Aetna considers palivizumab (Synagis) prophylaxis medically necessary for the following indications when criteria are met:
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.
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.
Variations in the onset and offset of the RSV season in the state of Florida affect the timing of Synagis (palivizumab) administration. Despite varied onsets, the RSV season is of equal duration in the different regions of Florida. For this reason, infants and young children in Florida who qualify for prophylaxis for the season should receive Synagis palivizumab) only during the three or five months following onset of RSV season. For southeast Florida (Miami-Dade County), the earliest date for initiation of 3 to 5 doses of Synagis is July 1. For north central and southwest Florida, the earliest date for initiation of Synagis is September 1. For most other areas of the United States, the earliest date for initiation of 3 to 5 doses of Synagis is November 1.
On the basis of the epidemiology of RSV in Alaska, particularly in remote regions where the burden of RSV disease is significantly greater than the general US population, the selection of Alaska Native infants eligible for prophylaxis may differ from the remainder of the United States. RSV surveillance data generated by the state of Alaska may be used to assist in determining onset and end of the RSV season for qualifying infants.
Limited information is available concerning the burden of RSV disease among American Indian populations. However, special consideration may be prudent for Navajo and White Mountain Apache infants in the first year of life.Background
Synagis (palivizumab) is a humanized monoclonal antibody (IgG1k) produced by recombinant DNA technology, directed to an epitope in the A antigenic site of the F protein of respiratory syncytial virus. Palivizumab exhibits neutralizing and fusion‐inhibitory activity against respiratory syncytial virus (RSV). The populations at highest risk are premature babies and children with congenital heart disease, patients with chronic lung disease, or immunodeficient patients.
Synagis (palivizumab) is indicated for the prevention of serious lower respiratory tract disease caused by RSV in pediatric patients at high risk of RSV disease. Safety and efficacy were established in infants with bronchopulmonary dysplasia (BPD), infants with a history of premature birth (≤5 weeks gestational age), and children with hemodynamically significant congenital heart disease (CHD).
Synagis is available in single use vials containing either 50mg or 100mg of palivizumab. Palivizumab 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 stated children who qualify for palivizumab prophylaxis for the entire RSV season 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.
Prophylaxis against RSV should be initiated just before the onset of the RSV season and terminated at the end of RSV season.In most seasons and in most regions of the Northern Hemisphere, the first dose of palivizumab should be administered at the beginning of November and the last dose should be administered at the beginning of March, which will provide protection into April. If prophylaxis is started in October in a geographic area with an earlier onset of RSV season, the last dose (5th dose) should be administered in February.
Recent surveillance data from the Centers for Disease Control (CDC) and Prevention have identified variations in the onset and offset of the RSV seasons within Florida. This should affect the timing of palivizumab administration.
Synagis (palivizumab) serum levels are decreased after cardio‐pulmonary bypass. Patients undergoing cardiopulmonary bypass should receive a dose of palivizumab as soon as possible after the cardiopulmonary bypass procedure (even if sooner than a month from the previous dose). Thereafter, doses should be administered monthly.
Synagis (palivizumab) is not indicated for the treatment of RSV disease. If an infant or child who is receiving immunoprophylaxis experiences a breakthrough RSV infection, prophylaxis should be discontinued because of the extremely low likelihood of a second RSV hospitalization in the same season
Physicians should arrange for drug administration within six hours after opening a vial as this product does not contain a preservative.
Synagis (palivizumab) does not interfere with the response to vaccines.
Randomized placebo controlled clinical trials have demonstrated the safety and efficacy of palivizumab (Impact RSV Study, 1998) in reducing hospitalizations due to RSV infection, and in producing reductions in other measures of severity of RSV infection for a very specific group of infants and children. Epidemiologic data indicate that the risk of severe RSV infection most likely to require hospitalization is greater in the presence of risk factors.
The American Academy of Pediatrics (AAP) issued updated guidelines regarding the use of immune prophylaxis for RSV in the AAP Red Book (2014). The AAP Red Book was developed by members of the AAP Committee on Infectious Diseases in conjunction with the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), and other leading institutions. A summary of the AAP (2014) RSV guidance is as follows:
Congenital Heart Disease:
A 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. The data showed significantly fewer RSV‐related hospital days and fewer days of increased oxygen usage, 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. Infants and children with hemodynamically insignificant heart disease were not included in this study, as they are not considered to be at increased risk from RSV. Paired palivizumab serum levels were available for 139 children before and after cardiopulmonary bypass surgery. Mean serum concentrations were reduced by 58% (98 mcg/ml [ ±52], to 41.4 mcg/ml [ ±33]) after bypass. Based on this observation, the authors recommended that another dose of palivizumab be administered following cardiopulmonary bypass (Feltes, 2003).
The AAP (2014) reports that certain children who are 12 months or younger with hemodynamically significant CHD may benefit from palivizumab prophylaxis. The children with CHD who are most likely to benefit from prophylaxis, according to the AAP, include infants with acyanotic heart disease who are on medication to control congestive heart failure and will require cardiac surgical procedures and infants with moderate to severe pulmonary hypertension. In regards to infants with cyanotic heart defects in the first year of life, the AAP states that decisions regarding palivizumab prophylaxis may be made in consultation with a pediatric cardiologist. These AAP recommendations apply to qualifying infants in the first year of life who are born within 12 months of onset of the RSV season.
Decisions regarding prophylaxis with palivizumab in children with CHD should be made on the basis of the degree of physiologic cardiovascular compromise. The AAP Red Book (2014) guidelines suggest that the following groups of infants are not at increased risk from RSV and generally should not receive immunoprophylaxis:
The available limited data indicates a slight increase in RSV hospitalization rates for children with Down syndrome. However, the AAP (2014) reports: "data are insufficient to justify a recommendation for routine use of prophylaxis in children with Down syndrome unless a qualifying heart disease, CLD, airway clearance issues, or prematurity (<29 weeks, 0 days' gestation) is present."
Use in the Second Year of Life :
Prevention of Health Care Associated RSV Disease:
The Center for Disease Control and Prevention (CDC) National Respiratory and Enteric Virus Surveillance System (NREVSS) is a laboratory-based system that monitors temporal and geographic patterns associated with the detection of RSV and other viruses. Annual summaries and alerts based on NREVSS data have been published periodically in CDC's 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. CDC surveillance summaries of weekly RSV laboratory test result data for each region of the United States are posted at: http://www.cdc.gov/surveillance/nrevss/rsv/state.html.
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 who require medical therapy may benefit from prophylaxis for 2 RSV seasons. Children with less severe underlying disease may benefit only for the first season.
The literature also suggests that infants born before 29 weeks of gestation 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.
Palivizumab is not approved by the Food and Drug Administration (FDA) for patients with congenital heart disease (CHD). However, a 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 (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 (2015) 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.
In a Cochrane review, Robinson et al (2014) determined 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. The authors concluded that they identified 1 RCT 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 firm conclusions on the safety and tolerability of RSV prophylaxis with palivizumab in infants with CF. They reported no clinically meaningful differences in outcomes 6 months after treatment. They stated that additional randomized studies are needed to establish the safety and effectiveness of palivizumab in children with CF.
Childhood Interstitial Lung Disease (chILD):
Drummond et al (2015) noted that there is a lack of evidence concerning the effectiveness of immunoprophylaxis with palivizumab in children with childhood interstitial lung disease (chILD). In this retrospective study, these researchers evaluated the effectiveness of palivizumab for decreasing the rate of RSV-related hospitalizations in children under the age of 24 months with chILD treated with corticosteroids. A retrospective national study was conducted in France. Patients born between 2007 and 2013, diagnosed with chILD and on corticosteroid treatment were identified through the French online database for pediatric interstitial lung disease (Respirare® ). Data were collected for the etiology and severity of chILD, risk factors and preventive measures for bronchiolitis, palivizumab immunoprophylaxis, and hospitalizations for bronchiolitis and RSV-bronchiolitis. These investigators evaluated 24 children during their first 2 RSV seasons, corresponding to 36 patient-seasons. The observed rate of RSV-related hospitalization (305/1,000 patient-seasons), and the median length of stay (7 days), were higher than those for the general population. However, RSV-related hospitalization rates did not differ significantly between children with and without palivizumab prophylaxis (5/16 versus 4/18, respectively, p = 0.70). The authors concluded that children with chILD on corticosteroid treatment are at high risk of hospitalization for RSV-bronchiolitis, which tends to be more severe in these children than in the general population. Moreover, they stated that the effectiveness of palivizumab prophylaxis in this population remains to be demonstrated.
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.
|CPT Codes / HCPCS Codes / ICD-10 Codes|
|Information in the [brackets] below has been added for clarification purposes.  Codes requiring a 7th character are represented by "+":|
|CPT codes covered if selection criteria are met:|
|90378||Respiratory syncytial virus, monoclonal antibody recombinant, for intramuscular use, 50 mg each|
|Other CPT codes related to the CPB:|
|33120||Excision of intracardiac tumor, resection with cardiopulmonary bypass|
|33305||Repair of cardiac wound; with cardiopulmonary bypass|
|33315||Cardiotomy, exploratory (includes removal of foreign body, atrial or ventricular thrombus); with cardiopulmonary bypass|
|33322||Suture repair of aorta or great vessels; with cardiopulmonary bypass|
|33335||Insertion of graft, aorta or great vessels; with cardiopulmonary bypass|
|33403||Valvuloplasty, aortic valve; using transventricular dilation, with cardiopulmonary bypass|
|33405||Replacement, aortic valve, with cardiopulmonary bypass; with prosthetic valve other than homograft or stentless valve|
|33406||Replacement, aortic valve, with cardiopulmonary bypass; with allograft valve (freehand)|
|33410||Replacement, aortic valve, with cardiopulmonary bypass; with stentless tissue valve|
|33422||Valvotomy, mitral valve; open heart, with cardiopulmonary bypass|
|33425||Valvuloplasty, mitral valve, with cardiopulmonary bypass|
|33426||Valvuloplasty, mitral valve, with cardiopulmonary bypass; with prosthetic ring|
|33427||Valvuloplasty, mitral valve, with cardiopulmonary bypass; radical reconstruction, with or without ring|
|33430||Replacement, mitral valve, with cardiopulmonary bypass|
|33460||Valvectomy, tricuspid valve, with cardiopulmonary bypass|
|33465||Replacement, tricuspid valve, with cardiopulmonary bypass|
|33474||Valvotomy, pulmonary valve, open heart; with cardiopulmonary bypass|
|33496||Repair of non-structural prosthetic valve dysfunction with cardiopulmonary bypass (separate procedure)|
|33500||Repair of coronary arteriovenous or arteriocardiac chamber fistula; with cardiopulmonary bypass|
|33504||Repair of anomalous coronary artery from pulmonary artery origin; by graft, with cardiopulmonary bypass|
|33641||Repair atrial septal defect, secundum, with cardiopulmonary bypass, with or without patch|
|33702||Repair sinus of Valsalva fistula, with cardiopulmonary bypass|
|33710||Repair sinus of Valsalva fistula, with cardiopulmonary bypass; with repair of ventricular septal defect|
|33720||Repair sinus of Valsalva aneurysm, with cardiopulmonary bypass|
|33736||Atrial septectomy or septostomy; open heart with cardiopulmonary bypass|
|33814||Obliteration of aortopulmonary septal defect; with cardiopulmonary bypass|
|33853||Repair of hypoplastic or interrupted aortic arch using autogenous or prosthetic material; with cardiopulmonary bypass|
|33860||Ascending aorta graft, with cardiopulmonary bypass, includes valve suspension, when performed|
|33864||Ascending aorta graft, with cardiopulmonary bypass with valve suspension, with coronary reconstruction and valve sparing aortic root remodeling (e.g., David Procedure, Yacoub Procedure|
|33870||Transverse arch graft, with cardiopulmonary bypass|
|33875||Descending thoracic aorta graft, with or without bypass|
|33877||Repair of thoracoabdominal aortic aneurysm with graft, with or without cardiopulmonary bypass|
|33910||Pulmonary artery embolectomy; with cardiopulmonary bypass|
|33916||Pulmonary endarterectomy, with or without embolectomy, with cardiopulmonary bypass|
|33922||Transection of pulmonary artery with cardiopulmonary bypass|
|33926||Repair of pulmonary artery arborization anomalies by unifocalization; with cardiopulmonary bypass|
|33946 - 33986||Extracorporeal membrane oxygenation (ECMO)/extracorporeal life support (ECLS) provided by physician|
|33987||Arterial exposure with creation of graft conduit (eg, chimney graft) to facilitate arterial perfusion for ECMO/ECLS (List separately in addition to code for primary procedure)|
|33988||Insertion of left heart vent by thoracic incision (eg, sternotomy, thoracotomy) for ECMO/ECLS|
|33989||Removal of left heart vent by thoracic incision (eg, sternotomy, thoracotomy) for ECMO/ECLS|
|87252||Virus isolation; tissue culture inoculation, observation, and presumptive identification by cytopathic effect|
|87420||Infectious agent antigen detection by immunoassay technique, (eg, enzyme immunoassay [EIA], enzyme-linked immunosorbent assay [ELISA], immunochemiluminometric assay [IMCA]) qualitative or semiquantitative, multiple-step method; respiratory syncytial virus|
|96372||Therapeutic, prophylactic or diagnostic injection (specify substance or drug); subcutaneous or intramuscular|
|HCPCS codes covered if selection criteria are met:|
|S9562||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-10 codes covered if selection criteria are met:|
|C91.00 - C91.02||Acute lymphoblastic leukemia [ALL] [children younger than 24 months who will be profoundly immunocompromised during the RSV season]|
|C92.00 - C92.02, C92.40 - C92.92||Acute myeloid leukemia [children younger than 24 months who will be profoundly immunocompromised during the RSV season]|
|D80.0 - D89.9||Certain disorders involving the immune mechanism [severe combined immunodeficiency or severe acquired immunodeficiency syndrome in children younger than 24 months who will be profoundly immunocompromised during the RSV season]|
|E84.0 - E84.9||Cystic fibrosis [for infants with clinical evidence of CLD and/or nutritional compromise in the first year of life and for continued in the second year for infants who have manifestations of severe lung disease (previous hospitalization for pulmonary exacerbation in the first year of life or abnormalities on chest radiography or chest computed tomography that persist when stable) or weight for length less than the 10th percentile] [ Not covered for routine use of palivizumab prophylaxis in infants and children with cystic fibrosis, including neonates diagnosed with cystic fibrosis by newborn screening, is considered experimental and investigational unless other indications are present]|
|G70.00 - G73.7||Disease of myoneural junction and muscle [that impair the ability to clear secretions from the upper airways because of ineffective cough]|
|I27.0 - I27.9||Other pulmonary heart disease [chronic lung disease] [infants with moderate to severe pulmonary hypertension]|
|I50.20 - I50.9||Congestive heart failure [infants receiving medication for control and will require cardiac surgical procedures]|
|J40 - J44.9, J47.0 - J47.9||Chronic lower respiratory disease [chronic lung disease]|
|P07.20 - P07.26||Extreme immaturity of newborn, gestational age less than 28 completed weeks|
|P07.30 - P07.35||Preterm [premature] newborn[other] [when a risk factor is present] [less than 33 weeks completed]|
|P27.1||Bronchopulmonary dysplasia originating in the perinatal period [chronic lung disease (CLD) of prematurity]|
|P29.3||Persistent fetal circulation [primary pulmonary hypertension of newborn] [infants with moderate to severe pulmonary hypertension]|
|Q20.0 - Q28.9||Congenital malformations of the circulatory system [congenital heart disease|
|Q33.0 - Q33.9||Congenital malformation of lung [anatomic pulmonary abnormalities that impair the ability to clear secretions from the upper airways because of ineffective cough]|
|T59.5x1+ - T59.894+||Toxic effect of other specified gases, fumes, or vapors [exposure to indoor air pollutants]|
|Z23||Encounter for immunization [respiratory syncytial virus (RSV)] [not covered for prevention of health-care associated RSV disease] [not covered for prophylaxis against RSV in immunocompromised adults]|
|Z48.21, Z94.1||Heart transplant status [for children younger than 2 years who undergo cardiac transplantation during the RSV season]|
|Z94.81||Bone marrow transplant status [postoperative dose of palivizumab (15 mg/kg) is considered medically necessary after cardiac bypass for infants and children younger than 24 months who are receiving palivizumab prophylaxis and who continue to require palivizumab prophylaxis]|
|Z94.84||Stem cells transplant status [children younger than 24 months who will be profoundly immunocompromised during the RSV season]|
|ICD-10 codes not covered for indications listed in the CPB:|
|B97.4||Respiratory syncytial virus as the cause of disease classified elsewhere|
|J12.1||Respiratory syncytial virus pneumonia|
|J21.0||Acute bronchiolitis due to respiratory syncytial virus|
|J45.20 - J45.998||Asthma|
|J84.848||Other interstitial lung diseases of childhood [child]|
|P07.36 - P07.39||Preterm newborn, gestational age 33 - 36 completed weeks|
|Q21.0 - Q21.9||Congenital malformations of cardiac septa|
|Q22.1||Congenital pulmonary valve stenosis|
|Q23.0||Congenital stenosis of aortic valve|
|Q25.0||Patent ductus arteriosus|
|Q25.1||Coarctation of aorta (preductal) (postductal)|
|Q90.0 - Q90.9||Down syndrome|