Canada Communicable Disease Report
Volume 29 ACS-7
15 September 2003

An Advisory Committee Statement (ACS) 
National Advisory Committee on Immunization (NACI)*^†

STATEMENT ON THE RECOMMENDED USE OF MONOCLONAL ANTI-RSV ANTIBODY (PALIVIZUMAB)

Adobe Downloadable Document
16 Pages - 242 KB

Preamble

The National Advisory Committee on Immunization (NACI) provides Health Canada with ongoing and timely medical, scientific, and public health advice relating to immunization. Health Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge, and is disseminating this document for information purposes. People administering or using the immunizing agent should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out here may differ from that set out in the product monograph(s) of the Canadian licensed manufacturer(s) of the immunizing agent(s). Manufacturer(s) have sought approval of the immunizing agent(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. 

Introduction 

In 1997, respiratory syncytial virus immune globulin intravenous (human) (RSV-IGIV) was approved for use in Canada for the prevention of RSV infection among children aged < 2 years with bronchopulmonary dysplasia (BPD) or chronic lung disease (CLD), or a history of premature birth (<= 35 weeks' gestation). This product, an intravenous IG derived from pools of human plasma with high concentrations of protective antibodies that neutralize RSV, had the disadvantage of requiring monthly intravenous injections of a high fluid load over several hours; carried the theoretical risks associated with any human blood product; and was contraindicated in children with certain congenital heart lesions. In the Canadian Immunization Guide, NACI indicated that RSV-IGIV prophylaxis might be beneficial for certain children < 2 years of age with BPD or infants born at 29 to 32 weeks of gestation in the first 6 months of life⁽¹⁾. 

In June 2002, Health Canada approved a monoclonal anti-RSV antibody, palivizumab (Synagis^TM, Abbott Laboratories, Ltd., Saint-Laurent, Quebec) for the prevention of serious lower respiratory tract disease caused by RSV in pediatric patients at high risk of RSV disease. Although palivizumab was not licensed in Canada until June of 2002, it had been available since 1999 through Health Canada's Therapeutic Products Special Access Program for children with certain high-risk conditions⁽²⁾. This NACI statement provides recommendations on the use of palivizumab for the prevention of RSV disease.

Epidemiology and Clinical Disease 

RSV is the most common cause of lower respiratory tract illness in young children worldwide and infects almost all by age 2^(3-5) in yearly epidemics every winter. Primary infection does not confer protective immunity, and re-infection occurs in sequential seasons and throughout the lifespan^(6,7). 

The most common clinical presentation of RSV in young children is bronchiolitis, an acute lower respiratory tract infection associated with symptoms of tachypnea, cough, and wheezing following an upper respiratory tract illness⁽⁸⁾. About 1% to 2% of all children with bronchiolitis will be ill enough to require hospitalization for oxygen supplementation, intravenous fluids, or other supportive care. Hospitalization accounts for at least 65% of the economic burden of RSV in children < 4 years old⁽⁹⁾, and there is evidence that hospitalization rates have been increasing in the last two decades⁽¹⁰⁾. 

Among children < 2 years of age, those at highest risk of severe lower respiratory tract infection are previously well infants < 6 weeks of age, the premature, those with underlying cardiac or pulmonary disease, and the immunocompromised. Prospective cohort studies of Canadian children hospitalized for RSV infection show that these children are more likely to have prolonged hospital stays, require admission to an intensive care unit, and need mechanical ventilation^(11-16). About 1% of children hospitalized with RSV bronchiolitis die, but mortality is about 3% in those with pre-existing cardiac or lung disease.

Infants with BPD/CLD subsequent to management of respiratory disease associated with premature birth have high rates of rehospitalization for lower respiratory tract infection acquired in the community. Viral infection, particularly RSV, may lead to up to half of these infants being readmitted for supportive care because of acute deterioration in pulmonary function^(17,18). In Canada, about 26% of very low birth weight infants (< 1500 g) who survive have CLD⁽¹⁹⁾. Studies by the Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) over multiple epidemic years show that children with chronic lung disease account for about 13% of all admissions to hospital, and are more likely to have prolonged hospital stay and admission to intensive care units^(11,12,15).

Children with other lung diseases not associated with prematurity (e.g. recurrent aspiration pneumonitis, cystic fibrosis, pulmonary malformation), particularly those using home oxygen, also appear to be at increased risk of severe lower respiratory infection with RSV⁽²⁰⁾. High rates of lower respiratory tract infection associated with RSV, particularly in those < 6 months of age, have been observed among Inuit infants (484/1000 infants)⁽²¹⁾, up to 38% of infants requiring hospitalization⁽²²⁾ and 12% requiring intubation for respiratory support⁽²¹⁾. This finding is consistent with observations of other aboriginal groups that this population has a high incidence of lower respiratory tract infection and a complicated course compared with nonaboriginals^(23,24).

Premature birth (< 36 weeks' gestation) is an independent risk factor for severe lower respiratory tract infection with RSV and may manifest as apnea, respiratory failure, or the need for intravenous nutrition because of an inability to feed^(12,13,15). The reported risk of hospitalization for RSV in premature infants without other risk factors who are discharged into the community has varied greatly among studies, from 1% to 20%^(25,26-29). Infants born at <= 32 weeks' gestation account for about 75% of those currently receiving palivizumab prophylaxis in Canada⁽²⁾.

Children with hemodynamically significant cardiac disease have limited ability to increase cardiac output and oxygen delivery during a lower respiratory tract infection and are at significant risk of respiratory or cardiac failure during such illnesses⁽³⁰⁾. Although an early study indicated very high mortality rates associated with RSV infection in children with congenital heart disease⁽³¹⁾, recent Canadian studies have shown a 3.4% mortality rate in hospitalized children, a 33.4% rate of admission to the intensive care unit, and requirement for mechanical ventilation in about 18%⁽³²⁾. Children with pulmonary hypertension appear to be at particularly high risk^(30,33). RSV infection in the pre or postoperative period of corrective cardiac surgery may significantly worsen clinical outcome^(34,35). 

RSV is an increasingly recognized cause of lower respiratory tract infection in adults^(36,37). Although second and subsequent infections may cause milder disease than the first infection⁽³⁸⁾, RSV infection after childhood may cause community-acquired lower respiratory tract infection among hospitalized adults⁽³⁹⁾ and exacerbations of chronic bronchitis⁽⁴⁰⁾. Frail, elderly people living in the community or in institutions and adults with underlying cardiac or pulmonary disease are at particularly high risk of severe RSV disease. Outbreaks among elderly people in long-term care facilities have been reported to be complicated by pneumonia in 5% to 55% of cases and carry a mortality of up to 20%^(36,41). In the United States, it is estimated that 78% of RSV-associated deaths occur among people >= 65 years⁽⁴²⁾. Severe infections also occur in the immunocompromised, particularly transplant recipients of all ages^(36,43). The highest mortality rates occur among bone marrow transplant recipients before marrow engraftment, when up to 80% may die from severe pneumonia⁽³⁶⁾.

Preparations Licensed for Immunization 

The only licensed monoclonal anti-RSV antibody in Canada is palivizumab. Palivizumab is a humanized, monoclonal immunoglobulin G-1 (IgG-1) directed against an epitope on the F glycoprotein of RSV, a surface protein that is highly conserved among RSV isolates⁽⁴⁴⁾. It is produced by recombinant DNA technology, in which the complementarity determining regions from the mouse monoclonal antibody are grafted into a human antibody framework. Palivizumab consists of 95% human and 5% murine amino acid sequences. Because palivizumab is not derived from human immune globulin, it is free of potential contamination from bloodborne infectious agents. 

Efficacy and Serum Levels Correlating with Protection 

Before efficacy studies had been carried out in children, dose ranging studies were done in an animal model of lower respiratory tract RSV infection to determine the serum concentration of RSV immunoglobulin that would correlate with protection from pulmonary infection. In that model, serum concentrations of 25 to 30 µg/mL resulted in a mean 99% reduction of pulmonary RSV, while a minimum of 99% reduction was achieved when the serum concentration was > 40 µg/mL⁽⁴⁴⁾. Dose ranging studies in children evaluating 5 to 15 mg/kg of palivizumab determined that intramuscular injection or intravenous doses of 15 mg/kg resulted in serum concentrations up to 30 days that were well above those found to be protective in animal studies⁽⁴⁵⁾.

According to the product monograph, palivizumab 15 mg/kg of body weight in children achieves a mean 30-day trough serum drug concentration of 37 (standard deviation [sd] 21) µg/mL after the first injection, 57 (sd 41) µg/mL after the second injection, 68 (sd 51) µg/mL after the third injection, and 72 (sd 50) µg/mL after the fourth injection. In pediatric patients given palivizumab for a second season, the mean serum concentrations following the first and fourth injections were 61 (sd 17) µg/mL and 86 (sd 31) µg/mL respectively. In pediatric patients < 4 months of age the mean half-life of palivizumab was 20 days (range 16.8 to 26.8 days). 

There have been only two randomized controlled clinical trials of palivizumab, which assessed its efficacy in reducing hospitalization due to RSV in two pediatric populations: children with prematurity and/or CLD⁽²⁶⁾ and children with hemodynamically significant heart disease⁽⁴⁶⁾. In both studies, the primary outcome measure was reduction in hospitalization with confirmed RSV infection. 

In the first trial, 1502 children born at <= 35 weeks' gestation who were <= 6 months of age, or <= 24 months old with a clinical diagnosis of BPD requiring ongoing medical treatment (i.e. supplemental oxygen, steroids, bronchodilators or diuretics within the previous 6 months) were eligible⁽²⁶⁾. Nine of the 139 sites in this multicentre study were in Canada. Children received monthly injections of 15 mg/kg of body weight on the day of injection of palivizumab, or placebo, for 5 months beginning in December. The incidence of hospitalization due to RSV was 10.6% in the placebo group and 4.8% in the palivizumab group, representing a 55% reduction in relative risk for this primary outcome measure. Reductions were also reported for some secondary outcome measures: duration of hospital stay (62.4 versus 36.4 days per 100 children), duration of moderate to severe illness in hospitalized children (47.4 versus 29.6 days per 100 children) and duration of time that oxygen supplementation was required (50.6 days versus 30.3 days/100 children). 

Subgroup analysis of the enrollees showed some variation in protection afforded by palivizumab prophylaxis. When compared with placebo recipients, palivizumab recipients showed a reduced risk of hospitalization due to RSV of 80% for children born at 32 to 35 weeks' gestation (9.8% versus 2%), 78% for all premature infants without BPD (8.1% versus 1.8%), 47% for infants born at < 32 weeks' gestation (11% versus 5.8%), and 39% for infants with BPD (12.8% versus 7.9%). No difference was observed between placebo and palivizumab recipients in the need for or duration of mechanical ventilation, duration of stay in the intensive care unit, development of otitis media or occurrence of non-RSV related hospitalization. 

Children with cyanotic congenital heart disease who received RSV-IGIV in studies of its efficacy showed a significantly higher frequency of unanticipated cyanotic episodes and of poor outcomes after surgery (22 of 78, 28%) than those in the control group (4 of 47, 8.5%, p = 0.009)⁽⁴⁶⁾, and therefore the product was not licensed for this indication. It was thought that the fluid load of RSV-IGIV played a role in this complication. A multicentre trial of palivizumab that focused specifically on this population has recently been completed⁽⁴⁷⁾; six of the 76 participating sites were in Canada. The trial randomly assigned 1287 children < 24 months of age with hemodynamically significant heart disease that had not been surgically corrected or had been only partially corrected to receive placebo or palivizumab monthly for 5 months during the winter respiratory season. Monthly prophylaxis was associated with a 45% reduction in hospitalization for RSV (9.7% versus 5.3%). In Canada, the RSV hospitalization rate in placebo and prophylaxis groups was 11.9% versus 7.6%, as compared with 10.6% versus 5.9% in the United States and 7% versus 3% in Europe. These reductions were seen in children with either cyanotic or acyanotic heart disease. When compared with the placebo recipients, the palivizumab group also showed reductions in the number of days of hospitalization (129 versus 57.4 days/100 children, 56% reduction), hospital days when oxygen supplementation was required (101.5 versus 27.9 days/100 children, 73% reduction), mechanical ventilation for RSV infection (2.2 versus 1.3%, 41% reduction), and intensive care stay (71.2 versus 15.9 days/100 children, 78% reduction).

Recommended Usage 

Palivizumab has been licensed for the prevention of serious lower respiratory tract disease caused by RSV in pediatric patients at high risk of RSV disease, and NACI recommends that it be used just before and during the winter season for a maximum of five doses, as follows. 

Premature Infants 

Infants born prematurely at <= 32 weeks' gestation if they are < 6 months of chronological age at the start of, or during, the local winter season at which they are expected to be at risk of RSV infection. 

Infants with Lung Disease 

Children < 24 months of age with BPD/CLD requiring oxygen and/or medical therapy for that illness in the previous 6 months or other pulmonary disorders requiring oxygen therapy (e.g. recurrent aspiration). 

Children with Heart Disease 

Children < 24 months of age with hemodynamically significant heart disease. It is not expected that children with uncomplicated small atrial or ventricular septal defects or hemodynamically insignificant lesions, such as patent ductus arteriosus, without other risk factors would be at high risk of severe pulmonary RSV, and therefore palivizumab prophylaxis is not recommended for this population.

Children in Remote Communities 

Children born at < 35 weeks' gestation who are < 6 months of age at the start of the winter season and who live in remote northern communities may be considered for prophylaxis according to an assessment of access to medical care and other factors known to increase risk. 

Schedule and Dosage 

Palivizumab is given monthly at a dose of 15 mg/kg of body weight during the period in which the patient is expected to be at high risk of exposure to RSV. In clinical trials^(26,47) and since licensure in Europe and the United States, this period of exposure has been assumed to be 5 months during the winter season beginning in November or December, with the last dose given in March or April. If possible, the first dose of palivizumab should be given before the onset of the period of highest risk in order to provide sufficient serum concentration of antibody to confer protection. 

RSV is not a reportable disease in Canada, and therefore the population-based incidence of disease throughout the year across provinces and territories, incorporating year-to-year changes, is not known. Studies in various regions of Canada indicate that the RSV season begins between November and January^{(11,21,32,48)}, and the peak of the yearly epidemic is usually over by the end of April. Surveillance of RSV activity in the United States, conducted by a laboratory-based surveillance system in almost 50 states, indicates that season onset and conclusion dates vary widely⁽²³⁾. The median onset date tends to be later in northeastern than southern states and later still in the midwest. In the latest complete reporting year, 2000-01, the median week of onset and conclusion were 25 November and 5 May for the northeast, 9 December and 26 May for the midwest, and 2 October and 26 May for the west.

At present, there is no validated method to accurately determine when the number of isolates identified in local laboratories or the incidence of respiratory infections in the community indicates sufficient risk to initiate prophylaxis of high-risk children with monoclonal antibody in Canada. In hospital-based studies carried out by PICNIC, the occurrence of two admissions to hospital in 1 week was used to indicate that there was a sufficient amount of local community RSV illness to initiate active hospital surveillance⁽¹⁵⁾, and this seemed to occur before the annual epidemic had become established. This, in addition to local and national surveillance activities, can assist local decision making about the appropriate time to begin monthly palivizumab prophylaxis programs. Selected Canadian laboratories report RSV isolates to Health Canada weekly as part of the Respiratory Virus Detection Surveillance System; this collated information is available on the Health Canada Website, at <http://www.phac-aspc.gc.ca/bid-bmi/dsd-dsm/rvdi-divr/index.html>.

Since infection with RSV does not confer protective immunity⁽⁶⁾, it is recommended that children who become infected with RSV continue to receive monthly doses of palivizumab throughout the RSV season. 

Route of Administration 

Palivizumab is given by the intramuscular route only. Because it is given predominantly to infants, the preferred site of injection is the anterolateral thigh. If the injection volume is over 1 mL, it should be given as a divided dose. 

Booster Doses and Re-immunization 

After cardiac bypass surgery palivizumab levels fell by 58%, from a mean of 98 (sd 52) µg/mL to 41.4 (sd 33) µg/mL⁽⁴⁷⁾. Since this post-bypass concentration may be significantly below the serum concentration at which protection is achieved (> 40 µg/mL), repeat dosing of palivizumab should be given if the child remains at risk of RSV infection. 

Although most children will be eligible for prophylaxis for one season only, children with certain underlying cardiac or pulmonary conditions will be eligible for prophylaxis during a second winter season. 

Storage and Handling Requirements 

Palivizumab is supplied as a sterile lyophilized powder that is reconstituted for administration. Prior to reconstitution it should be stored between 2° C and 8° C in its original container and must not be frozen. To prepare the product for administration, sterile water is injected using an aseptic technique and the vial gently swirled for 30 seconds. The vial should not be shaken, as this may cause the diluent and dissolved powder to separate. 

Reconstituted palivizumab should stand at room temperature for at least 20 minutes until the solution clarifies or appears slightly opalescent on visual inspection. The product does not contain a preservative, and therefore the manufacturer recommends that it be used within 6 hours of reconstitution, and preferably within 3 hours of reconstitution. 

Simultaneous Administration with Other Vaccines 

Palivizumab is a passive immunizing agent with a highly specific antigen target (the F glycoprotein of RSV). It therefore does not interfere with the immune response to vaccines and can be administered at the same time at a separate site. 

Adverse Reactions 

In the randomized, double blind, placebo controlled trial of palivizumab prophylaxis in children with prematurity or CLD, rates of adverse events were similar in placebo (10%) and intervention (11%) groups⁽²⁶⁾. There were no statistically significant differences in rates of adverse events by body system, including the injection site (1.8% of the placebo group and 2.7% of the palivizumab group). Injection site reactions included erythema (1.2% versus 1.7%), pain (0.0% versus 0.3%), induration/swelling (0.2% versus 0.6%) and bruising (0.4% versus 0.3%). Injections were discontinued for an adverse event related to palivizumab in 0.3% of participants. Five children in the placebo group (1%) and four in the palivizumab group (0.4%) died during the trial for reasons judged to be unrelated to immunization. 

In children with hemodynamically significant heart disease, significant differences in adverse events were not found between groups (palivizumab versus placebo)⁽⁴⁶⁾. Rates of adverse events for fever were 27.1% (palivizumab) versus 23.9% (placebo), for infection 5.6% versus 2.9%, for injection site reaction 3.7% versus 2.2%, for arrhythmia 3.1% versus 1.7%, and for cyanosis 9.1% versus 6.9%. No drug injections in the study were discontinued because of a related adverse event. Serious adverse events, which included hospitalizations related to RSV infection, were more common in the placebo group (63.1% versus 55.4%, p = 0.005), and the incidence of cardiac surgeries classified as urgent, planned, or earlier than planned was similar in both groups. Deaths occurred in 48/1287 children: 3.3% in the palivizumab group and 4.2% in the placebo group. No serious adverse events judged to be related to palivizumab were reported. 

In open label trials and registries reported from North America and Europe, serious adverse events are not described, and the incidence of other adverse events is not higher than in the two randomized controlled trials^(49-53). A worldwide safety database maintained by Abbott Laboratories Ltd., which contains reports on 533 390 infants receiving prophylaxis in North America, Europe, and Japan, has not identified any increase in frequency of severe adverse events or deaths compared with baseline rates for high-risk premature infants (Dr. Jessie Groothuis, Global Medical Director, Immunoscience Development, Abbott Laboratories Ltd., Chicago: personal communication, 2003). The rate of allergic reactions is 0.02 cases per 1000 children, or 1 for every 35 000 palivizumab doses, with two anaphylactic events recorded. The mortality rate is 0.5/1000 patient exposures, comparable to the trial in high-risk infants with prematurity or lung disease⁽²⁶⁾.

A summary of adverse events recorded by the Food and Drug Administration Medwatch program reported palivizumab to be the most common drug cited as the principal suspect for serious or fatal outcome in children < 2 years⁽⁵⁴⁾. Because the Medwatch program is a passive surveillance system that does not collect data on the denominator of children exposed to a drug or the recipient's underlying illness, there is no evidence from this report to support a causal association between the clinical events reported and the administration of palivizumab. 

Although most children will be eligible for monthly palivizumab prophylaxis for only one winter season (five doses) some high-risk children will still be at high risk in the second year of life or beyond. Adverse immune responses, including appearance of anti-monoclonal antibody, and adverse events in children in their second season of palivizumab prophylaxis do not appear to differ from those in children receiving it for the first time⁽⁵⁵⁾. Anti-palivizumab binding in children receiving the product for one season occurred at a titre of > 1:40 in 2.8% of the placebo group and 1.2% of the palivizumab group, suggesting that the binding is non-specific⁽²⁶⁾. No palivizumab-resistant RSV viruses have been identified. 

Contraindications 

Hypersensitivity to any component of palivizumab is a contraindication to use of this product. 

Precautions 

Minor illnesses such as the common cold, with or without fever, are not contraindications to immunization. Moderate to severe illness, with or without fever, is a reason to defer routine immunization with most vaccines; this is to avoid superimposing adverse effects from the vaccine on the underlying illness, or mistakenly identifying a manifestation of the underlying illness as a complication of vaccine use. The decision to delay vaccination depends on the severity and etiology of the underlying disease.

Other Considerations 

If an entire vial (500 mg, 1 g) is not required for a patient's monthly injection, physicians should arrange for more than one patient to receive palivizumab within 6 hours in order to minimize product wastage. Weekly clinics for eligible infants in a locality may facilitate efficient immunization with minimal product wastage. 

There have been at least six economic evaluations of palivizumab using a variety of methods^(56,57). These have not found palivizumab to be cost-effective if administered to all infants for whom it is approved. 

Each province or region should determine the local epidemiology of RSV in order to plan the winter period of prophylaxis (initiation and duration) in the most efficient manner. 

Palivizumab is effective in reducing hospitalization due to RSV in infants born prematurely at 33 to 35 weeks' gestation. However, these children account for up to 5% of the birth cohort in Canada, and therefore the current cost of prophylaxis is seen to be prohibitive if gestational age is the only risk factor for a child.

Table 1.    Recommendations for palivizumab administration 

Table 2.    Levels of evidence for recommendations 

References

1. Health Canada. Canadian immunization guide, 6th ed. Ottawa: Health Canada, 2002:247. Cat. No. H49-9/2002E. 

2. Oh PI, Lanctjt KL, Yoon A et al. Palivizumab prophylaxis for respiratory syncytial virus in Canada: utilization and outcomes. Pediatr Infect Dis J 2002;21:512-18. 

3. Parrott RH, Kim HW, Arrobio JO et al. Epidemiology of respiratory syncytial virus infection in Washington, D.C. II. Infection and disease with respect to age, immunologic status, race and sex. Am J Epidemiol 1973;98:289-300. 

4. Simoes EA. Respiratory syncytial virus infection. Lancet 1999;354: 847-52. 

5. Hall C. Respiratory syncytial virus. In: Feigin R, Cherry J, eds. Textbook of pediatric infectious diseases, vol. 2. Philidelphia: WB Saunders Co, 1998:2087.

6. Glezen WP, Taber LH, Frank AL et al. Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child 1986;140: 543-46. 

7. Domachowske JB, Rosenberg HF. Respiratory syncytial virus infection: immune response, immunopathogenesis, and treatment. Clin Microbiol Rev 1999;12:298-309. 

8. Hall CB. Respiratory syncytial virus: a continuing culprit and conundrum. J Pediatr 1999;135:2-7. 

9. Langley J, Wang E, Law BJ et al. Economic evaluation of respiratory syncytial virus infection in Canadian children: a Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) study. J Pediatr 1997;131:113-17. 

10. Shay DK, Holman RC, Newman RD et al. Bronchiolitis-associated hospitalizations among US children, 1980-96. JAMA 1999;282:1440-46. 

11. Wang E, Law B, Boucher FD et al. Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) study of admission and management variation in patients hospitalized with respiratory syncytial viral lower respiratory tract infection. J Pediatr 1996;129:390-95. 

12. Opavsky MA, Stephens D, Wang EE. Testing models predicting severity of respiratory syncytial virus infection on the PICNIC RSV database. Pediatric Investigators Collaborative Network on Infections in Canada. Arch Pediatr Adolesc Med 1995;149:1217-20. 

13. Law B, MacDonald N, Langley J et al. Severe respiratory syncytial virus infection among otherwise healthy prematurely born infants: What are we trying to prevent? Paediatr Child Health 1998;3:402-404. 

14. Law B, Wang E, MacDonald N et al. Does ribavirin impact on the hospital course of children with respiratory syncytial virus (RSV) infection? An analysis using the Pediatric Investigators Collaborative Network in Infections in Canada database. Pediatrics 1997;99:e7. URL: <http://www.pediatrics.org/cgi/content/full/99/3/e7>. 

15. Law BJ, De Carvalho V, Pediatric Investigators Collaborative Network on Infections in Canada. Respiratory syncytial virus infections in hospitalized Canadian children: regional differences in patient populations and management practices. Pediatr Infect Dis J 1993;12:659-63. 

16. Langley J, LeBlanc J, Wang E et al. Nosocomial respiratory syncytial virus infection in Canadian pediatric hospitals: a Pediatric Investigators Collaborative Network on Infections in Canada study. Pediatrics 1997;100:943-46. 

17. Groothuis JR, Gutierrez KM, Lauer BA. Respiratory syncytial virus infection in children with bronchopulmonary dysplasia. Pediatrics 1988;82:199-203. 

18. McCormick MC, Shapiro S, Starfield BH. Rehospitalization in the first year of life for high-risk survivors. Pediatrics 1980;66:991-99. 

19. Lee SK, McMillan DD, Ohlsson A et al. Variations in practice and outcomes in the Canadian NICU network: 1996-1997. Pediatrics 2000;106:1070-79. 

20. Arnold S, Wang E, Law B et al. Variable morbidity of respiratory syncytial virus infection in patients with underlying lung disease: a review of the PICNIC RSV database. Pediatr Infect Dis J 1999;18:866-69. 

21. Banerji A, Bell A, Mills EL et al. Lower respiratory tract infections in Inuit infants on Baffin Island. Can Med Assoc J 2001;164:1847-50. 

22. Orr P, Macdonald S, Milley D et al. Bronchiolitis in Inuit children from a Canadian Central Arctic community, 1995-1996. Int J Circumpolar Health 2001;60:649-58. 

23. Bockova J, O'Brien KL, Oski J et al. Respiratory syncytial virus infection in Navajo and White Mountain Apache children. Pediatrics 2002;110:e20. 

24. Karron RA, Singleton RJ, Bulkow L et al. Severe respiratory syncytial virus disease in Alaska native children. RSV Alaska Study Group. J Infect Dis 1999;180:41-9. 

25. Joffe S, Escobar GJ, Black SB et al. Rehospitalization for respiratory syncytial virus among premature infants. Pediatrics 1999;104:894-99. 

26. The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998;102:531-37. 

27. The PREVENT Study Group. Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis. Pediatrics 1997;99:93-9.

28. Carbonell-Estrany X, Quero J. Hospitalization rates for respiratory syncytial virus infection in premature infants born during two consecutive seasons. Pediatr Infect Dis J 2001;20:874-79.

29. Carbonell-Estrany X, Quero J, Bustos G et al. Rehospitalization because of respiratory syncytial virus infection in premature infants younger than 33 weeks of gestation: a prospective study. IRIS Study Group. Pediatr Infect Dis J 2000;19:592-97. 

30. Fixler DE. Respiratory syncytial virus infection in children with congenital heart disease: a review. Pediatr Cardiol 1996;17:163-68. 

31. MacDonald NE, Hall CB, Suffin SC et al. Respiratory syncytial viral infection in infants with congenital heart disease. N Engl J Med 1982;307:397-400. 

32. Navas L, Wang E, de Carvalho V et al. Improved outcome of respiratory syncytial virus infection in a high-risk hospitalized population of Canadian children. J Pediatr 1992;121:348-54. 

33. Moler FW, Khan AS, Meliones JN et al. Respiratory syncytial virus morbidity and mortality estimates in congenital heart disease patients: a recent experience. Crit Care Med 1992;20:1406-13. 

34.  Khongphatthanayothin A, Wong PC, Samara Y et al. Impact of respiratory syncytial virus infection on surgery for congenital heart disease: postoperative course and outcome. Crit Care Med 1999;27:1974-81. 

35. Altman CA, Englund JA, Demmler G et al. Respiratory syncytial virus in patients with congenital heart disease: a contemporary look at epidemiology and success of preoperative screening. Pediatr Cardiol 2000;21:433-38. 

36. Falsey AR, Walsh EE. Respiratory syncytial virus infection in adults. Clin Microbiol Rev 2000;13:371-84. 

37. Hall CB. Respiratory syncytial virus and parainfluenza virus. N Engl J Med 2001;344:1917-28. 

38. Glezen WP, Paredes A, Allison JE et al. Risk of respiratory syncytial virus infection for infants from low-income families in relationship to age, sex, ethnic group, and maternal antibody level. J Pediatr 1981;98:708-15. 

39. Dowell SF, Anderson LJ, Gary HE, Jr et al. Respiratory syncytial virus is an important cause of community-acquired lower respiratory infection among hospitalized adults. J Infect Dis 1996;174:456-62. 

40. Sommerville R. Respiratory syncytial virus in acute exacerbations of chronic bronchitis. Lancet 1963;2:1247-48. 

41. Han LL, Alexander JP, Anderson LJ. Respiratory syncytial virus pneumonia among the elderly: an assessment of disease burden. J Infect Dis 1999;179:25-30. 

42. Thompson WW, Shay DK, Weintraub E et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003;289:179-86. 

43. Moscona A. Management of respiratory syncytial virus infections in the immunocompromised child. Pediatr Infect Dis J 2000;19:253-54. 

44. Johnson S, Oliver C, Prince GA et al. Development of a humanized monoclonal antibody (MEDI-493) with potent in vitro and in vivo activity against respiratory syncytial virus. J Infect Dis 1997;176:1215-24. 

45. Saez-Llorens X, Castano E, Null D et al. Safety and pharmacokinetics of an intramuscular humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia. The MEDI-493 Study Group. Pediatr Infect Dis J 1998;17:787-91. 

46. Simoes EA, Sondheimer HM, Top FH, Jr et al. Respiratory syncytial virus immune globulin for prophylaxis against respiratory syncytial virus disease in infants and children with congenital heart disease. The Cardiac Study Group. J Pediatr 1998;133:492-99. 

47. Feltes TF, Cabalka AK, Meissner HC et al. Palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically significant heart disease. J Pediatr 2003 (in press). 

48. Bollegraaf E. Infections due to respiratory syncytial virus in Canada. Can Med Assoc J 1987;136:159-60. 

49. Parnes C, Habersang R, Nicholes P et al. Palivizumab prophylaxis of respiratory syncytial virus disease in 2000-2001: results from the Palivizumab Outcomes Registry. Pediatr Pulmonol 2003;35:484-89. 

50. Carbonell-Estrany X. Palivizumab outcomes registry data from Spain: Infeccion Respiratoria Infantil por Virus Respiratorio Sincitial (IRIS) Study Group. Pediatr Infect Dis J 2003;22:S55-7. 

51. Romero JR. Palivizumab prophylaxis of respiratory syncytial virus disease from 1998 to 2002: results from four years of palivizumab usage. Pediatr Infect Dis J 2003;22:S46-54. 

52. Lacaze-Masmonteil T, Roze JC, Fauroux B. Incidence of respiratory syncytial virus-related hospitalizations in high-risk children: follow-up of a national cohort of infants treated with palivizumab as RSV prophylaxis. Pediatr Pulmonol 2002;34:181-88.

53. Groothuis JR. Safety and tolerance of palivizumab administration in a large Northern Hemisphere trial. Northern Hemisphere Expanded Access Study Group. Pediatr Infect Dis J 2001;20:628-30. 

54. Moore TJ, Weiss SR, Kaplan S et al. Reported adverse drug events in infants and children under 2 years of age. Pediatrics 2002;110:e53. 

55. Lacaze-Masmonteil T, Seidenberg J, Mitchell I et al. Evaluation of the safety of palivizumab in the second season of exposure in young children at risk for severe respiratory syncytial virus infection. Drug Safety 2003;26:283-91. 

56. Klassen TP. Economic evaluations of immunoprophylaxis in infants at high risk for respiratory syncytial virus: shedding light or creating confusion? Arch Pediatr Adolesc Med 2002;156:1180-81. 

57. Kamal-Bahl S, Doshi J, Campbell J. Economic analyses of respiratory syncytial virus immunoprophylaxis in high-risk infants: a systematic review. Arch Pediatr Adolesc Med 2002;156:1034-41.

[Canada Communicable Disease Report] [Table of Contents] [Next]