|Subject:||Prevention of Respiratory Syncytial Virus Infections|
|Policy #:||DRUG.00015||Current Effective Date:||11/17/2014|
|Status:||Revised||Last Review Date:||11/13/2014|
This document addresses prevention of respiratory syncytial virus (RSV) infection with palivizumab (Synagis®) a monoclonal antibody produced by DNA recombinant technology. The goal of passive immunoprophylaxis for protectionof high-risk infants and children against RSV lower respiratory tract infection is to reduce the rate of serious lower respiratory tract disease leading to hospitalization in this population.
Note: RSV Season:
Because five (5) monthly doses of palivizumab will provide more than six (6) months of adequate serum concentrations for most infants, administration should be limited to the peak RSV seasons in the continental US, of October to March or November to April. Qualifying infants born during RSV season will need fewer than five (5) doses for protection until the season ends.
Specific information about national and regional RSV trends, especially pertaining to the peak variations in Florida and Alaska, is available from the National Respiratory and Enteric Virus Surveillance System (NREVSS) at: http://www.cdc.gov/surveillance/nrevss/rsv/default.html.
Immunoprophylaxis for respiratory syncytial virus (RSV) with intramuscular palivizumab (Synagis) is considered medically necessary for the prevention of serious lower respiratory tract diseasein infants and young children who are at high risk, when the criteria below are met:
Not Medically Necessary:
Administration of more than 5 doses of palivizumab (Synagis) in one RSV season, including in Florida, is considered not medically necessary.
Immunoprophylaxis for RSV is considered not medically necessary for children less than 24 months of age when the above criteria are not met.
Continued RSV immunoprophylaxis is considered not medically necessary for children who experience breakthrough RSV hospitalization.
RSV immunoprophylaxis is considered not medically necessary for primary asthma prevention or to reduce subsequent episodes of wheezing.
Investigational and Not Medically Necessary:
Immunoprophylaxis for RSV is considered investigational and not medically necessary for children who reach age 24 months prior to the commencement of the RSV season.
Palivizumab (Synagis) is considered investigational and not medically necessary for treatment in children or infants with known RSV disease.
Immunoprophylaxis for RSV is considered investigational and not medically necessary for infants and children with hemodynamically insignificant heart disease (for example, secundum atrial septal defect, small ventricular septal defect, uncomplicated pulmonic stenosis, uncomplicated aortic stenosis, mild coarctation of the aorta, and patent ductus arteriosus) who do not otherwise meet criteria above.
Immunoprophylaxis for RSV is considered investigational and not medically necessary for infants and children with surgically corrected congenital heart disease, who do not otherwise meet criteria above.
Immunoprophylaxis for RSV is considered investigational and not medically necessary for all other indications not otherwise addressed as medically necessary, including, but not limited to, individuals with cystic fibrosis or Down syndrome who do not otherwise meet criteria above.
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:
According to the AAP (2014), palivizumab prophylaxis may be given to preterm infants born before 29 weeks, 0 days gestation who are younger than 12 months at the beginning of the RSV season. For infants born during the RSV season, less than 5 monthly doses will be needed. Available data has demonstrated that the greatest increased risk for hospitalization is in preterm infants born before 29 weeks gestation. For infants born at 29 weeks, 0 days gestation or later, a definite cutoff of gestational age for which RSV prophylaxis may be beneficial has not been demonstrated. Infants born at 29 weeks, 0 days gestation or later are not generally recommended by the AAP to receive prophylaxis, unless they qualify to receive it based on other conditions, such as CHD or CLD. Additionally, palivizumab prophylaxis is not recommended by the AAP in the second year of life based on a history of prematurity alone.
Preterm infants who develop CLD of prematurity defined as gestational age <32 weeks, 0 days and a requirement for >21% oxygen for at least the first 28 days after birth may be considered for palivizumab prophylaxis during the RSV season in the first year of life. During the second year of life prophylaxis is recommended by the AAP only for infants who meet the definition of CLD of prematurity and continue to require medical support (chronic corticosteroid therapy, diuretic therapy, or supplemental oxygen) during the 6-month period prior to the start of the second RSV season. For infants with CLD who do not continue to require medical support in the second year of life, the AAP does not recommend prophylaxis.
Congenital Heart Disease (CHD)
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 AAP (2014) reports the following in reference to immunocompromised children:
No population based data are available on the incidence of RSV hospitalization in children who undergo solid organ or hematopoietic stem cell transplantation. Severe and even fatal disease attributable to RSV is recognized in children receiving chemotherapy or who are immunocompromised because of other conditions, but the efficacy of prophylaxis in this cohort is not known. Prophylaxis may be considered for children younger than 24 months of age who are profoundly immunocompromised during the RSV season.
Cortez and colleagues (2002) studied whether RSV-IVIg provided sufficient RSV immune prophylaxis to prevent RSV pneumonia in 54 individuals undergoing stem-cell transplantation. The authors reported a low incidence of RSV infection in the 54 RSV-IVIg subjects, as well as in 31 others not enrolled in the study, but could not determine the preventive effect of RSV-IVIg. Hynicka and Ensor (2012), in a literature review, reported that data are limited on RSV prophylaxis in immunocompromised adults.
In reference to children with cystic fibrosis, the AAP Red Book (2014) states:
Routine use of palivizumab prophylaxis in patients with cystic fibrosis, including neonates diagnosed with cystic fibrosis by newborn screening, is not recommended unless other indications are present. An infant with cystic fibrosis and clinical evidence of CLD and/or nutritional compromise in the first year of life may be considered for prophylaxis. Continued use of palivizumab prophylaxis in the second year may be considered for infants with 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.
A Cochrane review initially published in 2010 and updated in 2014 assessed the use of palivizumab in infants with cystic fibrosis. One randomized controlled trial met the inclusion criteria for both reviews. The study compared 5 monthly doses of palivizumab to placebo in infants up to 2 years of age with cystic fibrosis. The authors of the review concluded that the overall incidence of adverse events was similar in both groups and it was not possible to draw conclusions on the safety and tolerability of RSV prophylaxis and palivizumab in infants with cystic fibrosis because the trial did not specify how adverse events were classified and additional randomized studies are needed.
Winterstein and collegues (2013) evaluated palivizumab effectiveness in children with cystic fibrosis by utilizing Medicaid Extract files provided by the Centers for Medicare and Medicaid Services. A cohort was established consisting of children 0–2 years of age from 27 states with a CF diagnosis between 1999 and 2006. Eligible children entered the cohort after CF diagnosis and after RSV season onset, and were followed until season end, second birthday, death, or hospitalizations for reasons other than a study outcome. The primary endpoint was hospitalization for RSV-related infections (RSV-ha). The secondary endpoint was based on hospitalization for acute respiratory illness (ARI-ha). Palivizumab exposure was defined based on pharmacy or procedure claims. Both primary and secondary outcomes were examined in a Cox regression model, adjusting for RSV risk factors and CF severity via exposure propensity score. The matched cohort included 1974 infants (2875 infant seasons), who experienced 32 RSV-ha and 212 ARI-ha (3.9 and 26.2/1000 season months, respectively). Compared to periods of no use, the adjusted hazard ratio for current use was 0.57 (95% confidence interval [CI]: 0.20–1.60) for RSV-related hospitalization and 0.85 (95% CI: 0.59–1.21) for ARI-related hospitalization. Each month of increasing age reduced the ARI-ha by 5.8%. The authors concluded that adjusted and unadjusted RSV-hospitalization incidence rates suggested potentially positive effects of palivizumab, but results were inconclusive due to small event rates. The authors also reported that age greatly affected infection risk with incidence rates for 1-2 year olds reduced to half when compared to 0-1 year old infants.
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
RSV hospitalization rates decrease during the second RSV season for all children. The AAP (2014) recommends use of palivizumab prophylaxis during the second RSV season only for preterm infants born at <32 weeks, 0 days gestation who required at least 28 days of oxygen after birth and who continue to require supplemental oxygen, chronic systemic corticosteroid therapy, or bronchodilator therapy within 6 months of the start of the second RSV season.
Prevention of Health Care Associated RSV Disease
The AAP Red Book (2014) includes the following statement regarding the use of palivizumab in controlling outbreaks of health care associated disease:
No rigorous data exist to support palivizumab use in controlling outbreaks of health care-associated disease, and palivizumab use is not recommended for this purpose. Infants in a neonatal unit who qualify for prophylaxis because of CLD, prematurity, or CHD may receive the first dose 48 to 72 hours before discharge to home or promptly after discharge.
Strict adherence to infection-control practices is the basis for reducing health care-associated RSV disease.
The AAP (2014) policy statement reports variations in the RSV season which usually begins in November or December, peaks in January or February, and ends by March or sometime in April in the temperate climates of North America (which includes most of the United States). In equatorial countries, RSV seasons vary throughout the year. There are also variations in the RSV season in the state of Florida. Although the timing of RSV seasons vary in different regions of Florida, a maximum of 5 monthly doses is adequate for qualifying infants for most RSV seasons in Florida. Florida Department of Health data may be used to determine the correct timing for the first dose of palivizumab for qualifying infants. Alaska Native infants in southwestern Alaska have longer RSV seasons and experience higher RSV hospitalization rates; therefore practitioners in this area may want to use RSV surveillance data generated by the state of Alaska to determine the start and finish of the RSV season. There is limited information available regarding RSV disease among American Indian children. However, the AAP (2014) reports that "special consideration may be prudent for Navajo and White Mountain Apache infants in the first year of life."
RSV is the leading cause of lower respiratory tract infection in infants and young children. Almost all children have been infected with RSV by age 2 years, and severe RSV disease requiring hospitalization occurs most commonly, among infants age 1 to 3 months. RSV is estimated to account for 57,500 annual hospitalizations among children younger than 5 years of age and accounts for approximately 1 out of every 334 hospitalizations in this age group yearly (Hall, 2009). RSV is usually transmitted by direct or close human contact. Risk factor reduction is important in the prevention of RSV. Infants should never be exposed to tobacco smoke and should be kept away from crowds and from situations in which exposure to infected individuals cannot be controlled. Participation in group childcare should be restricted, during the RSV season, for high-risk infants whenever feasible. It is especially important for caregivers to follow good hand hygiene practices.
The AAP guidance on palivizumab prophylaxis was previously published in 2012 and most recently updated in 2014 with new information that has become available in many areas, including:
Administration is on a monthly basis during the RSV season, and dosage is based on an individual's weight. In most seasons and regions of the continental United States, a total of 5 doses are administered, with the first dose at the beginning of November and the last dose at the beginning of March, (which will provide coverage into April). The initial recommendation for 5 doses is derived from the design of the clinical trials of palivizumab, and is corroborated by ongoing evaluation of laboratory data. In the IMpact-RSV trial and in the Feltes, et al. (2003) trial involving children with hemodynamically significant CHD, 5 monthly doses of palivizumab resulted in serum concentrations greater than or equal to 37 µg/mL for more than 20 weeks in almost all subjects. One month after the fourth monthly dose of palivizumab, the mean concentration was 72 µg/mL among subjects in the Impact-RSV trial and 90 µg/mL, in the subjects in the cardiac trial. A serum concentration greater than or equal to 30 µg/mL is the proposed serologic correlate of protection, in which this concentration results in a decrease in pulmonary RSV replication by greater than 100-fold.
The National Respiratory and Enteric Virus Surveillance System (NREVSS) is a voluntary, laboratory-based surveillance system of clinical and public health laboratories which report weekly to the Centers for Disease Control and Prevention (CDC) on the number of specimens tested and the number that tested positive for several respiratory and enteric viruses. Specific information from NREVSS about national and regional RSV trends is available at: http://www.cdc.gov/surveillance/nrevss/rsv/default.html. The CDC uses RSV antigen detection data from the NREVSS to help define the RSV season. Mullins and colleagues (2003) from the CDC defined the season onset week for a given laboratory as the first of two consecutive weeks of at least 10% positive test results with at least two positive samples in the numerator of the reports of both weeks. Offset week was defined as the last of the final two consecutive weeks of at least 10% positive tests with at least 2 positive samples in the numerator in the reports of both weeks.
Synagis is currently the only drug commercially available in the U.S. that is FDA-approved for prevention of RSV infections. It is postulated that use of Synagis was preferred over the formerly available RespiGam (RSV IgIV) in the practice community, due to the ease of administration, lack of interference with measles-mumps-rubella (MMR) vaccine and varicella vaccine, and lack of complications, associated with intravenous administration. RSV infection in adults, though recognized for several decades, has been overlooked, at least in part, because of the importance of RSV in the pediatric population. A recent study has placed the public health dimensions of RSV infection in adults in perspective. Though there are no immediate clinical implications of this study, it does have important repercussions for public health strategy and for the prioritization of the development of vaccines and antiviral agents (Falsey, 2005). Palivizumab has become the standard for the prevention of RSV infection in high-risk infants; however, the agent is untested in the elderly.
Chronic lung disease (CLD) and bronchopulmonary dysplasia (BPD): Abnormal development or growth (dysplasia) of the lungs and air passages developed by premature infants exposed to oxygen therapy.
Congenital heart disease (CHD): Heart problems present at birth.
Cyanotic: Turning pale or blue because of breathing or circulation problems; some lung or heart conditions do not allow the proper amount of oxygen to reach the blood and the body; the individual may appear very pale or even slightly blue, for example in the lips or fingers.
Ig (immune [or immuno-] globulin): An antibody, a protein made by the immune system.
Immunoprophylaxis: Prevention of disease by the use of vaccine or a serum containing antibodies.
Lower respiratory tract infection: Infection of the lungs, such as bronchiolitis or pneumonia.
The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.
When services may be Medically Necessary when criteria are met:
|90378||Respiratory syncytial virus, monoclonal antibody, recombinant, for intramuscular use, 50 mg, each [Synagis]|
|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-9 Diagnosis||[For dates of service prior to 10/01/2015]|
|ICD-10 Diagnosis||[For dates of service on or after 10/15/2015]|
When services are Not Medically Necessary:
For the procedure codes listed above, for the circumstances indicated in the Position Statement section as not medically necessary.
When services are Investigational and Not Medically Necessary:
For the procedure codes listed above when criteria are not met; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
|Websites for Additional Information|
Chronic Lung Disease
The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.
|Revised||11/13/2014||Medical Policy & Technology Assessment Committee (MPTAC) review. Clarified "profoundly immunocompromised" in medically necessary statement. Description and Reference sections updated.|
|Revised||08/14/2014||MPTAC review. Position statements revised to correspond with updated 2014 AAP recommendations. Description, Rationale, Background and Reference sections updated.|
|Revised||08/08/2013||MPTAC review. Position statement clarified regarding other siblings in the home. Rationale and Reference sections updated.|
|Revised||08/09/2012||MPTAC review. Note in position statement clarified. Position statement #2 removed and integrated into #1 and #6 (now #5). Rationale, Background and Reference sections updated.|
|Revised||08/18/2011||MPTAC review. Clarified investigational and not medically necessary statements for hemodynamically insignificant heart disease and for surgically corrected congenital heart disease with the addition of the wording "who do not otherwise meet criteria above." Revised medically necessary statement for infants with congenital abnormalities of the airway or a neuromuscular condition that compromises handling of respiratory secretions. Rationale, Background, Definition, and Reference sections updated.|
|Reviewed||08/19/2010||MPTAC review. Description, Note in position statement, Rationale, Background, References, and Index updated.|
|01/01/2010||Updated Coding section with 01/01/2010 CPT/HCPCS changes; removed codes 90379 and J1565 deleted 12/31/2009.|
|Revised||08/27/2009||MPTAC review. The criteria for RSV prophylaxis were revised for premature infants born between 32 and 35 weeks' and for infants with congenital abnormalities of the airway or neuromuscular disease who were born before 35 weeks of gestation who have either congenital abnormalities of the airway or a neuromuscular condition that compromises handling of respiratory secretions. The Rationale section has been updated with information about the 2009 updated Red Book recommendations from the American Academy of Pediatrics (AAP). The descriptions of gestational age within the medical necessity criteria for premature infants have been revised consistent with the AAP update. References were updated.|
|Revised||11/20/2008||MPTAC review. The medically necessary criteria for use of Synagis in premature infants was clarified to indicate that infants born at 28, or less, weeks of gestation (up to and including 28 weeks, 0 days) may benefit if they are less than 12 months of age at the start of the RSV season; or infants born at 29 to 32 weeks gestation (beginning 28 weeks, 1 day through 32 weeks, 0 days) may benefit if they are less than 6 months of age at the start of the RSV season; and infants born between 32 and 35 weeks gestation, (beginning 32 weeks, 1 day through 35 weeks, 0 days) may benefit if they are less than 6 months of age at the start of the RSV season and have 2 or more risk factors. An additional position statement was added to clarify that continued monthly doses of palivizumab beyond the end of the present-year RSV season is considered not medically necessary. Also, the investigational and not medically necessary position statement was revised to add the following: cystic fibrosis patients without reduced lung reserve and the separate position statement was clarified regarding children aged 24 months or older at the start of the RSV season as being considered investigational and not medically necessary. Rationale and References were also updated.|
|Revised||11/29/2007||MPTAC review. Information was added to the medical necessity criteria under hemodynamically significant congenital heart disease (CHD) recommending a dose of palivizumab for children who undergo cardiopulmonary bypass, to be given as soon as possible post-bypass. A new statement was added under the "Not Medically Necessary" section as follows: Immunoprophylaxis for RSV is considered not medically necessary for children less than 24 months of age when criteria are not met. A new statement was also added to the "Investigational and Not Medically Necessary" section as follows: Immunoprophylaxis for RSV is considered investigational and not medically necessary for children ages 24 months or older when criteria are not met. The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary." Information was also added to the Background section for clarification of the definition of RSV prevalence in a given community. References were updated.|
|Revised||08/23/2007||MPTAC review. Minor revisions were made to the medical necessity criteria for clarification regarding reduced lung reserve patients requiring medical treatment within six months before the start of the RSV Season and for premature candidates exposed to environmental air pollutants within the home. The investigational/not medically necessary statement regarding children/infants with known disease was also clarified to refer to treatment, not prophylaxis (which was the former language). Information was also clarified within the 'Background/Overview' section regarding the recommended serum concentration level (changed from 40 ug/mL to 30 ug/mL taken from the Impact-RSV trial) and the recommendation that once a child meets criteria for treatment with Synagis, administration should continue throughout the season and not stop at the point that the infant reaches either six or 12 months of age (taken from the 2006 AAP Red Book).|
|Reviewed||05/17/2007||MPTAC review. No change to criteria. References were updated.|
|Revised||06/08/2006||MPTAC review. Revision made to Position statement to remove reference to RespiGam which is no longer available. References also updated.|
|Revised||07/14/2005||MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.|
Last Review Date
|Anthem, Inc.||09/30/2004||DRUG.00015||Prevention of Respiratory Syncytial Virus Infections|
|WellPoint Health Networks, Inc.||06/24/2004||8.05.01||Immune Prophylaxis for Respiratory Syncytial Virus|