Several randomized clinical trials have demonstrated the success of immune prophylaxis of respiratory syncytial virus (RSV). A systematic review was conducted in the United Kingdom to evaluate the effectiveness of palivizumab for the prevention of RSV in children. (2) Two randomized controlled trials (RCTs) were identified in the review. (3, 4) In the 1998 Impact-RSV Study Group, prophylaxis with palivizumab for preterm infants without chronic lung disease (CLD) or children with CLD resulted in a 55% reduction in RSV hospital admission; 4.8% (48/1,002) in the palivizumab group and 10.6% (53/500) in the no prophylaxis group. (3) Similar reductions in other measures of RSV severity in breakthrough infections were also reported. In a 2003 double-blind, placebo-controlled randomized trial of 1,287 children with hemodynamically significant CHD, Feltes et al. reported prophylaxis with palivizumab was associated with a 45% reduction in hospitalization rate for RSV among children with congenital heart disease (CHD). (4) Hospitalization rates for RSV were 5.3% (34/639) in the palivizumab group and 9.7% (63/648) in the no prophylaxis group. The authors concluded that prophylaxis with palivizumab is clinically effective for reducing the risk of serious lower respiratory tract infection caused by RSV infection and requiring hospitalization in high-risk children.
In 1997, the PREVENT Study Group reported on a trial that randomly assigned 510 infants with prematurity or CLD to receive either placebo or RSV-intravenous immunoglobulin (IVIg) infusions monthly for 5 months. The authors reported a 41% reduction in hospitalization due to RSV infection and reductions in other measures of severity of RSV infection when it did occur. (5) Palivizumab eventually became the preferred product over the IVIg product due to the convenience of intramuscular administration, safety concerns regarding immunoglobulin pooled from multiple donors, and the unlimited supply of a bioengineered product.
In 1998, the American Academy of Pediatrics (AAP) published revised guidelines regarding the use of RSV-IVIg or palivizumab for RSV immune prophylaxis, which focused on infants with chronic lung disease and preterm infants. (6) In 2003, the AAP Red Book, which summarizes immunization recommendations and the AAP policy statement on the prevention of RSV, added indications for children with hemodynamically significant heart disease. (7)
Immune prophylaxis has also been suggested for patients 24 months of age or younger with congenital heart disease (CHD). The AAP guidelines note that children with cyanotic CHD who received RSV-IVIg and underwent cardiac surgery appeared to experience an increased surgical mortality rate. Therefore, according to the AAP guidelines, RSV-IVIg is contraindicated in children with cyanotic CHD. The AAP guidelines indicate the use of palivizumab in children with CHD should be based on the degree of cardiovascular compromise. Infants with CHD who are younger than 24 months may benefit from palivizumab if they are receiving medication for heart failure, have moderate-to-severe pulmonary hypertension, or have cyanotic heart disease.
The 2003 recommendation by the AAP (6) was based on the results of the Feltes RCT noted above. (4) In 2009, AAP updated its guidelines regarding the use of immune prophylaxis for RSV. The updated guidelines were published in the new AAP Red Book 2009 in the chapter on RSV. (8) The following is a summary, provided by the AAP, of the major changes to the guidelines:
- “Recommendations for initiation and termination of prophylaxis are modified to reflect current CDC [Centers of Disease Control and Prevention] descriptions of RSV seasonality in different geographic locations within the United States.
- The recommendations remain unchanged for infants with congenital heart disease, chronic lung disease of prematurity and birth before 32 weeks' gestation.
- Regardless of the month when the first dose is administered, the recommendation for a maximum number of 5 doses for all geographic areas is emphasized for infants with hemodynamically significant congenital heart disease, chronic lung disease of prematurity or birth before 32 weeks' gestation and for a maximum number of 3 doses for infants with a gestational age of 32 to 35 weeks without hemodynamically significant congenital heart disease or chronic lung disease.
- Risk factors for severe RSV lower respiratory tract disease among infants born between 32 to 35 weeks' gestation have been modified to include only:
- Infant attends child care
- Siblings living in the household are less than 5 years of age
- Infants 32 to 35 weeks' gestation age who are born within the 3 months before the onset of RSV season and throughout the RSV season will qualify for prophylaxis if they have at least one [of the modified] risk factors. Earlier recommendations required 2 of 5 [different] risk factors.
- Infants who qualify for prophylaxis in the 32 to 35 weeks' gestation age group should receive prophylaxis only until they reach 90 days of age or a maximum of 3 doses (whichever comes first). This is a change from the previous recommendation for 5 months of prophylaxis.
- The AAP's definition of gestational age is used throughout this document. For example, 32 to 35 weeks' gestation is defined as 32 weeks, 0 days through 34 weeks, 6 days.”
In August 2009, AAP released a policy statement (including references and evidence grading) that supported their revised indications for the use of palivizumab for the prevention of respiratory syncytial virus infections. (9) In commenting on their 2009 recommendations, the AAP policy statement indicates, "they [the 2009 AAP recommendations] specifically target infants in this [32 to less than 35 weeks' gestational age] with consistently identified risk factors for RSV hospitalization during the period of greatest risk, which is the first 3 months of life.”
In 2008, Cohen and colleagues evaluated the characteristics of patients (n=19,548) enrolled in The Palivizumab Outcomes Registry with CHD over the 4 RSV seasons. (10) The Palivizumab Outcomes Registry prospectively collected data on patients who received RSV prophylaxis with palivizumab during the 2000–2004 RSV seasons. The percentage of registry subjects with CHD increased from 4.8% (102/2,116) in the first season to 11.4% (688/6,050) in the last season. Across all 4 seasons, 1,500 subjects with CHD were enrolled; 71% of whom had acyanotic CHD. The proportion with cyanotic CHD increased from 19.6% (20/102) in the 2000–2001 season to 37.5% (258/688) in the 2003–2004 season, while the proportion of all CHD in the registry more than doubled during this time. The cumulative RSV hospitalization rate was 1.9% among patients with CHD who received prophylaxis. Among subjects with cyanotic and acyanotic CHD, hospitalization rates were 2.6% and 1.6%, respectively. The authors concluded, “…the prospective data collected in the Palivizumab Outcomes Registry provides the largest published dataset available on infants with CHD receiving palivizumab; shows low hospitalization rates, use consistent with prelicensure clinical trial data and the revised American Academy of Pediatrics guidelines.”
A review article discussed the development of a second-generation humanized monoclonal antibody (mAb), motavizumab, which is no longer under study in Phase III clinical trials, and most recently, a third generation mAb, Numax-YTE. (11)
A Cochrane review was published in 2010 and updated in 2012, assessing the use of palivizumab in children with cystic fibrosis. (12, 13) One randomized comparative trial met the inclusion criteria of both reviews. In the study, 186 infants younger than 2 years with cystic fibrosis were randomly assigned to receive 5 monthly doses of palivizumab (n=92) or placebo (n=94). One member of each group was hospitalized for RSV within the 6-month follow-up period. The rate of adverse event noted in each group was relatively high, with serious adverse events not significantly different between the palivizumab and placebo groups (20.2% and 17.3%, respectively). The authors noted that it was not possible to draw conclusions on the tolerability and safety of RSV immune prophylaxis in cystic fibrosis. The single study reported similar adverse events but did not specify how adverse events were classified. No clinically meaningful outcome differences were noted at 6-month follow-up. The authors of the review called for additional randomized studies to establish both efficacy and safety of immune prophylaxis in children with cystic fibrosis.
The use of RSV-IVIg or palivizumab in patients with documented immunodeficiencies has also been suggested. The AAP guidelines note, "Palivizumab or RSV-IVIg has not been evaluated in randomized trials in immunocompromised children. Although specific recommendations for immunocompromised patients cannot be made, children with severe immunodeficiencies (e.g., severe combined immunodeficiency or severe acquired immunodeficiency syndrome) may benefit from prophylaxis. If these infants and children are receiving standard immune globulin intravenous monthly, physicians may consider substituting RSV-IVIg during the RSV season."
Immunocompromised patients undergoing stem-cell transplantation are also at risk for potentially lethal respiratory viral infections. Cortez and colleagues studied whether RSV-IVIg provided sufficient RSV immune prophylaxis to prevent RSV pneumonia in 54 patients undergoing stem-cell transplantation. (14) The authors reported a low incidence of RSV infection in the 54 RSV-IVIg patients, as well as in 31 patients not enrolled in the study, and could not determine the preventive effect of RSV-IVIg. In a literature review, Hynicka and Ensor found data are limited on RSV prophylaxis in immunocompromised adult patients. (15) The only prospective study identified in the review was by Kassis et al. (16) in which intravenous pavilizumab was given to 16 high-risk stem-cell transplant patients to prevent the nosocomial spread of RSV infection from 5 stem-cell transplant patients. After one week, no further RSV cases occurred, but whether controlling the spread of RSV on the stem-cell transplant unit was related to RSV prophylaxis versus implementation of strict quarantine and infection control practices cannot be determined.
Duration of Prophylaxis
The RSV season typically occurs from November to April. Within the United States, the inevitability of the RSV season is predicable, but the severity of the season and time of onset are variable from year to year and also between geographic areas within a given year. This has led to requests for either earlier or later immunoprophylaxis, or greater than 5 monthly doses. Nevertheless, as pointed out by Meissner and colleagues from the Centers of Disease Control and Prevention (CDC), “…this yearly and regional variation still occurs within the overall pattern of RSV outbreaks, usually beginning in November or December, peaking in January or February, and ending by March. Communities in the southern region tend to experience the earliest onset of RSV activity, and Midwestern states tend to experience the latest onset, but community to community variation in timing precludes using either national or regional data to precisely predict individual community RSV outbreaks. The duration of the season for western and northeast regions typically occurs between that noted in the South and the Midwest.” The authors point out that the recommendation for 5 monthly doses is derived from the randomized studies of palivizumab. A serum palivizumab concentration of greater than 30 μg/mL is the target level for protection, and in randomized studies, the trough level of palivizumab exceeded 30 μg/mL for at least 30 days after the fifth dose. This indicates that 5 monthly doses will provide substantially more than 20 weeks of protective serum antibody levels, covering most of the RSV season even with variation in season onset and end. (17)
Frogel and colleagues reviewed the medical literature on compliance with palivizumab therapy and the relation between hospitalization rates in fully compliant and less compliant groups. (18) A total of 25 articles and abstracts met review inclusion criteria. Significant heterogeneity was detected due to between-study differences in the population studied and the definition of compliance used. Differences in compliance definitions led to a compliance rate range of 25% to as high as 100%, compared to rates in licensing studies of 92% and 93%. This led the authors to the conclusion that compliance in practice is far more variable. Minorities and patients on Medicaid were less likely to receive the full complement of palivizumab doses, while patients participating in a home health program tended to have higher compliance and less hospitalization. Home health programs were defined as nurse-delivered injections performed in the home setting.
RSV is the most common cause of lower respiratory infections in children. At highest risk are those younger than 2 years of age with prematurity, CLD [formerly known as bronchopulmonary dysplasia]), congenital heart disease, or multiple congenital anomalies. Immune prophylaxis against RSV is a prevention strategy to reduce the incidence of infection and its associated morbidity, including hospitalization, in high-risk infants.
Based on the weight of the clinical evidence from randomized clinical trials, systematic reviews and strong clinical consensus, immune prophylaxis for RSV has demonstrated reductions in RSV-related hospitalizations in select populations of susceptible infants and children; therefore, immune prophylaxis for RSV may be considered medically necessary for those patients, as listed in the Coverage section above. For all other uses of immune prophylaxis, the clinical evidence is not convincing that RSV hospitalizations will decrease. Therefore, the Coverage section above notes indications that are considered not medically necessary, or experimental, investigational and unproven. The Coverage statements are in agreement with the 2009 AAP Guidelines.
Practice Guidelines and Position Statements
In 2003, the AAP released a policy statement with revised indications for the use of palivizumab and RSV-IVIg for the prevention of RSV infections. (7)
In June 2009, the AAP released updated guidelines regarding the use of immune prophylaxis for RSV. The updated guidelines were published in the new AAP Red Book 2009 in the chapter on RSV. (8)
In August 2009, the AAP released a policy statement (including references and evidence grading) with revised indications for the use of palivizumab for the prevention of RSV infections. (9)
In 2012, the AAP released their 2012 Red Book; the 2012 Red Book does not have any changes that would alter the Coverage position of this policy. (19)
In 2008, Department of Public Health and Epidemiology, University of Birmingham, Birmingham, UK, released a Health Technology Assessment on immunoprophylaxis against RSV with palivizumab in children. (2) The authors concluded that prophylaxis with palivizumab is clinically effective for the reducing the risk of serious lower respiratory tract infection caused by RSV infection and requiring hospitalization in high-risk children.
Disclaimer for coding information on Medical Policies
Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.
The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.
Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.