Aetna considers palivizumab (Synagis™) medically necessary for prophylaxis of respiratory syncytial virus (RSV), in infants and children who are less than 2 years of age at the start of RSV season with chronic lung disease of prematurity (CLD [formerly known as broncho-pulmonary dysplasia or BPD]) who have required medical therapy (supplemental oxygen, bronchodilator, and diuretic or corticosteroid therapy) for their CLD within 6 months before the anticipated RSV season†.
Aetna considers palivizumab medically necessary for prophylaxis of RSV in infants and children with any of the following conditions:
Infants born at 31 weeks, 6 days gestation or earlier (with or without CLD)*:
Infants born at 28 weeks, 6 days of gestation or earlier and who are younger than 12 months of age at the start of RSV season; or
Infants born at 29 weeks, 0 days through 31 weeks, 6 days of gestation and who are younger than 6 months of age at the start of RSV season; or
Infants born at 32 weeks, 0 days through 34 weeks, 6 days of gestation and who are younger than 3 months of age at the start of RSV season** when at least one of the following 2 risk factors is present:
Child care attendance outside the home (defined as a home or facility where care is provided for any number of infants or young toddlers in the child care facility); or
Sibling younger than 5 years of age at the start of RSV season.
Infants who have either congenital abnormalities of the airway or a neuromuscular condition that compromises handling of respiratory secretions during the first year of life.†
Infants and children with severe immunodeficiencies who are less than 2 years of age at the start of the RSV season (e.g., severe combined immunodeficiency or severe acquired immunodeficiency syndrome, acute myeloid leukemia/acute lymphoblastic leukemia, hematopoietic stem cell transplant recipients); or
Infants and children with hemodynamically significant cyanotic or acyanotic congenital heart disease who are 2 years of age or younger at the onset of the RSV season†, including the following:
Infants receiving medication to control congestive heart failure; or
Infants with moderate to severe pulmonary artery hypertension; or
Infants with cyanotic congenital heart disease.
Aetna considers an additional dose of palivizumab medically necessary after surgical procedures that require cardiopulmonary bypass for children 2 years of age or younger who still require prophylaxis.
Aetna considers palivizumab experimental and investigational for all other indications (e.g., active RSV infection treatment, cystic fibrosis prophylaxis, prophylaxis against RSV in immunocompromised adults, and use in recipients of hematopoietic stem cell transplants who do not otherwise meet criteria above; not an all inclusive list) because its effectiveness for these indications has not been established.
Aetna considers home administration of palivizumab a medically necessary alternative to office- or clinic-based administration.
Aetna considers palivizumab is of no proven value for infants with the following congenital heart disease conditions:
Hemodynamically insignificant heart disease (e.g., secundum atrial septal defect; small ventricular septal defect (VSD); pulmonic stenosis; uncomplicated aortic stenosis; mild coarctation of the aorta; and patent ductus arteriosus); or
Infants with lesions adequately corrected by surgery unless they continue to require medication for congestive heart failure; or
Infants with cardiomyopathy who are not receiving medical therapy for the condition.
According to the American Academy of Pediatrics (AAP, 2009), these infants generally should not receive immunoprophylaxis because they are not at increased risk of RSV.
Aetna considers administration of palivizumab more frequently than monthly (every 30 days) not medically necessary.
*For infants born at 31 weeks, 6 days gestation or earlier (with or without CLD) and who are less than 12 months of age at the start of RSV season, administration should continue throughout the season and not stop at the point an infant reaches either 6 months (infants born at 29 weeks, 0 days through 31 weeks, 6 days of gestation) or 12 months of age (infants born at 28 weeks, 6 days of gestation or earlier). A maximum of 5 monthly doses is recommended for infants in this category.
**Infants born at 32 weeks, 0 days through 34 weeks, 6 days and who are younger than 3 months of age at the start of RSV season and who qualify for initiation, should receive a maximum of 3 monthly doses and administration should stop at the point the infant reaches 3 months of age.
*** AAP (2012) stated "passive household exposure to tobacco smoke has not been associated with an increased risk of RSV hospitalization on a consistent basis. Exposure to tobacco smoke must be controlled by families with infants, especially with infants who are at increased risk of RSV disease. Such preventive measures will be far less costly than palivizumab prophylaxis.”
**** In most areas of the United States, the usual time for the beginning of RSV outbreaks is November or December, with RSV activity peaking in January or February, and RSV outbreaks ending by the end of March or sometime in April, but regional differences occur (AAP, 2012). The onset of RSV season occurs earlier in southern states than in northern states (see Appendix). To determine if there is an RSV outbreak in a geographic area, please refer to CDC surveillance summaries for RSV published in the Morbidity and Mortality Weekly Report at http://www.cdc.gov/rsv/research/us-surveillance.html, or http://www.cdc.gov/surveillance/nrevss/rsv/state.html.
†A maximum of 5 monthly doses is recommended for infants in this category (AAP, 2012).
According to AAP (2012), hospitalized infants who qualify for prophylaxis during the RSV season should receive the first dose of palivizumab 48 to 72 hours before discharge or promptly after discharge. Thus, any palivizumab doses received prior to discharge from a hospital stay (e.g., NICU, nursery) count as one of the seasonal doses.
Palivizumab (Synagis), a humanized monoclonal antibody, is administered by intramuscular injection in monthly doses of 15 mg/kg body weight. Palivizumab is administered once a month (i.e., every 30 days) during the respiratory syncytial virus (RSV) season.
Results from clinical trials indicate that palivizumab trough serum concentrations greater than 30 days after the 5th dose will be well above the protective concentration for most infants. If the first dose is administered in November, 5 monthly doses of palivizumab will provide substantially more than 20 weeks of protective serum antibody concentrations for most of the RSV season, even with variation in season onset and end.
The American Academy of Pediatrics (AAP, 2009) stated "[c]hildren who qualify for palivizumab prophylaxis for the entire RSV season (infants and children with CLD or congenital heart disease or preterm infants born before 32 weeks’ gestation) should receive palivizumab only during the 5 months following the onset of RSV season in their region (maximum of 5 doses), which should provide coverage during the peak of the season, when prophylaxis is most effective." The onset of the RSV season typically occurs in November.
In a review, Meissner et al (2004) explained that strategies that focus administration of palivizumab during months when RSV infection is most likely to occur should protect the patient from RSV disease and avoid unnecessary waste.
Meissner et al (2004) explained that most hospitalizations for bronchiolitis occur during the RSV season: "Data on likely RSV-associated hospitalizations suggest that RSV disease matches the conclusions from RSV-detection data; 81 % of hospitalizations due to bronchiolitis in infants and young children occur from November through April. Bronchiolitis outbreaks are correlated closely with RSV detection, and many prospective studies have found that most hospitalizations for bronchiolitis are caused by RSV."
Meissner et al (2004) cited evidence supporting the AAP position that 5 monthly doses of palivizumab will provide effective protection during the RSV season, even with variations in the onset and end of the season: "The recommendation for 5 monthly doses of palivizumab was derived from the design of clinical trials with both RespiGam and palivizumab. In the IMpact-RSV trial and in the trial involving children with hemodynamically significant congenital heart disease, 5 monthly doses of palivizumab resulted in serum concentrations 30 µg/ml for over 20 weeks in almost all subjects. A serum palivizumab concentration 30 µg/ml is the proposed serologic correlate of protection, derived from animal models, in which this concentration results in a decrease in pulmonary RSV replication by more than 100-fold. One month after the 4th monthly dose of palivizumab, the mean serum trough concentration was 72 µg/ml among subjects in the IMpact-RSV trial and 90 µg/ml in subjects in the cardiac trial, indicating that the trough serum level more than 30 days after the 5th dose will be greater than 30 µg/ml for most children. Thus, for most infants, 5 monthly doses of palivizumab will provide substantially over 20 weeks of serum antibody levels, which should be protective and cover most of the RSV season even with variation in season onset and end."
Meissner et al (2004) stated that "it is important to remember that results from antigen detection assays do not provide an adequate basis for determination of onset and offset of the RSV season." Meissner et al explained that RSV antigen detection assays may overestimate the risk of RSV outside of the RSV season, as the positive predictive value of a test decreases as disease incidence goes down. Because the sensitivity and specificity of antigen-detection assays are low both at the onset and the end of the season, the risk to the child in these periods will be less than that predicted by RSV detection using antigen-based assays.
Although there have been reports of year-round prevalence of RSV in certain localities (e.g., Chattanooga, TN, South Florida), these reports are based on antigen detection assays, which are only reliable during periods of extremely high population prevalence (Meissner, 2005). During periods of relatively low RSV prevalence, antigen detection assays are associated with false positive rates greater than 50 %, and no good correlation with actual disease prevalence in the community or with clinical risk to patients.
Children with more severe chronic lung disease may benefit from prophylaxis for 2 RSV seasons, especially those who require medical therapy. Children with less severe underlying disease may benefit only for the first season. Decisions regarding individual patients may need additional input from neonatologists, intensivists, or pulmonologists.
The literature also suggests that infants born at 32 weeks of gestation or earlier without chronic lung disease of prematurity (CLD) may also benefit from RSV prophylaxis. In these infants, major risk factors to consider are gestational age and chronologic age at the start of the RSV season. Infants born at 28 weeks of gestation or earlier may benefit from prophylaxis up to 12 months of age. Infants born at 29 to 32 weeks gestation may benefit most from prophylaxis up to 6 months of age.
Palivizumab is not approved by the Food and Drug Administration (FDA) for patients with congenital heart disease (CHD). However, a recent multi-center, prospective, controlled clinical trial demonstrated that palivizumab significantly reduced the rate of hospitalizations, hospital days, and days of increased oxygen usage in children with serious CHD. Children born with serious CHD who have decreased cardiac or pulmonary reserve appear to be at highest risk of serious RSV infection. These children have been shown to require intensive care and use mechanical ventilation more frequently than children who do not have CHD. A 4-year, double-blind, placebo-controlled study was designed to assess the safety and efficacy of palivizumab in children less than 2 years of age with serious CHD. The study was conducted at 76 centers in North America and Europe, and involved 1,287 children who were randomized to receive 5 monthly intramuscular injections (15 mg/kg) of either palivizumab or placebo during the RSV season. Compared to placebo, the palivizumab group had 45 % fewer hospitalizations due to RSV (p = 0.003). The data showed significantly fewer RSV-related hospital days (p = 0.003) and fewer days of increased oxygen usage (p = 0.014) in the treated group than in the placebo group. The proportions of subjects in the placebo and palivizumab groups who experienced any adverse events were similar.
According to the AAP Committee on Infectious Diseases, decisions regarding the use of palivizumab prophylaxis in children with congenital heart disease should be made on the basis of the degree of physiological cardiovascular impairment. Infants most likely to benefit from immunoprophylaxis include those receiving medication to control congestive heart failure, those with moderate to severe pulmonary artery hypertension, and infants with cyanotic heart diseases. A decrease in the serum concentration of palivizumab by a mean of 58 % has been reported after surgical procedures that use cardiopulmonary bypass. Thus, after surgical procedures that use cardiopulmonary bypass, the AAP recommends a post-operative dose of palivizumab (15 mg/kg) be considered for children 2 years of age or less who still require prophylaxis as soon as the patient is medically stable. The AAP (2012) concluded that the following groups of infants are not at increased risk of RSV and generally should not receive immunoprophylaxis: infants with hemodynamically insignificant heart disease (e.g., secundum atrial septal defect) small ventricular septal defect (VSD), pulmonic stenosis, uncomplicated aortic stenosis, mild coarctation of the aorta, and patent ductus arteriosus). In addition, prophylaxis is not necessary in infants with lesions adequately corrected by surgery unless they continue to require medication for congestive heart failure, and infants with mild cardiomyopathy who are not receiving medical therapy for their condition.
Chang and Chen (2010) evaluated the impact of palivizumab prophylaxis on RSV hospitalizations among children with hemodynamically significant CHD. In 2003, the AAP revised the bronchiolitis policy statement and recommended palivizumab in children less than 24 months old with hemodynamically significant CHD (HS-CHD). California statewide hospital discharge data from years 2000 to 2002 (pre-AAP policy revision) were compared to those from years 2004 to 2006 (post-AAP policy revision). Hospitalizations due to RSV bronchiolitis for children less than 2 years of age were identified by IDC-9 CM codes 4661.1, 480.1, and 079.6 as the principal diagnosis. Children with CHD and children with HS-CHD were identified by the co-diagnoses. The overall RSV hospitalization rate was 71 per 10,000 children less than 2 years of age. Of all RSV hospitalizations, 3.0 % were among children with CHD, and 0.50 % among children with HS-CHD. HS-CHD patients accounted for 0.56 % of RSV hospitalizations in 2000 to 2002, compared to 0.46 % RSV hospitalizations in 2004 to 2006. That represents a 19 % reduction in RSV hospitalizations among HS-CHD patients after 2003. The 19 % decrease in RSV hospitalizations equates to 7 fewer hospitalizations (76 hospital days) per year among HS-CHD patients. The authors concluded that since the recommendation of palivizumab for children with HS-CHD in 2003, the impact on RSV hospitalizations in California among HS-CHD patients has been limited. Considering the high cost of palivizumab administration, the cost-benefit of RSV prophylaxis with palivizumab warrants further investigation.
Palivizumab prophylaxis has not been evaluated in randomized trials in immunocompromised children. Although specific recommendations for immunocompromised patients can not be made, the literature indicates that children with severe immunodeficiencies (e.g., severe combined immunodeficiency or severe acquired immunodeficiency syndrome) may benefit from prophylaxis.
Respiratory syncytial virus is known to be transmitted in the hospital setting and to cause serious disease in high-risk infants. In high-risk hospitalized infants, the major means to prevent RSV disease is strict observance of infection control practices, including the use of rapid means to identify and cohort RSV-infected infants. If an RSV outbreak is documented in a high-risk unit (e.g., pediatric intensive care unit), accepted guidelines indicate that primary emphasis should be placed on proper infection control practices. The need for and efficacy of prophylaxis in these situations has not been evaluated.
The AAP guidelines (2003) stated that one of the risk factors for complications from RSV infection is exposure to environmental air pollutants. This was meant to refer only to indoor air pollutants (i.e., wood stoves, indoor combustion of unprocessed solid fuels). The AAP Red Book (2012) stated: "Infants, especially those at high risk, never should be exposed to tobacco smoke. Tobacco smoke is a known risk factor for many adverse health-related outcomes. However, in published studies, passive household exposure to tobacco smoke has not been associated with an increased risk of RSV hospitalization on a consistent basis. Exposure to tobacco smoke must be controlled by families with infants, especially with infants who are at increased risk of RSV disease. Such preventive measures will be far less costly than palivizumab prophylaxis."
The AAP guidelines (2012) noted that limited studies suggest that some patients with cystic fibrosis (CF) may be at increased risk of RSV infection. However, there are insufficient data to determine the effectiveness of palivizumab use in this patient population. Therefore, a recommendation for routine prophylaxis in patients with CF can not be made. Furthermore, the European Cystic Fibrosis Society Vaccination Group (Malfroot et al, 2005) stated that there are no recommendations for palivizumab in CF as an alternative but expensive prophylaxis.
Giebels and colleagues (2008) stated that in CF patients, RSV infection is associated with significant morbidity. Although passive prophylaxis with palivizumab lowers hospitalization rate for RSV infection in populations at risk of severe infection, its use is not recommended in infants with CF disease. In a retrospective study, these researchers examined the effect of palivizumab prophylaxis on hospitalization for acute respiratory illness in young children with CF during the first RSV season following the diagnosis of CF. Medical records of patients diagnosed with CF between the years 1997 and 2005 inclusively and on whom the diagnosis was made before 18 months of age were reviewed. Collected data included age at diagnosis, palivizumab prophylaxis, occurrence of hospitalization for acute respiratory tract illness during the RSV season and identification of RSV infection. A diagnosis of CF was made in 76 young children and data collected from 75 children. Of those, 40 did not receive RSV prophylaxis while 35 received palivizumab injection monthly during the RSV season. Among non-recipient children, 7 out of 40 were hospitalized for acute respiratory illness during the RSV season. Of these 7 patients, RSV detection was positive in naso-pharyngeal secretions in 3 patients, negative in 1 patient and not requested in the others. Among palivizumab recipients, 3 out of 35 children were hospitalized for acute respiratory illness (p > 0.05 compared to non-recipients group). In these 3 palivizumab recipients, RSV detection was negative in naso-pharyngeal secretions. Palivizumab recipients experienced fewer hospital days per patient for acute respiratory illness (mean +/- SD: 0.8 +/- 3.07 days) as compared to non-recipients (mean +/- SD: 1.73 +/- 4.27 days); but this difference did not reach statistical significance. The authors concluded that CF infants may benefit from RSV immunoprophylaxis with palivizumab.
Speer and associates (2008) noted that the Palivizumab Outcomes Registry collected data on 19,548 high-risk infants who received 1 or more dose(s) of palivizumab and followed prospectively from 2000 through 2004. A total of 91 children with CF were identified who received palivizumab off-label. None of the infants with CF who received prophylaxis was hospitalized as a result of RSV lower respiratory tract infection. The authors concluded that evaluations of palivizumab use in infants with CF could be warranted.
The Cystic Fibrosis Foundation's evidence-based guidelines for management of infants with CF (2009) noted that 2 studies have addressed the use of palivizuma in infants with CF. A chart review of hospitalized infants found that fewer children who received palivizumab were hospitalized and their length of stay was shorter, although these differences did not reach statistical significance. Extrapolation of data from other populations suggested that there could be benefit from the use of RSV prophylaxis in infants with CF. Thus, the Foundation recommended the use of palivizumab be considered for prophylaxis of RSV for infants with CF under 2 years of age (Certainty: low; Benefit: moderate; consensus recommendation). The committee made consensus recommendations for topics not included in the evidence review, for topics where prior guidelines were available, and for topics for which there was limited or no evidence, but the potential benefit was assessed as at least moderate.
In a Cochrane review, Robinson et al (2012) examined the safety and effectiveness of palivizumab compared with placebo, no prophylaxis or other prophylaxis, in preventing hospitalization and mortality from RSV infection in children with CF. These investigators searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register and scanned references of the eligible study and related reviews.Date of last search: October 25, 2011. Randomized and quasi-randomized studies were searched. The authors independently extracted data and assessed risk of bias. One study (186 infants up to 2 years old) comparing 5 monthly doses of palivizumab (n = 92) to placebo (n = 94) over 1 RSV season was identified and met inclusion criteria. At 6 months follow-up, 1 participant in each group was hospitalized due to RSV; there were no deaths in either group. In the palivizumab and placebo groups, 86 and 90 children experienced any adverse event, while 5 and 4 children had related adverse events, respectively. A total of 19 children receiving palivizumab and 16 receiving placebo suffered serious adverse events; 1 participant receiving palivizumab discontinued due to this. At 12 months follow-up, there were no significant differences between groups in number of Pseudomonas bacterial colonisations or change in weight-to-height ratio. The authors identified 1 randomized controlled trial comparing 5 monthly doses of palivizumab to placebo in infants up to 2 years old with CF. While the overall incidence of adverse events was similar in both groups, it is not possible to draw conclusions on the safety and tolerability of RSV prophylaxis with palivizumab in infants with CF because the trial did not specify how adverse events were classified. Six months after treatment, the authors reported no clinically meaningful differences in outcomes; however no data were provided. The authors stated that additional randomized studies are needed to establish the safety and efficacy of palivizumab in children with CF.
Palivizumab reportedly does not interfere with response to vaccines. At this time, the available data do not support the need for supplemental doses of any routinely administered vaccines.
There is no adequate evidence that immune globulins (palivizumab or RSV-IVIG) are effective for treatment of RSV infections. A Cochrane systematic evidence review found no studies demonstrating statistically significant benefits of treatment with immune globulins added to supportive care compared with supportive care alone (Fuller and Del Mar, 2006).
In a phase I/II, multi-center, randomized, double-blind, placebo-controlled, escalating dose clinical trial, Saez-Llorens and colleagues (2004) described the safety, tolerance, pharmacokinetics and clinical outcome of a single intravenous dose of palivizumab in previously healthy children hospitalized with acute RSV infection. A total of 59 subjects less than or equal to 2 years of age received study drug -- 16 children received 5 mg/kg of palivizumab (n = 8) or placebo (n = 8); 43 received 15 mg/kg of palivizumab (n = 22) or placebo (n = 21). Adverse events judged to be related to study drug were seen in one 5-mg/kg palivizumab patient and one 15-mg/kg palivizumab patient. These events were transient or consistent with progression of RSV disease. No discontinuations of study drug infusion because of adverse events occurred. Mean serum concentrations of palivizumab in the 5- and 15-mg/kg groups, respectively, were 61.2 and 303.4 microg/ml at 60 mins and 11.2 and 38.4 microg/ml after 30 days. There were no significant differences in clinical outcomes between placebo and palivizumab groups for either dose.
Fernandez and colleagues (2010) stated that RSV is an important pathogen causing annual epidemics of bronchiolitis and pneumonia among infants worldwide. High-risk infants currently receive RSV prophylaxis with palivizumab, a humanized RSV monoclonal antibody (MAb). In pre-clinical in vitro and in vivo (cotton-rat model) studies, motavizumab, a new RSV MAb, was shown to have greater anti-RSV activity than palivizumab. Motavizumab is currently under review for licensing approval. Since both MAbs may be available concurrently, these researchers evaluated their safety and tolerability when administered sequentially during the same RSV season. Between April 2006 and May 2006, 260 high-risk infants were randomly assigned 1:1:1 to receive monthly intra-muscular injections: 2 doses of motavizumab followed by 3 doses of palivizumab (M/P); 2 doses of palivizumab followed by 3 doses of motavizumab (P/M); or 5 doses of motavizumab (control). Adverse events (AEs, serious AEs [SAEs]), development of anti-drug antibody (ADA), and serum drug trough concentrations were assessed. Most children received all 5 doses (246/260 [94.6 %]) and completed the study (241/260 [92.7 %]). While overall AE rates were similar (mostly level 1 or 2 in severity), SAEs and level 3 AEs occurred more frequently in the M/P group (SAEs: 22.9 % M/P, 8.4 % P/M, 11.8 % motavizumab only; level 3 AEs: 15.7 % M/P, 6.0 % P/M, 6.5 % motavizumab only). This trend in AE rates occurred before and after switching from motavizumab to palivizumab, suggesting a cause other than the combined regimen. Frequencies of AEs judged by the investigator to be related to study drug were similar among groups. Two deaths occurred on study (both in the M/P group, before palivizumab administration); neither was considered by the site investigator to be related to study drug. Mean serum drug trough concentrations were comparable among groups; ADA detection was infrequent (5.1 % or less of any group). The authors stated that conclusions drawn from this study are limited by the small sample size per group. However, within this small study, overall AE rates, serum drug trough concentrations, and development of ADA associated with administering motavizumab and palivizumab sequentially to high-risk children appear comparable to administering motavizumab alone during the same RSV season.
Hynicka and Ensor Pharmd (2012) reviewed the literature regarding current strategies and strategies under active development for the prevention and treatment of RSV infections in immunocompromised adults. The MEDLINE/PubMed, EMBASE, and Cochrane databases were queried from January 1980 to December 2011 for articles in English using these associated search terms: respiratory syncytial virus, ribavirin, intravenous immunoglobulin, IVIG, palivizumab, motavizumab, lung, pneumonia, transplantation, bone marrow, cancer, malignancy, and vaccine. All relevant original studies, meta-analyses, systematic reviews, and review articles were assessed for inclusion. References from pertinent articles were examined for additional content not found during the initial search. Respiratory syncytial virus in the immunocompromised adult can lead to significant morbidity and mortality. Treatment of RSV-infected adults is limited to anti-viral therapy with ribavirin (aerosolized, oral, intravenous) as well as immunomodulation with intravenous immunoglobulins, corticosteroids, and palivizumab. Existing literature is predominantly case reports, small trials, and retrospective reviews of patients infected with RSV who have undergone lung or hematopoietic stem cell transplantation (HSCT). Palivizumab may be a viable option for prophylaxis against RSV in high-risk adults. Ribavirin is the most studied treatment option and should remain the backbone of multi-drug regimens. Of the routes of administration, aerosolized ribavirin carries the preponderance of evidence and, though challenging, is preferred to limit systemic toxicities in the infected patient. Addition of an immunomodulator to ribavirin may provide a survival benefit over ribavirin alone; however, this has only been studied in a subset of HSCT patients with lower respiratory tract RSV infection. The authors concluded that research most strongly supports the use of aerosolized ribavirin as the treatment strategy for immunocompromised adults with RSV. Addition of an immunomodulator may provide a survival benefit over ribavirin alone. Strategies and supportive data for the prevention of RSV infection in the high-risk adult are critically needed.
Boeckh et al (2001) stated that intravenous palivizumab (15 mg/kg) was investigated in 2 phase I studies among recipients of hematopoietic stem cell transplants (HSCTs). Study 1 included 6 HSCT patients without active RSV infection. Study 2 included 15 HSCT patients with RSV upper respiratory tract infection (URTI; n = 3) or RSV interstitial pneumonia (IP; n = 12), all of whom also received aerosolized ribavirin. Peak serum concentrations of palivizumab in the 2 studies were similar. The mean serum half-life was 22.4 days in study 1, which mainly included autologous HSCT recipients, and 10.7 days in study 2, which mainly included allogeneic HSCT recipients. No antibodies to palivizumab were detected in study 1. No adverse events were attributed to palivizumab in the 2 studies. In study 2, all 3 patients with RSV URTI recovered without progression to lower respiratory tract disease, and 10 (83 %) of the 12 patients with RSV IP survived the 28-day study period. Thus, palivizumab appears to be safe and well-tolerated in HSCT recipients. Well-designed studies are needed to validate the findings of these phase I studies.
Shah and Chemaly (2011) noted that RSV is a common cause of seasonal respiratory viral infection in patients who have undergone HSCT. Respiratory syncytial virus usually presents as an URTI in this patient population but may progress rapidly to lower respiratory tract infection. Available therapies that have been used for the treatment of RSV infections are limited to ribavirin, intravenous immunoglobulin (IVIG), and palivizumab. The use of aerosolized ribavirin, alone or in combination with either palivizumab or IVIG, remains controversial.
Santos et al (2012) presented the findings of 2 children with acute lymphocytic leukemia (ALL) and persistent RSV infection while receiving chemotherapy. Patient A is a 4-year old male with Down syndrome, ALL, and persistent RSV infection for at least 3 months. Patient B is a 3-year old female with pre-B cell ALL whose chemotherapy intensification phase was delayed due to a month-long RSV infection. Respiratory syncytial virus infections were determined by using real-time polymerase chain reaction assays from nasopharyngeal swabs before IV palivizumab therapy; patient A was positive for RSV at 36 cycles and patient B was positive for RSV at 29 cycles. Respiratory syncytial virus infection was cleared in both patients within 72 hours after receiving IV palivizumab (patient A: 16 mg/kg; patient B: 15 mg/kg). The authors stated that intravenous palivizumab may be a treatment option for persistent RSV infection among immune-compromised patients.
Seo et al (2013) evaluated the effect of transplant and treatment factors on overall survival, mortality from respiratory failure, and pulmonary function among 82 HSCT recipients who had RSV lower respiratory tract disease (LRD) between 1990 and 2011. All patients received aerosolized ribavirin. In multi-variable analyses, only the use of marrow or cord blood as graft source (adjusted hazard ratio [aHR], 4.1; 95 % confidence interval [CI]: 1.8 to 9.0; p < 0.001) and oxygen requirement (aHR, 3.3; 95 % CI: 1.5 to 6.7; p = 0.003) remained independently associated with overall mortality and death due to respiratory failure (aHR, 4.7; 95 % CI: 1.8 to 13; p = 0.002 and aHR, 5.4; 95 % CI: 1.8 to 16; p = 0.002, respectively). Antibody-based treatments, including IVIG and palivizumab, were not independently associated with improved outcome and did not alter the associations of the graft source and oxygen requirements in statistical models. The authors concluded that use of peripheral blood stem cells as graft source and lack of oxygen requirement at diagnosis appear to be important factors associated with improved survival of HSCT recipients with RSV LRD. These results may explain differences in outcomes reported from RSV infection over time and may guide the design of future interventional trials.
Sanchez-Solis et al (2013) noted that infections by RSV are more severe in patients with CF, and many CF units use palivizumab as prophylaxis; however, information about the effectiveness of palivizumab in CF patients is almost lacking. These investigators performed a literature search up to December 2012 on the morbidity of RSV bronchiolitis in CF patients and on the safety and effectiveness of palivizumab in those patients. A random-effects meta-analysis was conducted for those studies meeting pre-specified search criteria. Historical controls were allowed. The number of patients who received palivizumab was 354 and the hospital admission rate was 0.018 (95 % CI: 0.0077 to 0.048). The corresponding number in the non-treated groups was 463 patients with an admission rate of 0.126 (95 % CI: 0.086 to 0.182) (Q = 13.9; p < 0.001). The authors concluded that palivizumab may have a role in the prevention of severe lower airway infection by RSV in CF patients.
However, the updated Cochrane review on “Palivizumab for prophylaxis against respiratory syncytial virus infection in children with cystic fibrosis” (Robinson et al, 2013) still maintained that additional randomized studies are needed to establish the safety and effectiveness of palivizumab in children with CF.
Note on RespiGam Respiratory Syncytial Virus Immune Globulin (RSV-IVIG): On October 1, 2003, MedImmune and Massachusetts Public Health & Biologics Laboratory (MPHBL), the manufacturers of RespiGam, announced that production of RespiGam will be discontinued. As of March 15, 2004 all current inventory levels of RespiGam had been depleted and no product is available for sale from MedImmune or MPHBL.
Maximum Number of Monthly Doses of Palivizumab for Respiratory Syncytial Virus Prophylaxis
Infants Eligible for a Maximum of 5 Doses
Infants Eligible for a Maximum of 3 Doses
Infants younger than 2 years of age with chronic lung disease and requiring medical therapy
Preterm infants with gestational age of 32 weeks, 0 days to 34 weeks, 6 days with at least 1 risk factor and born 3 months before or during RSV season.
Infants younger than 2 years of age and requiring medical therapy for congenital heart disease
Preterm infants born at 31 weeks, 6 days of gestation or less
Certain infants with neuromuscular disease or congenital abnormalities of the airways
Maximum Number of Palivizumab Doses for RSV Prophylaxis of Preterm Infants Without Chronic Lung Disease, on the Basis of Birth Date, Gestational Age, and Presence of Risk Factors (Shown for Geographic Areas Beginning Prophylaxis on November 1)a
Maximum No. of Doses for Season Beginning November 1
Month of Birth
≤ 28 Weeks, 6 Days of Gestation and < 12 Months of Age at Start of Season
29 Weeks, 0 Days Through 31 Weeks, 6 Days of Gestation and < 6 Months of Age at Start of Season
32 Weeks, 0 Days Through 34 Weeks, 6 Days of Gestation and With Risk Factorb
November 1 –March 31 of previous RSV season
aIf infant is discharged from the hospital during RSV season, fewer doses may be required. bFor risk factors, see policy section. cSome of these infants may have received 1 or more doses of palivizimab in the previous RSV season if discharged from the hospital during that season; if so, they still qualify for up to 5 doses during their second RSV season. dZero doses because infant will be older than 6 months of age at start of RSV season. eZero doses because infant will be older than 90 days of age at start of RSV season. fOn the basis of the age of patients at the time of discharge from the hospital, fewer doses may be required, because these infants will receive 1 dose every 30 days until the infant is 90 days of age.
Adapted from the American Academy of Pediatrics (AAP) 2012 Red Book.
CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes covered if selection criteria are met:
Other CPT codes related to the CPB:
HCPCS codes covered if selection criteria are met:
Home injectable therapy, palivizumab, including administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
ICD-9 codes covered if selection criteria are met:
204.00 - 204.02
Acute lymphoid [lymphoblastic] leukemia
205.00 - 205.02
Acute myeloid leukemia
279.00 - 279.9
Disorders involving the immune mechanism [severe immunodeficiencies]
Acute bronchiolitis due to RSV [active RSV infection]
Pneumonia due to RSV [active RSV infection]
745.4 - 745.5
Congenital stenosis of pulmonary valve
Congenital stenosis of aortic valve
Patent ductus arteriosus
Coarctation of aorta (preductal) (postductal)
Other ICD-9 codes related to the CPB:
425.0 - 425.9
Cardiomyopathy [no proven value in infants who are not receiving medical therapy]
Accidental poisoning by second-hand tobacco
Accidental poisoning by unspecified gases and vapors
The above policy is based on the following references:
American Academy of Pediatrics, Committee on Infectious Diseases and Committe on Fetus and Newborn. Prevention of respiratory syncytial virus infections: Indications for the use of palivizumab and update on the use of RSV-IVIG. Pediatrics. 1998;102(5):1211-1216.
MedImmune, Inc. Prescribing information for Synagis™ (palivizumab). Gaithersburg, MD: MedImmune; June 19, 1998.
MedImmune, Inc. and Massachusetts Public Health & Biologics Laboratories. RespiGam Respiratory Syncytial Virus Immune Globulin Intravenous (Human) (RSV-IVIG). Prescribing Information. 3AB1201. Ed. 002. Gaithersburg, MD: MedImmune; May 2000.
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(3 Pt 1):531-537.
Greenough A, Thomas M. Respiratory syncytial virus prevention: Past and present strategies. Expert Opin Pharmacother. 2000;1(6):1195-1201.
Prince AM, Jacobs RF. Prevention of respiratory syncytial virus infection in high risk infants. J Ark Med Soc. 2001;98(4):115-118.
Mayock DE. Recommended guidelines for the use of Synagis and Respigam in infants and children. Seattle, WA: University of Washington School of Medicine, Children's Hospital and Regional Medical Center; 2002. Available at:
MedImmune, Inc. Phase 3 study shows Synagis reduces RSV hospitalization in young children with congenital heart disease. Press Release. Boston, MA: MedImmune; October 18, 2002.
No authors listed. Synagis revisited. Med Lett. 2001;43(1098):13-14.
American Academy of Pediatrics (AAP). 2003 Red Book. Report of the Committee on Infectious Diseases. 26th Ed. Elk Grove Village, IL: AAP; 2003.
Simpson S, Burls A. A systematic review of the effectiveness and cost-effectiveness of palivizumab (Synagis) in the prevention of respiratory syncytial virus (RSV) infection in infants at high risk of infection. West Midlands Development and Evaluation Service Report. DPHE Report No. 30. Birmingham, UK: West Midlands Health Technology Assessment Collaboration, Department of Public Health and Epidemiology, University of Birmingham; 2001.
Canadian Coordinating Office for Health Technology Assessment (CCOHTA). Palivizumab (Synagis). Emerging Drug List No. 40. Ottawa, ON: CCOHTA; 2003.
Viswanathan M, King V, Bordley C. Management of bronchiolitis in infants and children. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ); 2003.
Meissner JC, Anderson LJ, Pickering LK. Annual variation in respiratory syncytial virus season and decisions regarding immunoprophylaxis with palivizumab. Pediatrics. 2004;104(4): 1082-1084.
Centers for Disease Control and Prevention (CDC), National Center for Infectious Diseases, Respiratory and Enteric Viruses Branch. Respiratory Syncytial Virus Regional Trends [website]. Atlanta, GA: CDC; February 1, 2005. Available at: http://www.cdc.gov/ncidod/dvrd/revb/nrevss/rsvtre1.htm. Accessed February 4, 2005.
Centers for Disease Control and Prevention (CDC). Update: Respiratory syncytial virus activity - United States, 1998-1999 season. MMWR Morbid Mortal Wkly Rep. 1999;48(48):1104-1106, 1115. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4848a2.htm. Accessed June 6, 2005.
Mullins JA, Lamonte AC, Bresee JS, Anderson LJ. Substantial variability in community respiratory syncytial virus season timing. Pediatr Infect Dis J. 2003;22(10):857-862.
Meissner HC, Division of Pediatric Infectious Disease, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, MA, personal communication to M. Schulman, Aetna, New York, NY, May 5, 2005.
American Academy of Pediatrics (AAP), Committee on Infectious Diseases. Revised indications for the use of palivizumab and respiratory syncytial virus immune globulin intravenous for the prevention of respiratory syncytial virus infections. Pediatrics. 2003;112(6 Pt 1):1442-1446. Available at: http://aappolicy.aappublications.org/cgi/content/full/pediatrics;112/6/1442. Accessed March 21, 2006.
Lozano JM. Bronchiolitis. In: Clinical Evidence, Issue 12. London, UK: BMJ Publishing Group; December 2004.
Embleton ND, Harkensee C, Mckean MC. Palivizumab for preterm infants. Is it worth it? Arch Dis Child Fetal Neonatal Ed. 2005;90(4):F286-F289.
Null D Jr, Pollara B, Dennehy PH, et al. Safety and immunogenicity of palivizumab (Synagis) administered for two seasons. Pediatr Infect Dis J. 2005;24(11):1021-1023.
American Academy of Pediatrics (AAP), 2006 Red Book. Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: AAP; 2006.
Harkensee C, Brodlie M, Embleton ND, Mckean M. Passive immunisation of preterm infants with palivizumab against RSV infection. J Infect. 2006;52(1):2-8.
Venkatesh MP, Weisman LE. Prevention and treatment of respiratory syncytial virus infection in infants: An update. Expert Rev Vaccines. 2006;5(2):261-268.
Mitchell I, Tough S, Gillis L, Majaesic C. Beyond randomized controlled trials: A 'real life' experience of respiratory syncytial virus infection prevention in infancy with and without palivizumab. Pediatr Pulmonol. 2006;41(12):1167-1174
Dunfield L, Mierzwinski-Urban M. Palivizumab prophylaxis against respiratory syncytial virus. Technology Report No. 80. Ottawa, ON: Canadian Agency for Drugs and Technologies in Health (CADTH); 2007.
Fuller H, Del Mar C. Immunoglobulin treatment of respiratory syncytial virus infection. Cochrane Database Syst Rev. 2006;(4):CD004883.
Underwood MA, Danielsen B, Gilbert WM. Cost, causes and rates of rehospitalization of preterm infants. J Perinatol. 2007;27(10):614-619.
Feltes TF, Sondheimer HM. Palivizumab and the prevention of respiratory syncytial virus illness in pediatric patients with congenital heart disease. Expert Opin Biol Ther. 2007;7(9):1471-1480.
Jeena PM, Ayannusi OE, Annamalai K, et al. Risk factors for admission and the role of respiratory syncytial virus-specific cytotoxic T-lymphocyte responses in children with acute bronchiolitis. S Afr Med J. 2003;93(4):291-294.
Simoes EA. Environmental and demographic risk factors for respiratory syncytial virus lower respiratory tract disease. J Pediatr. 2003;143(5 Suppl):S118-S126.
Sáez-Llorens X, Moreno MT, Ramilo O, et al; MEDI-493 Study Group. Safety and pharmacokinetics of palivizumab therapy in children hospitalized with respiratory syncytial virus infection. Pediatr Infect Dis J. 2004;23(8):707-712.
Malfroot A, Adam G, Ciofu O, et al; European Cystic Fibrosis Society (ECFS) Vaccination Group. Immunisation in the current management of cystic fibrosis patients. J Cyst Fibros. 2005;4(2):77-87.
Kristensen IA, Olsen J. Determinants of acute respiratory infections in Soweto--a population-based birth cohort. S Afr Med J. 2006l;96(7):633-640.
Cohen SA, Zanni R, Cohen A, et al; Palivizumab Outcomes Registry Group. Palivizumab use in subjects with congenital heart disease: Results from the 2000-2004 Palivizumab Outcomes Registry. Pediatr Cardiol. 2008;29(2):382-387.
Giebels K, Marcotte JE, Podoba J, et al. Prophylaxis against respiratory syncytial virus in young children with cystic fibrosis. Pediatr Pulmonol. 2008;43(2):169-174.
Speer ME, Fernandes CJ, Boron M, Groothuis JR. Use of palivizumab for prevention of hospitalization as a result of respiratory syncytial virus in infants with cystic fibrosis. Pediatr Infect Dis J. 2008;27(6):559-561.
Dherani M, Pope D, Mascarenhas M, et al. Indoor air pollution from unprocessed solid fuel use and pneumonia risk in children aged under five years: A systematic review and meta-analysis. Bull World Health Organ. 2008;86(5):390-398C.
Rudan I, Boschi-Pinto C, Biloglav Z, Mulholland K, Campbell H. Epidemiology and etiology of childhood pneumonia. Bull World Health Organ. 2008;86(5):408-416.
Wang D, Cummins C, Bayliss S, et al. Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children: A systematic review and economic evaluation. Health Technol Assess. 2008;12(36):iii, ix-x, 1-86.
Meissner HC, Bocchini JA, Jr. Reducing RSV hospitalizations: AAP modifies indications for use of palvizumab in high-risk infants, young children. American Academy of Pediatrics News. June 4, 2009. Available at: http://aapnews.aappublications.org/cgi/content/full/aapnews.20090604-1v1. Accessed on June 8, 2009.
American Academy of Pediatrics (AAP). 2012 Red Book. Report of the Committee on Infectious Diseases. 29th Ed. Elk Grove Village, IL: AAP; 2012.
Cystic Fibrosis Foundation, Borowitz D, Robinson KA, Rosenfeld M, et al. Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. J Pediatr. 2009;155(6 Suppl):S73-S93.
Chang RK, Chen AY. Impact of palivizumab on RSV hospitalizations for children with hemodynamically significant congenital heart disease. Pediatr Cardiol. 2010;31(1):90-95.
Fernandez P, Trenholme A, Abarca K, et al; Motavizumab Study Group. A phase 2, randomized, double-blind safety and pharmacokinetic assessment of respiratory syncytial virus (RSV) prophylaxis with motavizumab and palivizumab administered in the same season. BMC Pediatr. 2010;10:38.
Wang D, Bayliss S, Meads C. Palivizumab for immunoprophylaxis of respiratory syncitial virus (RSV) bronchiolitis in high-risk infants and young children: A systematic review and additional economic modelling of subgroup analyses Health Technol Assess. 2011;15(5):1-124.
Robinson KA, Odelola OA, Saldanha IJ, McKoy NA. Palivizumab for prophylaxis against respiratory syncytial virus infection in children with cystic fibrosis. Cochrane Database Syst Rev. 2012;(2):CD007743.
Hynicka LM, Ensor Pharmd CR. Prophylaxis and treatment of respiratory syncytial virus in adult immunocompromised patients. Ann Pharmacother. 2012;46(4):558-566.
Boeckh M, Berry MM, Bowden RA, et al. Phase I evaluation of the respiratory syncytial virus-specific monoclonal antibody palivizumab in recipients of hematopoietic stem cell transplants. J Infect Dis. 2001; 184(3):350-354.
Shah JN, Chemaly RF. Management of RSV infections in adult recipients of hematopoietic stem cell transplantation. Blood. 2011;117(10):2755-2763.
Santos RP, Chao J, Nepo AG, et al. The use of intravenous palivizumab for treatment of persistent RSV infection in children with leukemia. Pediatrics. 2012;130(6):e1695-e1699.
Hussman JM, Li A, Paes B, Lanctot KL. A review of cost-effectiveness of palivizumab for respiratory syncytial virus. Expert Rev Pharmacoecon Outcomes Res. 2012;12(5):553-567.
Hussman JM, Lanctot KL, Paes B. The cost effectiveness of palivizumab in congenital heart disease: A review of the current evidence. J Med Econ. 2013;16(1):115-124.
Seo S, Campbell AP, Xie H, et al. Outcome of respiratory syncytial virus lower respiratory tract disease in hematopoietic cell transplant recipients receiving aerosolized ribavirin: Significance of stem cell source and oxygen requirement. Biol Blood Marrow Transplant. 2013;19(4):589-596.
Robinson KA, Odelola OA, Saldanha IJ, McKoy NA. Palivizumab for prophylaxis against respiratory syncytial virus infection in children with cystic fibrosis. Cochrane Database Syst Rev. 2013;6:CD007743.
Sanchez-Solis M, Gartner S, Bosch-Gimenez V, Garcia-Marcos L. Is palivizumab effective as a prophylaxis of respiratory syncytial virus infections in cystic fibrosis patients? A meta-analysis. Allergol Immunopathol (Madr). 2013 Nov 11. [Epub ahead of print]
Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.