|MP 5.01.10||Immune Prophylaxis for Respiratory Syncytial Virus|
|Original Policy Date
|Last Review Status/Date
Reviewed with literature search/8:2014
|Return to Medical Policy Index|
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Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections in children. At highest risk are those younger than 2 years of age with prematurity, chronic lung disease (CLD) of prematurity (formerly known as bronchopulmonary dysplasia), congenital heart disease, or multiple congenital anomalies. Immune prophylaxis against RSV is a prevention strategy to reduce the incidence of infection and its associated morbidity, including hospitalization, in high-risk infants.
Based on the weight of the clinical evidence from randomized clinical trials (RCTs), systematic reviews, and strong clinical consensus, immune prophylaxis for RSV has demonstrated reductions in RSV-related hospitalizations in select populations of susceptible infants and children. Therefore, immune prophylaxis for RSV may be considered medically necessary for the patients listed in the policy statement below. For all other uses of immune prophylaxis, the clinical evidence is not convincing that RSV hospitalizations will decrease. Therefore, the policy statements below note indications that are considered investigational or not medically necessary. The policy statements are in agreement with the 2014 American Academy of Pediatrics (AAP) Guidelines.
RSV infections typically occur in the winter months, starting from late October to mid-January and ending from March to May.3 Considerable variation in the timing of community outbreaks is observed year to year. According to CDC, onset of the RSV season occurs when the median percentage of specimens testing positive for RSV is 10% higher over a 2-week period. During 1997 to 2006, an estimated 132,000 to 172,000 children aged younger than 5 years were hospitalized for RSV infection annually in the United States.3
CLD of prematurity (formerly known as bronchopulmonary dysplasia) is a general term for long-term respiratory problems in premature infants. CLD results from lung injury to newborns who, consequently, must use a mechanical ventilator and supplemental oxygen for breathing. With injury, lung tissues become inflamed, and scarring can result. Causes of lung injury include the following: prematurity, low amounts of surfactant, oxygen use, mechanical ventilation. Risk factors for developing CLD include birth at less than 34 weeks’ gestation; birth weight less than 2000 grams (4 pounds, 6.5 ounces); hyaline membrane disease; pulmonary interstitial emphysema; patent ductus arteriosus; Caucasian race; male sex; maternal womb infection (chorioamnionitis); and family history of asthma.
In contrast to the well-documented beneficial effect of breastfeeding against many viral illnesses, existing data are conflicting regarding the specific protective effect of breastfeeding against RSV infection. Breastfeeding should be encouraged for all infants in accordance with recommendations of the American Academy of Pediatrics (AAP). High-risk infants should be kept away from crowds and from situations in
which exposure to infected individuals cannot be controlled. Participation in group child care should be restricted during the RSV season for high-risk infants whenever feasible. Parents should be instructed on the importance of careful hand hygiene. In addition, all high-risk infants 6 months of age and older and their contacts should receive influenza vaccine, as well, as other recommended age-appropriate
This policy does not address therapies to treat RSV infection.
In June 1998, the biologic drug, Synagis® (palivizumab; MedImmune Inc., Gaithersburg, MA), was approved for marketing by FDA through the biologics licensing application for use in the prevention of serious lower respiratory tract disease caused by RSV in pediatric patients at high risk of RSV disease. In July 2004, FDA approved a liquid formulation of Synagis®, supplied as a sterile solution ready for injection, thus providing improved convenience for administration. This formulation is used in the physician office or home setting. There are no therapeutic equivalents to this drug. FDA application number: (BLA)103770.
RespiGam® RSV-IVIG for intravenous use was available from 1993 to 2009. It is no longer manufactured.
In August 2010, motavizumab (proposed to be marketed as Rezield™, MedImmune Inc.) received a complete response letter from FDA requesting additional clinical data on its biologics license application. Subsequently, AstraZeneca suspended motavizumab development and on the manufacturer’s request, FDA withdrew its biological license application.
Monthly administration of immune prophylaxis for respiratory syncytial virus (RSV) during the RSV season
with palivizumab may be considered medically necessary in the following infants and children in
accordance with current (2014) guidelines from the American Academy of Pediatrics:
1. In the first year of life, ie, younger than 12 months at the start of the RSV season or born during the RSV season:
a. Infants born before 29 weeks, 0 days’ gestation;
b. Preterm infants with chronic lung disease (CLD) of prematurity, defined as birth at less than 32 weeks, 0 days’ gestation and a requirement for more than 21% oxygen for at least the first 28 days after birth;
c. Certain infants with hemodynamically significant heart disease (eg, infants with acyanotic heart disease who are receiving medication to control congestive heart failure and will require cardiac surgical procedures; infants with moderate to severe pulmonary hypertension; infants with lesions adequately corrected by surgery who continue to require medication for heart failure);
i. Decisions regarding palivizumab prophylaxis for infants with cyanotic heart defects in the first year of life may be made in consultation with a pediatric cardiologist.
d. Children with pulmonary abnormality or neuromuscular disease that impairs the ability to clear secretions from the upper airways (eg, ineffective cough, recurrent Gastroesophageal tract reflux, pulmonary malformations, tracheoesophageal fistula, upper airway conditions, or conditions requiring tracheostomy);
e. Children with cystic fibrosis who have at least one of the following conditions:
i. Clinical evidence of CLD; and/or
ii. Nutritional compromise.
2. In the second year of life, ie, younger than 24 months at the start of the RSV season:
a. Children who were born at less than 32 weeks, 0 days’ gestation and required at least 28 days of supplemental oxygen after birth and who continue to require medical intervention (supplemental oxygen, chronic corticosteroid, or diuretic therapy) during the 6-month period before the start of the second RSV season.
b. Children with cystic fibrosis who have either:
i. 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
ii. Weight for length less than the 10th percentile.
3. In the first or second year of life:
a. Children who will be profoundly immunocompromised (eg, will undergo solid organ or hematopoietic stem-cell transplantation or receive chemotherapy) during the RSV season.
4. After surgical procedures that use cardiopulmonary bypass, for children who still require prophylaxis, a postoperative dose of palivizumab may be considered medically necessary after cardiac bypass or at the conclusion of extracorporeal membrane oxygenation for infants and children younger than 24 months.
Immunoprophylaxis for respiratory syncytial virus is considered not medically necessary in:
1. Infants and children with hemodynamically insignificant heart disease (eg, secundum atrial septal defect, small ventricular septal defect, pulmonic stenosis, uncomplicated aortic stenosis, mild coarctation of the aorta, and patent ductus arteriosus);
2. Infants with lesions adequately corrected by surgery, unless they continue to require medication for heart failure;
3. Infants with mild cardiomyopathy who are not receiving medical therapy for the condition; or
4. Children with congenital heart disease in the second year of life.
Other indications for immune prophylaxis for respiratory syncytial virus are considered investigational including, but not limited to, controlling outbreaks of health care-associated disease; or use in children with cystic fibrosis or Down syndrome, unless criteria for medical necessity (outlined above) are satisfied.
Dosing and Administration
Palivizumab is administered by intramuscular injection in a dose of 15 mg/kg of body weight per month. The anterolateral aspect of the thigh is the preferred injection site. Routine use of the gluteal muscle for the injection site can cause sciatic nerve damage.
Clinicians may administer up to a maximum of 5 monthly doses of palivizumab (15 mg/kg per dose) during the RSV season to infants who qualify for prophylaxis. Qualifying infants born during the RSV season will require fewer doses. For example, infants born in January would receive their last dose in March (see “Initiation and Termination of Immunoprophylaxis,” next).1
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.
If any infant or young child receiving monthly palivizumab prophylaxis experiences a breakthrough RSV hospitalization, monthly prophylaxis should be discontinued because of the extremely low likelihood of a second RSV hospitalization in the same season (<0.5%).1
Prevention of Health Care Associated RSV Disease
RSV is known to be transmitted in the hospital setting and to cause serious disease in high-risk infants. Among hospitalized infants, the major means to reduce RSV transmission is strict observance of infection control practices, including restriction of visitors to the neonatal intensive care unit during respiratory virus season and prompt initiation of precautions for RSV-infected infants. If an RSV outbreak occurs in a high- risk unit (eg, pediatric or neonatal intensive care unit or stem-cell transplantation unit), primary emphasis should be placed on proper infection control practices, especially hand hygiene. No data exist to support palivizumab use in controlling outbreaks of health care‒associated disease, and palivizumab use is not recommended for this purpose.
Palivizumab does not interfere with response to vaccines.
Palivizumab may interfere with RSV diagnostic tests that are immunologically based (eg, some antigen detection-based assays).
Risk Minimization Techniques
Infants, especially high-risk infants, should never be exposed to tobacco smoke. In published studies, passive household exposure to tobacco smoke has not been associated with an increased risk of RSV hospitalization on a consistent basis. However, exposure to tobacco smoke is a known risk factor for many adverse health-related outcomes. Exposure to tobacco smoke can be controlled by the family of an infant at increased risk of RSV disease, and preventive measures will be less costly than palivizumab prophylaxis.
For all infants, particularly those who are preterm, the environment should be optimized to prevent RSV and other viral respiratory infections by offering breast milk feeds, immunizing household contacts with influenza vaccine, practicing hand and cough hygiene, and by avoiding tobacco or other smoke exposure, and attendance in large group child care during the first winter season, whenever possible.²
Initiation and Termination of Immunoprophylaxis
Initiation of immunoprophylaxis in November and continuation for a total of 5 monthly doses will provide protection into April and is recommended for most areas of the United States. If prophylaxis is initiated in October, the fifth and final dose should be administered in February.
In the temperate climates of North America, peak RSV activity typically occurs between November and March, whereas in equatorial countries, RSV seasonality patterns vary and may occur throughout the year. The inevitability of the RSV season is predictable, but the severity of the season, the time of onset, the peak of activity, and the end of the season cannot be predicted precisely. Substantial variation in timing of community outbreaks of RSV disease from year to year exists in the same community and between communities in the same year, even in the same region. These variations occur within the overall pattern of RSV outbreaks, usually beginning in November or December, peaking in January or February, and ending by the end of March or sometime in April. Communities in the southern United States, particularly some communities in the state of Florida, tend to experience the earliest onset of RSV activity. In recent years, the national duration of the RSV season has been 21 weeks.3
Results from clinical trials indicate that palivizumab trough serum concentrations more than 30 days after the fifth dose will be well above the protective concentration for most infants. Five monthly doses of palivizumab will provide more than 20 weeks of protective serum antibody concentration. In the continental United States, a total of 5 monthly doses for infants and young children with congenital heart disease, CLD of prematurity, or preterm birth before 32 weeks’ gestation (31 weeks, 6 days) will provide an optimal balance of benefit and cost, even with variation in season onset and end.
Data from the Centers for Disease Control and Prevention (CDC) have identified variations in the onset and offset of the RSV season in the state of Florida that should affect the timing of palivizumab administration. Northwest Florida has an onset in mid-November, which is consistent with other areas of the United States. In north central and southwest Florida, the onset of RSV season typically is late September to early October. The RSV season in southeast Florida (Miami-Dade County) typically has its onset in July. Despite varied onsets, the RSV season is of equal duration in the different regions of Florida. Children who receive palivizumab prophylaxis for the entire RSV season should receive palivizumab only during the 5 months after 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.
BlueCard/National Account Issues
State or national mandates (e.g., FEP) may dictate that all FDA-approved biologics may not be considered investigational and thus these biologics may be assessed on the basis of their medical necessity.
This policy was created in 1999 and was regularly updated with searches of the MEDLINE database. The most recent literature search was performed for the period through July 7, 2014. The following is a summary of key findings to date.
In 2008, the U.K. Department of Public Health and Epidemiology, University of Birmingham, released a Health Technology Assessment (HTA) on immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children.4 This HTA report was updated in 2011; the update developed the economic model from the first report by cost-effectiveness in different subgroups of children with RSV infection.5 Thirteen studies published through August 2009 were included in this updated analysis. Most studies were small and not powered for outcomes of interest, and the quality of reporting also was frequently poor. In the original HTA report, 2 randomized controlled trials (RCTs) (summarized next)6,7 were used for establishing the relative risk of hospitalization in children given palivizumab compared with those not treated with palivizumab. No additional RCTs of palivizumab were found for the HTA update in 2011.5
Randomized Controlled Trials
Several RCTs have demonstrated the success of immune prophylaxis of RSV. In 2013, Blanken et al published the multicenter, double-blind, randomized, placebo-controlled MAKI trial to investigate the potential causal role of RSV infection in the pathogenesis of wheezing illness during the first year of life and the effect of palivizumab prophylaxis.8 The trial randomly assigned 429 otherwise healthy preterm infants born at a gestational age of 33 to 35 weeks to receive either monthly palivizumab injections (214 infants) or placebo (215 infants) during RSV season. The prespecified primary outcome was the total number of parent-reported wheezing days in the first year of life. Premature infants treated with palivizumab had a significant 61% relative decrease in the total number of wheezing days during the first year of life (95% confidence interval [CI], 56 to 65). Moreover, the effect of RSV prevention on the number of wheezing days persisted in the postprophylaxis period (ie, starting at 2 months after the last injection) for a relative reduction of 73% (95% CI, 66 to 80). Additionally, palivizumab treatment reduced hospitalizations related to RSV infection (12.6% in the RSV prevention group compared with 21.9% in the
placebo group [p=0.04]).
In the 1998 Impact-RSV Study, prophylaxis with palivizumab for preterm infants with or without chronic lung disease (CLD) resulted in a 55% reduction in RSV hospital admission (4.8% [48/1002] in the
palivizumab group and 10.6% [53/500] in the no-prophylaxis group).6 Similar reductions in other measures of RSV severity in breakthrough infections also were reported. In a 2003 double-blind, placebo- controlled randomized trial of 1287 children with hemodynamically significant congenital heart disease (CHD), Feltes et al reported that prophylaxis with palivizumab was associated with a 45% reduction in hospitalizations for RSV among children with CHD.7 Hospitalization for RSV occurred in 5.3% (34/639) of the palivizumab group and 9.7% (63/648) of the no prophylaxis group. The authors concluded that prophylaxis with palivizumab is clinically effective for reducing the risk of serious lower respiratory tract infection caused by RSV infection and requiring hospitalization in high-risk children.
In 1997, the PREVENT Study Group reported on a trial that randomly assigned 510 infants with prematurity or CLD to receive either placebo or RSV-intravenous immunoglobulin (IVIg) infusions monthly for 5 months.9 The authors reported a 41% reduction in hospitalization due to RSV infection and reductions in other measures of RSV infection severity when it did occur. Palivizumab eventually became the preferred product over IVIg due to the convenience of intramuscular administration, safety concerns regarding immunoglobulin pooled from multiple donors, and the unlimited supply of a bioengineered product.
In 2008, Cohen et al evaluated the characteristics of patients (N=19,548) enrolled in the Palivizumab Outcomes Registry who had CHD.10 The Palivizumab Outcomes Registry prospectively collected data on patients who received RSV prophylaxis with palivizumab during the 2000 to 2004 RSV seasons. The percentage of registry patients with CHD increased from 4.8% (102/2116) in the first season to 11.4% (688/6050) in the last season. Across all 4 seasons, 1500 patients with CHD were enrolled, 71% of whom had acyanotic CHD. The proportion with cyanotic CHD increased from 19.6% (20/102) in the 2000 to 2001 season to 37.5% (258/688) in the 2003 to 2004 season, while the proportion of all CHD in the registry more than doubled during this time. Cumulative incidence of RSV hospitalization was 1.9% among patients with CHD who received prophylaxis. Among patients with cyanotic and acyanotic CHD, hospitalizations occurred in 2.6% and 1.6%, respectively. As stated by the authors, “Prospective data collected in the Palivizumab Outcomes Registry provide the largest published dataset available on infants with CHD receiving palivizumab and show low hospitalization rates and use consistent with prelicensure clinical trial data and revised American Academy of Pediatrics guidelines.”
A 2008 review article discussed the development of a second-generation humanized monoclonal antibody (mAb), motavizumab, which is no longer under study in Phase 3 clinical trials, and a third generation version of motavizumab, Numax-YTE, which is designed to prolong half-life.11,12 More recently, a randomized trial in 112 children hospitalized for RSV lower respiratory tract infection showed no effect of motavizumab on RSV viral load, duration of hospitalization, severity of illness, or wheezing episodes during 12-month follow up compared with placebo.13
A Cochrane review published in 2010 and updated in 2013 and 2014 assessed the use of palivizumab in children with cystic fibrosis.14-16 Based on a literature search through February 2014, 1 randomized comparative trial met inclusion criteria of all reviews. In the trial, 186 infants younger than 2 years with cystic fibrosis were randomly assigned to receive 5 monthly doses of palivizumab (n=92) or placebo (n=94). One member of each group was hospitalized for RSV within the 6-month follow-up period. The incidence of adverse events was relatively high in both groups, with serious adverse events not significantly different between the palivizumab and placebo groups (20.2% and 17.3%, respectively). Cochrane authors noted that it was not possible to draw conclusions on the safety and tolerability of RSV immune prophylaxis in cystic fibrosis: Although the trial reported similar incidences of adverse events, it did not specify how adverse events were classified, and no clinically meaningful outcome differences were noted at 6-month follow-up. Cochrane authors called for additional randomized studies to establish safety and efficacy of immune prophylaxis in children with cystic fibrosis.
In 2013, Sánchez-Solis et al published a systematic review with meta-analysis of palivizumab prophylaxis for RSV infection in cystic fibrosis patients.17 Literature was searched through November 2012; 4 prospective and retrospective observational studies, a questionnaire, and the randomized trial included in the Cochrane review described earlier were included (total N=617). Historical controls and non- prophylaxed cohorts from 3 other studies also were included. In separate random effects meta-analyses, weighted mean hospitalization rates were 0.018 (95% CI, 0.007 to 0.048) for 354 palivizumab-treated patients and 0.126 (95% CI, 0.086 to 0.182) for 463 controls, a statistically significant difference (p<0.001). However, in a meta-analysis of the 3 studies that included treated and untreated patients (ie, contemporaneous controls), the between-group difference was no longer statistically significant (weighted mean hospitalization rate, 0.024 [95% CI, 0.005 to 0.098] for palivizumab-treated patients vs 0.093 [95% CI, 0.037 to 0.218] for controls; p=0.115).
The use of RSV-IVIg or palivizumab in patients with documented immunodeficiencies also has been suggested. AAP guidelines note, "Palivizumab or RSV-IVIg has not been evaluated in randomized trials in immunocompromised children. Although specific recommendations for immunocompromised patients cannot be made, children with severe immunodeficiencies (eg, severe combined immunodeficiency or severe acquired immunodeficiency syndrome) may benefit from prophylaxis. If these infants and children are receiving standard intravenous immune globulin monthly, physicians may consider substituting RSV- IVIg during the RSV season."18
Immunocompromised patients undergoing stem-cell transplantation also are at risk for potentially lethal respiratory viral infections. Cortez et al (2002) studied whether RSV-IVIg provided sufficient RSV immune prophylaxis to prevent RSV pneumonia in 54 patients undergoing stem-cell transplantation.19 The authors reported a low incidence of RSV infection in 54 RSV-IVIg patients, as well as in 31 patients not enrolled in the study, and could not determine the preventive effect of RSV-IVIg. In a 2012 literature review, Hynicka and Ensor found that data on RSV prophylaxis in immunocompromised adult patients are limited.20 The only prospective study identified in the review was by Kassis et al (2010)21 who administered intravenous pavilizumab to 16 high-risk stem-cell transplant recipients to prevent nosocomial spread of RSV infection from 5 stem-cell transplant recipients on the same adult inpatient unit. After 1 week, no further RSV cases occurred, but whether controlling the spread of RSV on the stem-cell transplant unit was related to RSV prophylaxis versus implementation of strict quarantine and infection control practices cannot be determined.
In 2014, Yi et al published a prospective cohort study of palivizumab prophylaxis for RSV infection in children with Down syndrome who were younger than 2 years of age.22 The primary efficacy outcome was RSV-related hospitalization during the RSV season, defined broadly as September 1 to May 31. Among 532 palivizumab-treated children with Down syndrome from the Canadian RSV Evaluation Study of Palivizumab registry who were enrolled between 2005 and 2012 (184 patient-years of follow-up), 8 (1.5%) were hospitalized for RSV. Among 233 nonprophylaxed children with Down syndrome from a national Dutch cohort enrolled between 2003 and 2005 (324 patient-years of follow-up), 23 (9.9%) were hospitalized for RSV. The incidence rate ratio for RSV-related hospitalization (adjusted for hemodynamically significant CHD, insignificant CHD, gestational age, and birth weight) in untreated patients compared with treated patients was 3.63 (95% CI, 1.52 to 8.67), indicating an approximately 4-fold risk of RSV-related hospitalization during the RSV season in untreated patients. Use of a noncontemporaneous comparative cohort from a different country introduced potential bias due to different indications for hospitalization and different environmental factors that could affect the severity of RSV infection. Conclusions that can be drawn from this study are therefore limited.
Duration of Prophylaxis
The RSV season typically occurs from November to April. Within the United States, the inevitability of the RSV season is predicable, but the severity of the season and time of onset are variable from year to year and also between geographic areas within a given year. This has led to requests for either earlier or later immunoprophylaxis, or more than 5 monthly doses. Nevertheless, as pointed out by Meissner et al (2004) from the Centers of Disease Control and Prevention (CDC), this yearly and regional variation “occurs within the overall pattern of RSV outbreaks, usually beginning in November or December, peaking in January or February, and ending by March. Communities in the southern region tend to experience the earliest onset of RSV activity, and Midwestern states tend to experience the latest onset, but community to community variation in timing precludes using either national or regional data to precisely predict individual community RSV outbreaks. The duration of the season for western and northeast regions typically occurs between that noted in the South and the Midwest.”23 The authors pointed out that the recommendation for 5 monthly doses is derived from randomized trials of palivizumab. A serum palivizumab concentration of greater than 30 μg/mL is the target level for protection, and in randomized trials, trough levels of palivizumab exceeded 30 μg/mL for at least 30 days after the fifth dose. This indicates that 5 monthly doses provide substantially more than 20 weeks of protective serum antibody levels, covering most of the RSV season even with variation in season onset and end.
In a 2014 article sponsored by MedImmune, manufacturer of palivizumab, Makari et al recommended full-season RSV prophylaxis with palivizumab for preterm infants of 32 to 34 weeks’ gestational age rather than discontinuation of palivizumab at 3 months of age, as is currently recommended.24 The authors reviewed several studies and concluded that elevated risk of RSV-related hospitalization persists through age 6 months. In contrast, Winterstein et al (2013) in a non-industry-sponsored study found support for a 3-month age limit for RSV prophylaxis among preterm infants of 32 to 34 weeks’ gestational age.25 The authors compared RSV-related hospitalizations among preterm and term infants with siblings using Medicaid databases in Florida and Texas (total N=247,566). In both databases, the risk of RSV-related hospitalization among preterm infants was similar to that for 1-month-old term infants at approximately 4.4 months of age (4.2 months in Florida [95% CI, 2.5 to 5.7] and 4.5 months in Texas [95% CI, 2.8 to 6.4]). Given palivizumab’s 30-day window of effectiveness, prophylaxis to age 3 months would provide coverage until the estimated 4.4-month age threshold. Currently, primary evidence to establish when infants of 32 to 34 weeks’ gestational age develop lung function and immunologic responses similar to their term counterparts is lacking. Given emerging and contradictory evidence about RSV prophylaxis duration in these infants, modifications of current guidance cannot be recommended.
Frogel et al (2010) reviewed the medical literature on compliance with palivizumab therapy and the relation between hospitalization rates in fully compliant and less compliant groups.26 A total of 25 articles and abstracts were included. Significant heterogeneity was detected due to between-study differences inpatient samples and the definition of compliance used. Incidence of compliance (however defined) ranged from 25% to 100%, compared with incidences reported in licensing studies of 92% to 93%. This led review authors to conclude that compliance in practice is far more variable. Minorities and patients on Medicaid were less likely to receive the full complement of palivizumab doses, and patients participating in a home health program (defined as nurse-delivered injections performed in the home) tended to have
higher compliance and less hospitalization.
Ongoing and Unpublished Clinical Trials
A search of online site ClinicalTrials.gov identified 2 active observational studies addressing palivizumab in infants 2 years or younger (NCT01155193; NCT01269528) and 1 observational study in infants and toddlers (NCT00420966).
Clinical Input Received from Physician Specialty Societies and Academic Medical Centers
In response to requests, input was received through 3 physician specialty societies (7 responders) while this policy was under review in 2009. While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted. Almost all of those providing input agreed with the policy statements approved in October 2009; these statements are in agreement with the 2009 AAP guidelines.
Summary of Evidence
Based on the weight of the clinical evidence from randomized clinical trials, systematic reviews, and strong clinical consensus, immune prophylaxis for respiratory syncytial virus (RSV) has demonstrated reductions in RSV-related hospitalizations in select populations of susceptible infants and children. Therefore, immune prophylaxis for RSV may be considered medically necessary for the patients listed in the previously stated policy statement. For all other uses of immune prophylaxis, clinical evidence has not
established that RSV hospitalizations will decrease. Therefore, the policy statements previously stated note indications that are considered investigational or not medically necessary. The policy statements are in agreement with the 2014 American Academy of Pediatrics (AAP) Guidelines. Current evidence for duration of prophylaxis in preterm infants of 32 to 34 weeks’ gestational age is inconsistent and insufficient to support deviation from AAP guidelines.
Practice Guidelines and Position Statements
Since 2003, AAP has released policy statements and guidelines on the use of palivizumab in high-risk infants.18,27-29 AAP’s most recent guidance was based on a technical report, and both were published in 2014.1,2 Current recommendations are summarized in the Policy Statements and Policy Guidelines.
American Association for the Study of Liver Diseases and the American Society of Transplantation
In 2013, American Association for the Study of Liver Diseases and American Society of Transplantation published joint practice guidelines for long-term medical management of the pediatric patient after liver transplantation.30 Although the risk of community-acquired infections, such as RSV, is associated with posttransplant immunosuppression, “no guidance exists for RSV prophylaxis” (grade 1 [strong] recommendation based on level B [moderate quality] evidence).
U.S. Preventive Services Task Force Recommendations
The U.S. Preventive Services Task Force (USPSTF) makes the following statement regarding immunizations for children:
“USPSTF recognizes the importance of immunizations in primary disease prevention. However, USPSTF does not wish to duplicate the significant investment of resources made by others to review new evidence on immunizations in a timely fashion and make recommendations. The USPSTF therefore will not update its 1996 recommendations. The Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP) publishes recommendations on immunizations for children and adults. The methods used by ACIP to review evidence on immunizations may differ from the methods used by the USPSTF. For ACIP's current recommendations on immunizations, please refer to the National Immunization Program site at http://www.cdc.gov/vaccines/schedules/index.html
ACIP does not specifically address RSV prevention/immunization. Currently, there is no safe and effective RSV vaccine. Scientists at the National Institutes of Health and at 2 pharmaceutical companies are working to develop RSV vaccines.32
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
- Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. Pediatrics. Aug 2014;134(2):415-420. PMID 25070315
- Technical report: updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. Pediatrics. Aug 2014;134(2):e620-e638. PMID 25070304
- Respiratory syncytial virus--United States, July 2011-January 2013. MMWR Morb Mortal Wkly Rep. 2013;62(8):141-144. PMID 21900874
- 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. Dec 2008;12(36):iii, ix-x, 1-86. PMID 19049692
- Wang D, Bayliss S, C. M. Palivizumab for immunoprophylaxis of respiratory syncytial 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):i-xii, 1-123. PMID
- Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. The IMpact-RSV Study Group. Pediatrics. Sep 1998;102(3 Pt 1):531-537. PMID 9738173
- Feltes TF, Cabalka AK, Meissner HC, et al. Palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically significant congenital heart disease. J Pediatr. Oct 2003;143(4):532-540. PMID 14571236
- Blanken MO, Rovers MM, Molenaar JM, et al. Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. N Engl J Med. May 9 2013;368(19):1791-1799. PMID 23656644
- Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis. The PREVENT Study Group. Pediatrics. Jan 1997;99(1):93-99. PMID 8989345
- Cohen SA, Zanni R, Cohen A, et al. Palivizumab use in subjects with congenital heart disease: results from the 2000-2004 Palivizumab Outcomes Registry. Pediatr Cardiol. Mar 2008;29(2):382-387. PMID 17926087
- Wu H, Pfarr DS, Losonsky GA, et al. Immunoprophylaxis of RSV infection: advancing from RSV-IGIV to palivizumab and motavizumab. Curr Top Microbiol Immunol. 2008;317:103-123. PMID 17990791
- Robbie GJ, Criste R, Dall'acqua WF, et al. A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrob Agents Chemother. Dec 2013;57(12):6147-6153. PMID 24080653
- Ramilo O, Lagos R, Saez-Llorens X, et al. Motavizumab treatment of infants hospitalized with respiratory syncytial virus infection does not decrease viral load or severity of illness. Pediatr Infect Dis J. Jul 2014;33(7):703-709. PMID 24356256
- Robinson KA, Odelola OA, Saldanha I, et al. Palivizumab for prophylaxis against respiratory syncytial virus infection in children with cystic fibrosis. Cochrane Database Syst Rev. 2010;2:CD007743. PMID 20166098
- Robinson KA, Odelola OA, Saldanha IJ, et al. Palivizumab for prophylaxis against respiratory syncytial virus infection in children with cystic fibrosis. Cochrane Database Syst Rev. 2013(6):CD007743. PMID 22336832
- Robinson KA, Odelola OA, Saldanha IJ. Palivizumab for prophylaxis against respiratory syncytial virus infection in children with cystic fibrosis. Cochrane Database Syst Rev. 2014;5:CD007743. PMID 24851825
- Sánchez-Solis M, Gartner S, Bosch-Gimenez V, et al. Is palivizumab effective as a prophylaxis of respiratory syncytial virus infections in cystic fibrosis patients? A meta-analysis. Allergol Immunopathol (Madr). Nov 11 2013. PMID 24231153
- Prevention of respiratory syncytial virus infections: indications for the use of palivizumab and update on the use of RSV-IGIV. American Academy of Pediatrics Committee on Infectious Diseases and Committee of Fetus and Newborn. Pediatrics. Nov 1998;102(5):1211-1216. PMID 9794957
- Cortez K, Murphy BR, Almeida KN, et al. Immune-globulin prophylaxis of respiratory syncytial virus infection in patients undergoing stem-cell transplantation. J Infect Dis. Sep 15 2002;186(6):834-838. PMID 12198619
- Hynicka LM, Ensor CR. Prophylaxis and treatment of respiratory syncytial virus in adult immunocompromised patients. Ann Pharmacother. Apr 2012;46(4):558-566. PMID 22395247
- Kassis C, Champlin RE, Hachem RY, et al. Detection and control of a nosocomial respiratory syncytial virus outbreak in a stem cell transplantation unit: the role of palivizumab. Biol Blood Marrow Transplant. Sep 2010;16(9):1265-1271. PMID 20304082
- Yi H, Lanctot KL, Bont L, et al. Respiratory syncytial virus prophylaxis in Down syndrome: a prospective cohort study. Pediatrics. Jun 2014;133(6):1031-1037. PMID 24799541
- Meissner HC, Anderson LJ, Pickering LK. Annual variation in respiratory syncytial virus season and decisions regarding immunoprophylaxis with palivizumab. Pediatrics. Oct 2004;114(4):1082-1084. PMID 15466107
- Makari D, Checchia PA, Devincenzo J. Rationale for full-season dosing for passive antibody prophylaxis of respiratory syncytial virus. Hum Vaccin Immunother. Dec 6 2013;10(3). PMID 24316863
- Winterstein AG, Knox CA, Kubilis P, et al. Appropriateness of age thresholds for respiratory syncytial virus immunoprophylaxis in moderate-preterm infants: a cohort study. JAMA Pediatr. Dec 2013;167(12):1118-1124. PMID 24126903
- Frogel MP, Stewart DL, Hoopes M, et al. A systematic review of compliance with palivizumab administration for RSV immunoprophylaxis. J Manag Care Pharm. Jan-Feb 2010;16(1):46-58. PMID 20131495
- Meissner HC, Long SS. Revised indications for the use of palivizumab and respiratory syncytial virus immune globulin intravenous for the prevention of respiratory syncytial virus infections. Pediatrics. Dec 2003;112(6 Pt 1):1447-1452. PMID 14654628
- American Academy of Pediatrics: Policy statement--Modified recommendations for use of palivizumab for prevention of respiratory syncytial virus infections. Pediatrics. Dec 2009;124(6):1694-1701. PMID 19736258
- 2012 Red Book. Report of the Committee on Infectious Disease. Respiratory Syncytial Virus. Vol 2012. Elk Grove Village, IL: American Academy of Pediatrics.
- Kelly DA, Bucuvalas JC, Alonso EM, et al. Long-term medical management of the pediatric patient after liver transplantation: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Liver Transpl. Aug 2013;19(8):798-825. PMID 23836431
- U.S. Preventive Services Task force (USPSTF). Immunizations for children 1996; http://www.uspreventiveservicestaskforce.org/uspstf/uspschil.htm. Accessed July 2014.
- Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices (ACIP). February 2014 ACIP Minutes. http://www.cdc.gov/vaccines/acip/meetings/meetings-info.html. Accessed July 2014.
|CPT||90378||Respiratory syncytial virus immune globulin for intramuscular use, 50 mg, each|
|96365||Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour|
|96366||Each additional hour (list separately in addition to code for primary procedure)|
|96372||Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular|
|ICD-9 Procedure||99.29||Injection or infusion of other therapeutic or prophylactic substance|
|ICD-9 Diagnosis||396||Diseases of mitral and aortic valves (code range)|
|417||Other disease of pulmonary circulation (code range)|
|424||Other diseases of endocardium (code range)|
|425||Cardiomyopathy (code range)|
|428||Heart failure (code range)|
|491||Chronic bronchitis (code range)|
|745||Bulbus cordis anomalies and anomalies of cardiac septal closure (code range)|
|746||Other congenital anomalies of the heart (code range)|
|747||other congenital anomalies of the circulatory system (code range)|
|765.2||Weeks of gestation (5th digit indicates specific weeks of gestation)|
|HCPCS||J1565||Injection, respiratory syncytial virus immune globulin, intravenous, 50mg (i.e., RespiGam)|
|ICD-10-CM (effective 10/1/15)||I08.0 – I08.9||Multiple valve diseases code range|
|I28.0 – I28.9||Other diseases of pulmonary vessels code range|
|I34.0 – I34.9||Nonrheumatic mitral valve disorders code range|
|I35.0 – I35.9||Nonrheumatic aortic valve disorders code range|
|I36.0 – I36.9||Nonrheumatic tricuspid valve disorders code range|
|I37.0 – I37.9||Nonrheumatic pulmonary valve disorders code range|
|I42.0 – I42.9||Cardiomyopathy code range|
|I43||Cardiomyopathy in diseases classified elsewhere|
|I50.1 – I50.9||Heart failure code range|
|J41.0 – J42||Chronic bronchitis code range|
|J44.0 – J44.9||Other chronic obstructive pulmonary disease code range|
|P07.00-P07.32||Disorders of newborn related to short gestation and low birth weight, not elsewhere classified code range|
|P27.0-P27.9||Chronic respiratory disease originating in the perinatal period (includes bronchopulmonary dysplasia P27.1)|
|P28.0 – P28.9||Other respiratory conditions originating in the perinatal period code range|
|Q20.0 – Q28.9||Congenital malformations of the circulatory system code range|
|ICD-10-PCS (effective 10/1/15)||ICD-10-PCS codes are only used for inpatient services.|
|3E0234Z||Administration, physiological systems and anatomical regions, introduction, muscle, percutaneous, serum, toxoid and vaccine|
|3E0334Z||Administration, physiological systems and anatomical regions, introduction, peripheral vein, percutaneous, serum, toxoid and vaccine|
|Type of Service||Prescription Drug|
|Place of Service||Outpatient|
Respiratory Syncytial Virus
|03/15/99||Add to Prescription Drug Section||New policy|
|11/10/99||Replace policy||New CPT code; policy unchanged|
|02/15/02||Replace policy||Policy updated with new references; policy statement unchanged|
|10/09/03||Replace policy||Policy revised; added indication for palivizumab for infants with hemodynamically significant heart disease and for those born between 32 and 35 weeks’ gestation with additional high risk factors. Policy based on AAP guidelines.|
|11/09/04||Replace policy||Literature review update for the period between June 2003 and September 2004; references added. RSV immune prophylaxis in stem-cell transplantation added to the investigational policy statement.|
|09/27/05||Replace policy||Policy updated with literature review; no change in policy statement. Information added regarding new liquid formulation of Synagis to Policy Guidelines section. Reference 9 added, discussing length and variation of RSV season.|
|12/14/05||Replace policy-coding update only||CPT coding updated|
|09/18/07||Replace policy||Policy updated with literature search through July 2007; treatment is considered investigational for children over 2 years of age. No changes in policy statements. Reference numbers 10–12 added.|
|12/13/07||Replace policy-correction only||Language “treatment…over 2 years of age” added to 9/18/07 policy history.|
|10/06/09||Replace policy||Policy updated with literature search from August 2007 through August 2009; clinical input reviewed; The policy statement has been modified to reflect the 2009 AAP; new reference numbers 13-17 added.|
|10/08/10||replace policy||Policy updated with literature search. References 15 and 16 added. Policy statements unchanged.|
|10/04/11||Replace policy||Policy updated with literature search. Policy statement number 4 modified with removal of “born before 35 weeks of gestation” to be consistent with the AAP guidelines. Deleted “congestive” from “congestive heart failure” in policy statements. Other policy statements are unchanged.|
|9/13/12||Replace policy||Policy updated with literature search. Rationale reorganized. References 1, 13 and 15-16 added. Policy statements unchanged.|
|8/8/13||Replace policy||Policy updated with literature search through June 18, 2013. References 3 and 6 added; references 1, 10, and 15 updated. Policy statements unchanged.|
|2/13/14||Replace policy - correction only||Removed contradictory statement in the Rationale section about RSV-IVIg being contraindicated in children with cyanotic CHD.|
|9/11/14||Replace policy||Policy updated with literature review through July 7, 2014; references 1-2, 16-17, 20-22, 25, 27-28, 30, and 32 added; reference 31 updated. Policy statements revised to reflect 2014 updated guidance from AAP.|