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Respiratory syncytial virus immune globulin intravenous (RSV-IGIV) (RespiGam, MedImmune Inc, Maryland) is currently licensed in Canada via the special release program of Health Protection Branch for the prevention of serious lower respiratory tract infection caused by respiratory syncytial virus (RSV). This paper provides a review of the product, with a view to developing guidelines for its use in Canada.
RSV-IGIV is an intravenous human plasma product with high titres of neutralizing antibody against RSV (1,2). Cohn-Oncley cold ethanol precipitation and a solvent-detergent viral inactivation process (3) are used to decrease the possibility of transmission of bloodborne pathogens, such as human immunodeficiency virus, and hepatitis B and C. The product contains approximately 50 mg immunoglobulin (Ig) per mL (mostly IgG, with trace amounts of IgA and IgM) (1). The antibodies neutralized 62 different clinical isolates of RSV subgroups A and B in vitro. Recommended dosage for prophylaxis is 750 mg/kg (about 15 mL/kg volume) once a month for five months, beginning before the onset of RSV season (1). In Canada, RSV season usually begins between October and December, and ends the following March to May.
RSV-IGIV has been evaluated in several randomized, controlled trials for prophylaxis against severe RSV disease.
Groothuis et al (4) conducted a multicentre trial in a group of 249 infants younger than 24 months with underlying bronchopulmonary dysplasia (BPD), congenital heart disease (CHD) or prematurity (35 or fewer weeks’ gestation). Participants received a course of one of two dosages of RSV-IGIV (750 mg/kg or 150 mg/kg) infused once a month from mid-November through to March or April or received no RSV-IGIV. Compliance with visits was better in the high dose group (97%) than control groups (91%), and at least 75% of the doses were administered at 85% of the visits (4). Infants receiving the higher dose (750 mg/kg) had a reduced rate of RSV-related hospitalization (65% reduction), and length of stay in hospital (63% reduction) and in the intensive care unit (ICU) (97% reduction) compared with controls (Table 1). Ribavirin was also used for a shorter duration among patients in the high dose group (4). Too few children required mechanical ventilation to allow comparison (two in the control group and none in either the high or low dose groups). The results for the low dose group (150 mg/kg) were less impressive, with only a significant reduction in the number of days in the ICU recorded (4). A separate analysis found fewer occurrences of acute otitis media per RSV season in a subgroup of patients on the high dose RSV-IGIV compared with control patients (5).
The PREVENT study group conducted a multicentre trial in a group of 510 infants younger than 24 months with BPD who were on oxygen within the six months before the start of the trial and/or were premature (35 or fewer weeks’ gestation at birth) (6). This trial compared once monthly 750 mg/kg RSV-IGIV infusions for five months with placebo (1% albumin) for the same period. In each group, 85% of infants completed at least four infusions. The group who received RSV-IGIV had a significantly better RSV-related outcome compared with the placebo group (6) (Table 1). This was demonstrated by a lower hospitalization rate (41% reduction overall; the effect was greater in the subgroup with BPD [49% reduction] than in the subgroup of premature infants without BPD [20% reduction] [6,7]), shorter hospital stay (53% reduction) and shorter time on oxygen (60% reduction) (6). The need for mechanical ventilation, time spent in the ICU and percentage usage of ribavirin were no different between the two groups. As an added benefit, a decrease in non-RSV respiratory hospitalization was noted in the RSV-IGIV group (a 38% reduction in hospitalization rate and 46% reduction in length of hospital stay for respiratory illness of any cause) (6). Otitis media was documented in 27% of the RSV-IGIV group and in 43% of the placebo group (6). This study was not designed (too few patient numbers) to distinguish differences in RSV hospitalization rates among subgroups of children.
A multicentre, randomized study compared RSV-IGIV infusions and no treatment in 416 children younger than 48 months with CHD (7). The groups were not equal because 39% of the group who received RSV-IGIV had cyanotic heart disease compared with 22% of the no-treatment group. Statistically, there was no reduction in RSV-related disease in the treatment group, except for infants younger than six months where there was a 57% lower hospitalization rate (P=0.01) (8). Despite lack of statistical significance, a trend toward reduced hospitalization rates and duration of hospitalization in treated patients with acyanotic CHD was found. However, for the patients with cyanotic CHD who received RSV-IGIV, there was a trend toward increased hospitalization rates (8). Surgically related severe events were also more common in the infants with cyanotic CHD who received RSV-IGIV (28% in the RSV-IGIV group versus 9% of the no-treatment group, P=0.009). None of the surgically related severe events was directly attributable to RSV-IGIV infusions (8). Nevertheless, sufficient concern was raised that the prophylactic use of RSV-IGIV has not been approved in the United States for infants and children with cyanotic CHD (1,7).
RSV-IGIV may induce severe allergic reactions or anaphylaxis at a low rate consistent with other immune globulin intravenous products. In the study by Groothuis et al (4), no anaphylactic events occurred in 580 infusions of RSV-IGIV; one child (of 160) developed fever and severe respiratory distress after the second infusion, and needed mechanical ventilation. Less severe adverse effects were seen in 3% of those who received RSV-IGIV (including a mixture of cases with mild fluid overload, mild oxygen desaturation and/or fever); none required discontinuation of treatment (4). Over the three-year study period, three deaths occurred in each of the high and low dose arms of the study, while none died in the control arm (P=0.15) (4). None of the deaths were attributed to RSV-IGIV infusions or RSV-related illness. However, five deaths occurred in patients with CHD. Three died within one day (two patients) and three months (one patient) after undergoing cardiac surgery between two and 13 weeks after the last infusion of RSV-IGIV (4). In the PREVENT study (6), two patients of 250 developed serious reactions (manifest by cyanosis, mottling and fever in one, and respiratory distress in the other), and RSV-IVIG treatments were discontinued. Less severe reactions (mild fluid overload or fever) were seen in 1% to 2% of both placebo and RSV-IVIG treated patients. Aseptic meningitis has rarely been reported after RSV-IGIV administration (6); this phenomenon is not unique to RSV-IGIV because it has also been reported with standard IGIV infusions. Death occurred in two placebo patients and five RSV-IGIV treated patients (P=0.28) during the seven month PREVENT study period; all were thought to be related to complications of prematurity or underlying illness (6).
No specific conclusions about these mortality data can be made (eg, whether RSV-IGIV is beneficial in decreasing mortality rates or conversely increases mortality rates because of adverse effects) because both the Groothuis et al (4) and PREVENT (6) studies were not specially designed to detect significant differences in mortality rates between treatment and no-treatment or placebo groups. Nevertheless, it is prudent to have medication and equipment for the management of anaphylaxis, fluid overload and/or respiratory deterioration available during infusions (1). Vital signs and cardiorespiratory status should be monitored, especially in children who are sensitive to extra fluid administration, such as those with BPD.
RSV-IGIV prophylaxis appears to be most beneficial for the following infants and children (7):
Infants born at 28 weeks’ gestation or less may benefit from prophylaxis up to 12 months of age. Infants born at 29 to 32 weeks’ gestation may benefit from prophylaxis up to six months of age.
While RSV-IGIV has not been evaluated for the prevention of RSV infection in immunocompromised pediatric patients, children with severe immunodeficiencies (such as severe combined immunodeficiency) may also benefit from RSV-IGIV (7). Clinicians may consider substituting RSV-IGIV in place of IGIV (if children are already receiving this monthly) during the RSV season. Standard IGIV does not contain enough neutralizing antibodies to RSV to prevent severe RSV disease (9).
RSV-IGIV is not approved for use in patients with CHD, especially those with cyanotic heart disease (1,2). However, patients with BPD or who were premature and have asymptomatic acyanotic heart disease (eg, patent ductus arteriosus or ventricular septal defect) may benefit from prophylaxis (7). RSV-IGIV should not be used in those with prior severe reactions to this product or to other human Ig preparations (1). Patients with selective IgA deficiency may develop antibodies to IgA, and have anaphylactic or allergic reactions to subsequent administration of RSV-IGIV (1). RSV-IGIV was evaluated for the treatment of hospitalized children with established RSV infection (rather than prevention) but was not found to be effective (10). Hence, RSV-IGIV is not indicated for inpatient treatment of proven RSV infection.
No change in the recommended schedules for immunizing children against diphtheria, pertussis (whole cell or acellular vaccines), tetanus, polio (injectable vaccine), Haemophilus influenzae b (Hib) or hepatitis B vaccines are needed while on RSV-IGIV treatments (7). There is insufficient evidence at present to recommend booster doses of diphtheria-acellular pertussis-tenanus (or diphtheria pertussis-tetanus) vaccine, injectable polio or Hib vaccines after completion of RSV-IGIV treatments (1,7).
RSV-IGIV interferes with the response to measles, mumps and rubella (MMR) vaccine. Hence, immunization with the first dose of MMR should be deferred for nine months after the last dose of RSV-IGIV (7). If MMR vaccine was administered during the infusions or within nine months after the last RSV-IGIV infusion, reimmunization at the end of that period is recommended (1). In provinces and territories where a second dose of MMR or measles-rubella (MR) vaccine is routinely provided at 18 months of age, RSV-IGIV infusions may delay the first dose of MMR vaccine past age 18 months. In such a case, the second dose of MMR or MR vaccine may be given one to two months after the first dose. There is insufficient information available about RSV-IGIV’s interaction with oral polio (Sabin) and influenza vaccines (1) to make recommendations.
Each centre should consider the following factors before deciding to embark on a RSV-IGIV prophylaxis program.
Results from a survey in 1993 and 1994 of nine Canadian pediatric tertiary care centres, with a total of 1516 infants hospitalized for RSV disease, may help. The results revealed that 6% to 17% of patients had underlying chronic lung disease and between 14% and 27% were born at less than 37 weeks’ gestation (11). Of the children with BPD, CHD, who were premature or had other high risk factors, between 25% and 48% required ICU care and of those about half needed mechanical ventilation (11). The mean hospital stay for patients with high risk factors varied from 8.6 to 11.8 days, and the proportion in which ribavirin was used varied considerably (18% to 54%) between centres (11). The use of ribavirin adds to the economic impact of RSV disease because ribavirin costs about $ 1,500 a day and is usually required for three to five days. A recent cost estimate for the tertiary care of patients with RSV disease in Canada was about $8,500 (US$6,000) per stay (where ribavirin was used in 7% of total patient-days) (12).
A detailed cost-benefit analysis of RSV-IGIV use in Canada is beyond the scope of this review, but was attempted in the United States (13). Extrapolation of these cost-benefit data in United States to Canada is difficult because heath care costs of RSV disease are different between the two countries (12). Cost savings can be obtained if RSV-IGIV use can decrease hospital or ICU admission and the length of hospitalization for RSV disease by 40% to 60% (as estimated by the RSV-IGIV studies above). There are insufficient data available at present to conclude whether RSV-IGIV can contribute to decreased ribavirin use.
To give another perspective, based on data from the PREVENT study (6), it was estimated that approximately 12 infants with BPD and 63 premature infants less than six months of age without BPD would have to be treated with a prophylactic RSV-IGIV course to avoid a single hospitalization in each group (14).
The cost of RSV-IGIV is approximately $680 for a 50 mL vial and $350 for a 20 mL vial. Children can be treated in an in-patient or out-patient setting, provided sufficient medical personnel and resources are available. Consequently, monthly infusions may only be feasible at tertiary pediatric centres.
Possible shortage of RSV-IGIV, the costs involved and the impracticality of infusions may mean that only a subgroup of infants with the most severe underlying conditions can receive RSV-IGIV during the 1997/98 RSV season (eg, those with BPD who are still ventilated or on oxygen therapy and are in hospital throughout the RSV season).
INFECTIOUS DISEASES AND IMMUNIZATION COMMITTEE
Members: Drs Gilles Delage, Directeur scientifique, Laboratoire de santé publique du Québec, Ste-Anne-de-Bellevue, Québec (chair); François Boucher, Département de pédiatrie, Centre Hospitalier Universitaire de Québec, Québec, Québec; Joanne Embree, Winnipeg, Manitoba; Elizabeth Ford-Jones, Division of Infectious Diseases, The Hospital for Sick Children, Toronto, Ontario; David Speert, Division of Infectious and Immunological Diseases, University of British Columbia, Vancouver, British Columbia; Ben Tan, Division of Infectious Diseases, Royal University Hopsital, University of Saskatchewan, Saskatoon, Saskatchewan (principal author)
Consultants: Drs Noni MacDonald, Division of Infectious Diseases, Children's Hospital of Eastern Ontario, Ottawa, Ontario; Victor Marchessault, Cumberland, Ontario
Liaisons: Drs Neal Halsey, 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); David Scheifele, Division of Infectious Diseases, BC’s Children's Hospital, Vancouver, British Columbia (Centre for Vaccine Evaluation); Ms Susan Tamblyn, Perth District Health Unit, Stratford, Ontario (Public Health); Dr John Waters, Provincial Health Officer, Alberta Health, Edmonton, Alberta (Epidemiology)
This article was also published in Can J Infect Dis 1998;9(1): 12–15.