duration of prophylaxis should be individual- trials without randomization; Evidence grade II-2: evidence obtained from ized according to the duration of the RSV sea- well-designed cohort or case-control analytic studies, preferably from more than one center or research group; Evidence grade II-3: evidence son. Pediatricians may wish to use RSV hos- obtained from multiple time series with or without the intervention, or pitalization data from their own region to dramatic results in uncontrolled experiments. assist in the decision-making process. Evidence grade III: opinions of respected authorities, based on clinical 5. Children who are 24 months or younger with experience, descriptive studies, or reports of expert committees. hemodynamically significant cyanotic and acya-

1444 REVISED INDICATIONSDownloaded FOR from THE www.aappublications.org/news USE OF PALIVIZUMAB by guest AND on September RSV-IGIV 29, 2021 notic CHD will benefit from 5 monthly intramus- • This recommendation is based on the observa- cular injections of palivizumab (15 mg/kg). (Ev- tion that high-risk infants may be hospitalized idence grade I.) more than once in the same season with RSV • Decisions regarding prophylaxis with palivi- lower respiratory tract disease and the fact zumab in children with CHD should be made that more than one RSV strain often cocircu- on the basis of the degree of physiologic lates in a community. cardiovascular compromise. Infants younger 10. Physicians should arrange for drug administra- than 12 months with CHD who are most likely tion within 6 hours after opening a vial, because to benefit from immunoprophylaxis include: this product does not contain a preservative. i. infants who are receiving medication to 11. Recommendations cannot be made regarding control congestive heart failure; the use of palivizumab as a means of prevention ii. infants with moderate to severe pulmo- of nosocomial RSV disease. nary hypertension; and • RSV is known to be transmitted in the hospi- iii. infants with cyanotic heart disease. tal setting and to cause serious disease in • Because a mean decrease in palivizumab se- high-risk infants. In high-risk hospitalized in- rum concentration of 58% was observed after fants, the major means to prevent RSV dis- surgical procedures that use cardiopulmonary ease is strict observance of infection control bypass, for children who still require prophy- practices including the use of rapid means to laxis, a postoperative dose of palivizumab (15 identify and isolate RSV-infected infants. If mg/kg) should be considered as soon as the an RSV outbreak is documented in a high- patient is medically stable. risk unit (eg, pediatric intensive care unit), The following groups of infants are not at in- primary emphasis should be placed on creased risk from RSV and generally should not proper infection control practices, especially receive immunoprophylaxis: hand hygiene. • infants and children with hemodynamically 12. Palivizumab does not interfere with the re- insignificant heart disease (eg, secundum sponse to vaccines. Infants and children receiv- atrial septal defect, small ventricular septal ing prophylaxis with RSV-IGIV should have defect, pulmonic stenosis, uncomplicated aor- immunization with measles-mumps-rubella and tic stenosis, mild coarctation of the aorta and varicella vaccines deferred for 9 months after patent ductus arteriosus) the last dose of RSV-IGIV. • infants with lesions adequately corrected by • The use of RSV-IGIV should not alter the surgery unless they continue to require med- primary immunization schedule for other ication for congestive heart failure recommended immunizations. Available • infants with mild cardiomyopathy who are data at this time do not support the need for not receiving medical therapy supplemental doses of any of these routinely Dates for initiation and termination of prophy- administered vaccines. laxis should be based on the same considerations as for high-risk preterm infants. Unlike palivi- Committee on Infectious Diseases, 2002–2003 zumab, RSV-IGIV is contraindicated in children Jon S. Abramson, MD, Chair with cyanotic CHD. Carol J. Baker, MD 6. Palivizumab or RSV-IGIV prophylaxis has not Robert S. Baltimore, MD been evaluated in randomized trials in immuno- Joseph A. Bocchini, Jr, MD Sarah S. Long, MD compromised children. Although specific recom- Julia A. McMillan, MD mendations for immunocompromised patients H. Cody Meissner, MD cannot be made, children with severe immuno- Keith R. Powell, MD deficiencies (eg, severe combined immunodefi- Charles G. Prober, MD ciency or severe acquired immunodeficiency Margaret B. Rennels, MD syndrome) may benefit from prophylaxis. If Thomas N. Saari, MD these infants and children are receiving standard Leonard B. Weiner, MD IGIV monthly, physicians may consider substi- tution of RSV-IGIV during the RSV season. (Ev- Liaisons idence grade III.) Joanne Embree, MD 7. Because RSV-IGIV and palivizumab are not ef- Canadian Paediatric Society fective in the treatment of RSV disease, neither is Marc A. Fischer, MD licensed for this indication. (Evidence grade I.) Centers for Disease Control and Prevention 8. Limited studies suggest that some patients with Bruce G. Gellin, MD, MPH National Vaccine Program Office cystic fibrosis may be at increased risk of RSV Caroline B. Hall, MD infection. However, there are insufficient data to Section on Infectious Disease determine the effectiveness of palivizumab use Martin C. Mahoney, MD in this patient population. American Academy of Family Physicians 9. If an infant or child who is receiving immuno- Mamodikoe Makhene, MD prophylaxis experiences a breakthrough RSV in- National Institutes of Health fection, prophylaxis should continue through the Walter A. Orenstein, MD RSV season. (Evidence grade III.) Centers for Disease Control and Prevention

Downloaded from www.aappublications.org/news byAMERICAN guest on September ACADEMY 29, 2021 OF PEDIATRICS 1445 Douglas R. Pratt, MD Kay M. Tomashek, MD Food and Drug Administration Centers for Disease Control and Prevention Jeffrey R. Starke, MD Carol Wallman, MSN, RNC, NNP American Thoracic Society National Association of Neonatal Nurses Jack Swanson, MD Staff American Academy of Pediatrics Practice Jim Couto, MA Action Group Ex Officio Larry K. Pickering, MD REFERENCES Red Book Editor 1. American Academy of Pediatrics, Committee on Infectious Diseases and Committee on Fetus and Newborn. Respiratory syncytial virus Consultant immune globulin intravenous: indications for use. Pediatrics. 1997;99: Edgar O. Ledbetter, MD 645–650 Staff 2. American Academy of Pediatrics, Committee on Infectious Diseases Martha Cook, MS and Committee on Fetus and Newborn. Prevention of respiratory syncytial virus infections: indications for the use of palivizumab and up- Committee on Fetus and Newborn, date on the use of RSV-IGIV. Pediatrics. 1998;102:1211–1216 2003–2004 3. Meissner HC, Long SS, and American Academy of Pediatrics, Commit- Lillian Blackmon, MD, Chairperson tee on Infectious Diseases and Committee on Fetus and Newborn. Daniel G. Batton, MD Technical report: revised indications for the use of palivizumab and Edward F. Bell, MD respiratory syncytial virus immune globulin intravenous for the pre- Susan E. Denson, MD vention of respiratory syncytial virus infections. Pediatrics. 2003;112: William A. Engle, MD 1447–1452 William P. Kanto, Jr, MD 4. American Academy of Pediatrics, Committee on Infectious Diseases. Gilbert I. Martin, MD Measles. In: Pickering LK, ed. Red Book: 2003 Report of the Committee on Ann R. Stark, MD Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2003:419–429 Liaisons 5. Gilchrist S, Torok TJ, Gary HE Jr, Alexander JP, Anderson LJ. National Keith J. Barrington, MD surveillance for respiratory syncytial virus, United States, 1985–1990. Canadian Paediatric Society J Infect Dis. 1994;170:986–990 Tonse Raju, MD, DCH National Institutes of Health Laura E. Riley, MD All policy statements from the American Academy of American College of Obstetricians and Pediatrics automatically expire 5 years after publication unless Gynecologists reaffirmed, revised, or retired at or before that time.

1446 REVISED INDICATIONSDownloaded FOR from THE www.aappublications.org/news USE OF PALIVIZUMAB by guest AND on September RSV-IGIV 29, 2021 Revised Indications for the Use of Palivizumab and Respiratory Syncytial Virus Immune Globulin Intravenous for the Prevention of Respiratory Syncytial Virus Infections Committee on Infectious Diseases and Committee on Fetus and Newborn Pediatrics 2003;112;1442

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Downloaded from www.aappublications.org/news by guest on September 29, 2021 Revised Indications for the Use of Palivizumab and Respiratory Syncytial Virus Immune Globulin Intravenous for the Prevention of Respiratory Syncytial Virus Infections Committee on Infectious Diseases and Committee on Fetus and Newborn Pediatrics 2003;112;1442

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