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Paediatr Child Health. Oct 1999; 4(7): 474–480.
PMCID: PMC2827759

Palivizumab and respiratory syncytial virus immune globulin intravenous for the prophylaxis of respiratory syncytial virus infection in high risk infants

A joint statement with the Fetus and Newborn Committee

Two antibody products are manufactured by MedImmune, Inc, Gaithersburg, Maryland - for the prophylaxis of respiratory syncytial virus (RSV) infection in high risk infants. Respiratory syncytial virus immune globulin intravenous (Respigam or RSV-IGIV) was licensed in Canada in 1997, while palivizumab (Synagis), a newer product that has not yet been licensed by the Health Protection Branch of Health Canada, is available in Canada through a special program from Abbott Laboratories, Montreal, Quebec. Guidelines for the use of RSV-IGIV were published by the Infectious Diseases and Immunization Committee of the Canadian Paediatric Society (1). This statement summarizes the information available about palivizumab, compares it with RSV-IGIV and provides updated recommendations for the use of these products in Canada.

PALIVIZUMAB AND THE IMpact-RSV TRIAL

Palivizumab is a humanized, mouse monoclonal antibody directed against the F protein of RSV. It is highly effective against type A and type B RSV isolates, and has been shown to be more specific and 50 to 100 times more potent than RSV-IGIV (2). Monthly intramuscular doses of 15 mg/kg in children maintained mean trough serum concentrations above 40 μg/mL, a level that resulted in a 99% reduction of pulmonary RSV in an animal model (1,3,4).

A multicentre, randomized, placebo controlled study of palivizumab for prophylaxis against RSV infection in high risk infants was conducted by the IMpact-RSV Study Group (5) involving 1502 children (1002 children received palivizumab and 500 children received a placebo containing the same components without the antibody) in the United States, the United Kingdom and Canada. Patients were enrolled if they were six months of age or younger and born at 35 weeks’ gestation or earlier, or if they were 24 months of age or younger and had a clinical diagnosis of bronchopulmonary dysplasia (BPD) requiring ongoing medical treatment. Children with congenital heart disease were excluded (except for those with patent ductus arteriosus or a hemodynamically stable septal defect) (5). Demographic parameters were similar in both study groups. Study patients received one monthly injection of 15 mg/kg palivizumab or an equal volume of placebo intramuscularly from December 1996 to April 1997; all five doses were received by 92% of the palivizumab group and 94% of the placebo group (5).

The results observed with palivizumab prophylaxis are summarized in Table 1. Patients who received palivizumab demonstrated statistically significant reductions in RSV-related hospitalizations (55% reduction, P<0.001), days spent in hospital (42% reduction, P<0.001) and the duration of time that increased oxygen was required (40% reduction, P<0.001) compared with the placebo group (5). Subgroup analysis demonstrated reductions in RSV-related hospitalizations for infants with BPD (39% reduction, P=0.038), infants without BPD (78% reduction, P<0.001), infants born before 32 weeks’ gestation (47% reduction, P=0.003) and infants born between 32 to 35 weeks’ gestation (80% reduction, P=0.002) (5). Among hospitalized children, the palivizumab group also had a shorter duration of moderate to severe respiratory illness compared with the placebo group (29.6 days versus 47.4 days, respectively; P<0.001) (5).

TABLE 1:
Summary of results from the IMpact-RSV study (5)

Admissions to the intensive care unit were required by 1.3% of the palivizumab recipients compared with 3% of the placebo patients (P=0.026) (5). The duration of stay in the intensive care unit, the need for mechanical ventilation and the duration of mechanical ventilation were not statistically different between the palivizumab and placebo groups (Table 1). No differences were observed between the two groups for non-RSV-related hospitalizations and the development of otitis media during the study period (5). Four children (0.4%) in the palivizumab group and five children (1%) in the placebo group died during the study. The deaths were not attributed to the study drug.

The number of adverse effects was similar in both the treatment (11%) and placebo (10%) groups (5). Local reactions were found in 2.7% of the palivizumab group and 1.8% of the placebo group. These reactions included local erythema, pain, induration and bruising; all reactions were mild and of short duration. Fever occurred equally often in both groups (fever was experienced by 2.8% of the palivizumab group and 3% of the placebo group). Discontinuation of palivizumab due to adverse events ensued in 0.3% of patients (5). No clinically significant elevations of liver transaminases, blood urea and creatinine levels occurred. Anaphylaxis was not observed in the study (5).

Antibodies to palivizumab were measured, and titres greater than 1:40 were present in 1.2% of the treatment group and 2.8% of the placebo group (5). The presence of these antibodies was not associated with increased adverse events, and did not result in lower palivizumab concentrations.

COMPARISON OF PALIVIZUMAB WITH RSV-IGIV

The major differences between palivizumab and RSV-IGIV are summarized in Table 2. Compared with RSV-IGIV, the advantages of palivizumab include the following: it is a recombinant product and, thus, has no potential for transmitting blood-borne infectious diseases; it can be given by intramuscular injection in an outpatient setting rather than through an established intravenous infusion program; and it does not affect the measles-mumps-rubella or measles-rubella immunization schedules (6). Palivizumab is a monoclonal antibody specific for RSV with no effect on other common respiratory pathogens (5).

TABLE 2:
Comparison of respiratory syncytial virus immune globulin intravenous (RSV-IGIV [Respigam, MedImmune Inc, Gaithersburg, Maryland]) and palivizumab (Synagis, MedImmune Inc)

RSV-IGIV is a blood product that has antibodies against RSV as well as other antigens, and appears to provide some protection against other non-RSV respiratory viral infections and otitis media (1,6,7). As with any IGIV administration, there is a small risk of anaphylaxis during intravenous infusions. A delay of 10 months for the administration of measles-mumps-rubella and/or measles-rubella vaccines is required because of interference from the infused antibodies (1,68). RSV-IGIV and palivizumab have been studied for the treatment (rather than prevention) of hospitalized children with established RSV infection, and neither has proven effective (9,10).

Data from one study on RSV-IGIV prophylaxis showed a trend toward higher hospitalization rates, as well as more surgically related severe events in children with cyanotic heart disease (11). There are no comparable data on palivizumab prophylaxis in children with congenital heart disease. Neither RSV-IGIV nor palivizumab is licensed for use in children with congenital heart disease, and neither product has been studied in children with immunodeficiency diseases (6).

Both RSV-IGIV and palivizumab were effective in decreasing hospitalizations due to RSV, shortening the duration of stay and decreasing the duration of oxygen supplements in high risk infants who were hospitalized (Table 2) (5,12,13). Palivizumab decreased the need for admissions to the intensive care unit; RSV-IGIV did not (5,11,12). However, there was no statistical difference in the need for mechanical ventilation or the mortality rate from RSV in patients who received either RSV-IGIV or palivizumab compared with the control groups. This may be due to the overall low incidence of these events and insufficient sample sizes to detect differences between the treatment and placebo groups in the studies (5,11,12). The extent of ribavirin use in high risk patients hospitalized with RSV was generally not explored, except in the PREVENT study (12), where ribavirin use was similar in the groups that received RSV-IGIV or placebo.

ECONOMIC CONSIDERATIONS

Three studies on the cost benefit of RSV-IGIV prophylaxis have been conducted in the United States (14,15,16). Hay et al (14) concluded that the use of RSV-IGIV appears to be cost beneficial when cost per life saved is factored into the equation, ie, the net cost of RSV-IGIV prophylaxis (estimated at US$4,460) is fully recovered by the economic benefit of years of life saved. The authors conducted their analysis from a societal perspective, factoring in the costs of a RSV-IGIV infusion program and the time spent by parents attending RSV-IGIV infusions against the costs of treating children infected with RSV and the economic impact of death from RSV infection. The authors made the assumption that RSV-IGIV prophylaxis would decrease mortality from RSV by half (from 2% to 1%), which is unsubstantiated by published studies (6,14). It was further assumed that only two 50 mL vials (5000 mg) of RSV-IGIV would be used each month (at 750 mg/kg/ dose), which is only applicable for children who weigh less than 6.7 kg (14). Clearly, the cost increases if more vials are required.

A cost benefit analysis conducted from a ‘payer’s perspective’ at the Wake Forest University School of Medicine, Winston-Salem, North Carolina was based on the premise that the only major economic benefit of RSV-IGV prophylaxis was the hospital costs avoided, with no reduced mortality from RSV and no regard to the indirect costs to the family from RSV illness or any potential long term complications (15). The risk of hospitalization for RSV illness at the institute was estimated at 12%, 17% and 28% for preterm infants without BPD, with mild BPD and with moderate to severe BPD, respectively. The average length of stay for RSV lower respiratory tract illness was five days, with per diem hospital cost estimated at US$971 (15). The expected reduction in hospitalization from RSV in infants given RSV-IGIV was taken from the PREVENT study (12). The cost of a full course of RSV-IGIV ranged from US$3,280 to US$8,800 for infants weighing 1.2 kg to 10.0 kg at the start of the five-month program (15). The authors concluded that RSV-IGIV was not cost beneficial, ie, the cost for RSV-IGIV typically exceeded the hospital costs avoided by several thousand dollars in all subgroups of children studied (15). The net loss was lowest for infants with BPD who were three months of age or younger. Even when higher estimates (ie, 25% and 45%) of the risk for RSV hospitalization were used (17), the cost of prophylaxis generally exceeded the hospital costs avoided, except for infants with BPD who were less than three months of age or who had a starting weight of less than 4 kg (the results for this population showed either no net savings or loss, or overall net savings) (15).

A ‘number-needed-to-treat’ analysis of the success of RSV-IGIV in preventing RSV hospitalization was conducted at the University of Arkansas for Medical Sciences, Little Rock, Arkansas (16). Using a 15% risk of RSV hospitalization for untreated patients (which is close to the 13.5% risk found in the PREVENT study), the authors calculated that, on average, 16 infants (varying from 12 premature infants with BPD and 63 premature infants without BPD) would have to be treated to prevent one hospitalization due to RSV (16). The authors then determined the ‘threshold’ number of patients who would have to be treated to achieve equality between the costs of using RSV-IGIV and the economic benefits of averting hospital admissions for RSV (the latter was estimated based on the amount a sample of well-informed parents stated they were willing to pay to avoid an RSV-related hospital admission). The authors concluded that the calculated number-needed-to-treat (16 infants) to prevent one RSV hospitalization generally exceeded the threshold number (which ranged from two to nine infants in their model), thereby suggesting that the prophylaxis program was not cost beneficial (16). The program would have been cost neutral if the risk of RSV hospitalization in untreated patients was much higher (between 30% to 50%) (16).

Cost benefit data were not available for palivizumab prophylaxis at the time when this statement was developed (6). For children with other high risk factors (such as immunodeficiency diseases), there are no efficacy, safety or cost-benefit data for either RSV-IGIV or palivizumab (6).

The conclusions drawn from the cost benefit studies on RSV-IGIV in the United States are debatable because the authors used different methods and made contentious clinical assumptions. It is also difficult to generalize the cost-benefit data to Canada because our health care costs are different from those in the United States (18). In Canada, the historical rates of hospital admissions for RSV lower respiratory tract infection appear to be lower (ranging from 1% to 4% for infants born at less than 33 weeks’ gestation and 0.5% to 2.5% for infants born between 33 to 36 weeks’ gestation in selected paediatric tertiary care centres) (19) than for patients receiving placebo in both the PREVENT RSV-IGIV study (12) and the IMpact-RSV palivizumab trial (5) (13% and 10%, respectively). Thus, the available information in Canada raises doubt about the cost benefit of RSV-IGIV (and palivizumab at current prices) in the average infant with or without BPD. The cost benefit for RSV prophylaxis of high risk children in areas where hospital care is not readily available (eg, in the isolated communities of the Yukon, Northwest and Nunavut Territories) is unknown. If these children develop severe RSV disease, they require air ambulance transportation to a paediatric tertiary care centre, which increases medical costs. Preventing or decreasing the severity of RSV disease in high risk children in these communities may be cost beneficial.

The information presented in this statement is supported by a recent meta-analysis of studies on the prevention of RSV infection (20).

RECOMMENDATIONS

  1. Given the limited clinical benefits of palivizumab and RSV-IGIV in the prevention of RSV infection in high risk patients, other preventive measures remain important. They are: emphasizing hand-washing when siblings or adult contacts have respiratory infections, eliminating exposure to tobacco smoke, and limiting exposure to contagious settings such as childcare centres (6).
  2. Palivizumab or RSV-IGIV prophylaxis has been shown to be effective for infants born at up to 35 weeks’ gestation (5). However, each year, there is a large number of patients in the subgroup born between 33 to 35 weeks’ gestation (the subgroup is estimated to be 3% to 5% of the birth cohort or about three to five times larger than the cohort born earlier than 33 weeks’ gestation) who appear to be at relatively low risk (less than 3%) of being hospitalized with RSV infection in Canada (19). Consequently, priority for palivizumab or RSV-IGIV prophylaxis should be given to patients who are at highest risk of developing severe RSV infection, ie, (a) children 24 months of age or younger with BPD who required oxygen within the six months preceding the RSV season, and (b) infants born at 32 weeks’ gestation or earlier who are six months of age or younger (with or without BPD) at the start of the RSV season. Palivizumab is generally preferred over RSV-IGIV because of its route of administration, theoretical safety and similar effectiveness; it also does not result in any delay in the administration of measles, mumps or rubella vaccines (Category of recommendation: B-I, see Table 3 for definitions). Children in isolated communities where hospital care is not readily accessible already qualify for RSV prophylaxis if they have the risk factors outlined in (a) and (b) above. Children born between 33 to 35 weeks’ gestation in these areas may be given special consideration for RSV prophylaxis; a study to assess the cost benefit of providing prophylaxis to these children is a research priority.
    TABLE 3:
    Rating system for the strength of recommendations presented in this statement and the quality of evidence supporting each recommendation (24)
  3. The RSV season typically lasts up to five months. The beginning of the season in any year varies across Canada, and clinicians should check with local infectious diseases specialists or microbiologists to determine when the RSV season begins in their communities. RSV prophylaxis with either RSV-IGIV or palivizumab, if undertaken, should be initiated at the start of the RSV season and continued monthly until the end of the season.
  4. Neither RSV-IGIV nor palivizumab is recommended for use in children with cyanotic heart disease (Category of recommendation: E-I for RSV-IGIV) (21). Children with asymptomatic, acyanotic heart disease (eg, patent ductus arteriosus or ventricular septal defect) who fulfill the criteria in recommendation 2 above may benefit from palivizumab prophylaxis (Category of recommendation: C-III).
  5. There are no data to support or refute the routine use of either palivizumab or RSV-IGIV for the prevention of severe RSV disease in children with severe immunodeficiency diseases. For children who routinely receive replacement IGIV infusions, some experts recommend using RSV-IGIV instead of standard IGIV during the RSV season because the latter does not contain enough neutralizing antibodies to RSV (22) (Category of recommendation: C-III). RSV-IGIV may decrease the risk of RSV, as well as non-RSV viral infections and otitis media in this situation (6).
  6. Neither RSV-IGIV nor palivizumab is indicated for the inpatient treatment of established RSV infection (9,10,21). (Category of recommendation: D-I for RSV-IGIV).
  7. Among hospitalized patients, the observance of strict infection control measures, such as the cohorting of infants infected with RSV, remains a major step in preventing the spread of the disease (23). The use of palivizumab or RSV-IGIV for preventing the spread of RSV among otherwise healthy patients in paediatric wards or intensive care settings has not been evaluated, and is not recommended (Category of recommendation: C-III).

The Canadian Blood Services and Hema Quebec have funded the use of palivizumab and RSV-IGIV for patients who fulfill criteria (a) and (b) listed in recommendation 2. An application for the use of either product in patients who do not fulfill these criteria will be considered on a case-by-case basis by the Canadian Blood Services or Hema Quebec. Contact the individual product distributors (Table 2) for further information.

Acknowledgments

The preparation of this paper was supported by an unrestricted grant from Abbott Laboratories, Montreal, Quebec.

Footnotes

INFECTIOUS DISEASES AND IMMUNIZATION COMMITTEE

Members: Drs Gilles Delage, Laboratoire de santé publique du Québec, Sainte-Anne-de-Bellevue, Québec (chair); François Boucher, Département de pédiatrie, Centre Hospitalier Universitaire de Québec, Pavillon CHUL, Sainte-Foy, Québec; H Dele Davies, Division of Infectious Diseases, Alberta Children’s Hospital, Calgary, Alberta; Joanne Embree, The University of Manitoba, Winnipeg, Manitoba; Charles Morin, Complexe hospitalier Sagamie, Chicoutimi, Québec (director responsible); David Speert, Division of Infectious and Immunological Diseases, University of British Columbia, Vancouver, British Columbia; Ben Tan, Division of Infectious Diseases, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan (principal author)

Consultants: Drs Noni MacDonald, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia; Victor Marchessault, Cumberland, Ontario

Liaisons: Drs Scott Halperin, Department of Pediatrics, IWK-Grace Health Centre, Halifax, Nova Scotia (IMPACT); Neal Halsey, The Johns Hopkins University, Baltimore, Maryland (American Academy of Pediatrics); Susan King, Division of Infectious Diseases, The Hospital for Sick Children, Toronto, Ontario (Canadian Paediatric AIDS Research Group); Monique Landry, Direction de la santé publique de Laval, Laval, Québec (Public Health); John Waters, Alberta Health, Edmonton, Alberta (Epidemiology)

FETUS AND NEWBORN COMMITTEE

Members: Drs Douglas McMillan, Foothills Hospital, Calgary, Alberta (chair); Arne Ohlsson, Mount Sinai Hospital, University of Toronto, Toronto, Ontario (co-chair); Deborah Davis, Children’s Hospital of Eastern Ontario, Ottawa, Ontario; Daniel Faucher, Royal Victoria Hospital, Montréal, Québec; John van Aerde, Stollery Children’s Health Centre, Edmonton, Alberta; Michael Vincer, IWK-Grace Health Centre, Halifax, Nova Scotia; John Watts, Children’s Hospital at Hamilton Health Sciences Corporation, Hamilton, Ontario (director responsible)

Liaisons: Ms Debbie Fraser-Askin, St Boniface Hospital, Winnipeg, Manitoba (Neonatal nurses); Drs Line Leduc, Hôpital Sainte-Justine, Montréal, Québec (Maternal-Fetal Medicine Committee, Society of Obstetricians and Gynaecologists of Canada); James Lemons, Riley Children’s Hospital, Indiana University Medical Center, Indianapolis, Indiana (Committee on Fetus and Newborn, American Academy of Pediatrics); Catherine McCourt, Laboratory Centre for Disease Control, Bureau of Reproductive & Child Health, Health Canada, Ottawa, Ontario (Health Canada); Saroj Saigal, Children’s Hospital at Hamilton Health Sciences Corporation, Hamilton, Ontario (Neonatal-Perinatal Medicine Section, Canadian Paediatric Society)

The recommendations in this statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate.

REFERENCES

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