Description:
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections in children. There are a few factors that put certain children at a higher risk for contracting RSV; these factors are: age (< 2 years old), prematurity, chronic lung disease of prematurity (formerly known as bronchopulmonary dysplasia), congenital heart disease, immunodeficiencies, and multiple congenital anomalies. Immune prophylaxis against RSV is a preventive strategy to reduce the incidence of infection and its associated morbidity, including hospitalization, in high-risk infants.

For individuals with high-risk indications for RSV in infancy who receive immune prophylaxis for RSV, the evidence includes several randomized controlled trials (RCTs) and systematic reviews. Relevant outcomes are overall survival, symptoms, morbid events, and hospitalizations. Evidence from systematic reviews of RCTs has demonstrated that RSV prophylaxis with palivizumab is associated with reductions in RSV-related hospitalizations and intensive care unit stays. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals with cystic fibrosis without other risk factors for RSV in infancy who receive immune prophylaxis for RSV, the evidence includes an RCT, several prospective and retrospective cohort studies, and multiple systematic reviews. Relevant outcomes are overall survival, symptoms, morbid events, and hospitalizations. Although some studies have demonstrated reductions in hospitalizations in palivizumab-treated patients, studies that used contemporaneous controls did not demonstrate reductions in hospitalizations. In the available RCT, rates of adverse events were high in both the palivizumab and the placebo groups, making it difficult to draw conclusions about the net benefit of palivizumab. A more recent nonrandomized study using noncontemporaneous controls found fewer RSV infections in palivizumab-treated patients with cystic fibrosis. Additional studies are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with immunodeficiencies without other risk factors for RSV in infancy who receive immune prophylaxis for RSV, the evidence includes case series. Relevant outcomes are overall survival, symptoms, morbid events, and hospitalizations. Descriptive findings from a consensus panel and case reports of 2 infants with primary immunodeficiencies and 2 infants with acquired immunodeficiencies in whom palivizumab was used with good compliance and efficacy have been reported in the literature. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with Down syndrome without other risk factors for RSV in infancy who receive immune prophylaxis for RSV, the evidence includes a prospective cohort study. Relevant outcomes are overall survival, symptoms, morbid events, and hospitalizations. The available cohort study reported reduced rates of RSV-related hospitalization in treated patients but had methodologic limitations, including the use of a noncontemporaneous comparative cohort from a different country; such limitations inhibited any conclusions that could be made at this time. The evidence is insufficient to determine the effects of the technology on health outcomes.

Decisions about the use of palivizumab prophylaxis involve selecting patients likely to derive the most benefit from reductions in RSV hospitalizations. Clinical input supported the use of immune prophylaxis for RSV for the indications listed in the policy statements, which include patients with immunocompromised states and cystic fibrosis, and are consistent with the 2014 American Academy of Pediatrics guidelines.

Background 
Respiratory Syncytial Virus Infections
RSV infections typically occur in the winter months, starting from late mid-October to mid-January and ending anywhere from March until early May.⁴ Considerable variation in the timing of community outbreaks is observed from year to year. Historically, the RSV season was defined by consecutive weeks when RSV antigen-based tests exceeded 10% positivity; however, laboratories have shifted away from antigen-based testing, and since 2014 the majority of tests are determined by polymerase chain reaction (PCR). Annually in the U.S., RSV infection has been associated with an estimated 57527 hospitalizations and 2.1 million outpatient visits among children less than 5 years of age.⁵ While RSV is a near-ubiquitous infection, infants with underlying medical issues, especially a history of prematurity with associated lung problems, are at risk of developing serious complications from bronchiolitis secondary to RSV.

Palivizumab (Synagis) is a humanized monoclonal antibody, made using recombinant DNA technology, directed against a site on the antigenic site of the F protein of RSV.⁶

Other RSV preventive agents, including vaccines, have been under development.⁷ A recombinant RSV fusion protein nanoparticle vaccine has been shown to induce an immune response in a phase 2 trial.⁸

This evidence review does not address therapies to treat RSV infection.

Regulatory Status
In June 1998, the biologic drug palivizumab (Synagis^®; MedImmune, Gaithersburg, MA) was approved for marketing by FDA through a biologics license application (BLA) for use in the prevention of serious lower respiratory tract disease caused by RSV in pediatric patients at high risk of RSV disease. In 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.  

Policy: 
Monthly administration of immune prophylaxis for respiratory syncytial virus (RSV) with palivizumab during the RSV season may be considered MEDICALLY NECESSARY in the following infants and children in accordance with guidelines-based recommendations (American Academy of Pediatrics [2014]):

1. In the first year of life, i.e., younger than 12 months at the start of the RSV season or born during the RSV season:
   • Infants born before 29 weeks, 0 days of gestation;
   • Preterm infants with chronic lung disease (CLD) of prematurity, defined as birth at less than 32 weeks, 0 days of gestation and a requirement for more than 21% oxygen for at least the first 28 days after birth;
   • Certain infants with hemodynamically significant heart disease (e.g., 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);
     • 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.
   • Children with pulmonary abnormality or neuromuscular disease that impairs the ability to clear secretions from the upper airways (e.g., ineffective cough, recurrent gastroesophageal tract reflux, pulmonary malformations, tracheoesophageal fistula, upper airway conditions, or conditions requiring tracheostomy);
   • Children with cystic fibrosis who have at least one of the following conditions:
   • Clinical evidence of CLD; and/or
   • Nutritional compromise.
2. In the second year of life, i.e., younger than 24 months at the start of the RSV season:
   • Children who were born at less than 32 weeks, 0 days of 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.
   • Children with cystic fibrosis who have either:
     • 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 persists when stable); or
     • Weight for length less than the 10th percentile.
3. In the first or second year of life:
   • Children who will be profoundly immunocompromised (e.g., will undergo solid organ or hematopoietic 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 (e.g., 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.

Palivizumab prophylaxis is considered unproven and NOT MEDICALLY NECESSARY for otherwise healthy infants born at or after 29 weeks, 0 days gestation.

Monthly prophylaxis with palivizumab for children who have had a breakthrough RSV hospitalization should be discontinued, as it is considered NOT MEDICALLY NECESSARY.

Other indications for immune prophylaxis for RSV are considered NOT MEDICALLY NECESSARY, including, but not limited to, controlling outbreaks of health care-associated disease; or use in children with cystic fibrosis or Down syndrome without other risk factors; or in children over 2 years of age, unless criteria for medical necessity (outlined above) are satisfied.

Policy Guidelines
DOSING AND ADMINISTRATION
Palivizumab is administered by intramuscular injection at 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 respiratory syncytial virus (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 subsection below) (American Academy of Pediatrics, 2015).

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.

BREAKTHROUGH RSV
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 (< 0.5%) of a second RSV hospitalization in the same season (AAP, 2015).

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 most effective ways of reducing RSV transmission is to strictly observe common infection control practices; this includes the restriction of visitors to the neonatal intensive care unit during peak respiratory virus season, and to promptly initiate all standard-set precautions when coming into contact with RSV-infected infants. If an RSV outbreak occurs in a high-risk unit (e.g., 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 for controlling outbreaks of health care‒associated disease, and the use of palivizumab is not recommended for this purpose. 

INTERACTIONS
Palivizumab does not interfere with response to vaccines.

Palivizumab may interfere with RSV diagnostic tests that are immunologically based (e.g., 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 doing the following: offering breast milk feeds, immunizing household contacts with influenza vaccine, practicing hand and cough hygiene, by avoiding tobacco or other smoke exposure, and by not attending large group child care during the first winter season, whenever possible (AAP Technical Report, 2014).

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 annual occurrence of the RSV season is predictable, but the severity, time of onset, peak activity, and 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 late March or sometime in April. Communities in the southern United States, particularly in Florida, tend to experience the earliest onset of RSV activity. In recent years, the national duration of the RSV season has been 21 weeks (MMWR, 2013).

Results from clinical trials have indicated 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, chronic lung disease of prematurity, or preterm birth before 32 weeks of 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 have identified variations in the onset and offset of the RSV season in the 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).

Benefit Application
BlueCard/National Account Issues
State or national mandates (e.g., FEP) may dictate that all U.S. Food and Drug Administration (FDA)-approved biologics may not be considered investigational, and, thus, these biologics may only be assessed on the basis of their medical necessity.

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical uses of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Immune Prophylaxis for Respiratory Syncytial Virus
High-Risk Infants
Clinical Context and Therapy Purpose
The purpose of immune prophylaxis in patients at increased risk for RSV in infancy is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of immune prophylaxis for RSV improve the net health outcome in infants at high-risk for RSV?

The following PICO was used to select literature to inform this review.

Patients
The relevant populations of interest include infants at high-risk for RSV. Prematurity is 1 of the most common risk factors for RSV. Chronic lung disease of prematurity (formerly known as bronchopulmonary dysplasia) is a general term for long-term respiratory problems in premature infants. Chronic lung disease results from lung injury to newborns who consequently must use a mechanical ventilator and supplemental oxygen for breathing. With an injury, lung tissues become inflamed, and scarring can result. Causes of lung injury include the following: prematurity, low amounts of surfactant, oxygen use, and mechanical ventilation. Risk factors for developing chronic lung disease include birth at less than 34 weeks of 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.

Clinically significant congenital heart disease is another risk factor for RSV infection in infancy.

Interventions
The therapy being considered is immune prophylaxis for RSV. Currently, palivizumab (Synagis) is approved by the U.S. Food and Drug Administration (FDA) for this indication. Treatment is administered once monthly for a maximum of 5 doses, during RSV season. In the U.S., RSV season typically has a median onset of mid-October and lasts until potentially early May. Monthly prophylaxis should be discontinued if an RSV infection or hospitalization occurs. Immune prophylaxis for RSV is administered in a clinician's office.

Comparators
The comparator is routine care without immune prophylaxis.

Outcomes
The general outcome of interest is the RSV hospitalization rate. Other outcomes include RSV infection rates and adverse events. Follow-up spans the RSV season, typically 5 months from November through March.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:  

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Homaira et al. (2014) reported on results of a systematic review that included real-world post-licensure studies of RSV prophylaxis.⁹ Reviewers included 20 observational studies that generally supported the benefit of RSV prophylaxis in high-risk infants.

A Cochrane review by Andabaka et al. (2013)¹⁰ evaluated 3 pivotal RCTs (total n=2831 patients)^11,12,13 assessing the efficacy of palivizumab in preventing severe RSV infection in high-risk infants. The review reported a reduction in hospitalization rate from 101 to 50 per 1000 (relative risk, 0.49; 95% confidence interval [CI], 0.37 to 0.64).

Randomized Controlled Trials
Several RCTs have demonstrated the success of immune prophylaxis of RSV. Among them, Tavsu et al. (2014) reported on a small RCT that evaluated developmental and growth outcomes for infants born at less than 32 weeks of gestation treated with palivizumab prophylaxis.¹⁴  The trial randomized 83 infants with an indication for palivizumab prophylaxis but without chronic lung disease (infants born at 28 weeks of gestation who were < 12 months old and those born at 29 – 32 weeks of gestation who were < 6 months old at the beginning of RSV season) to palivizumab prophylaxis (n = 41) or no therapy (n = 42) over 2 RSV seasons. Subjects in the palivizumab group had significantly lower rates of RSV-related lower respiratory tract infection and hospitalizations than the control group during the first year of prophylaxis (infection, 23.1% vs. 53.7%, p = 0.005; hospitalizations, 0% vs. 24.4%; p = 0.001, respectively), with similar differences in the second year of prophylaxis. However, anthropometric indices and results on the Guide for Monitoring Child Development (a developmental assessment tool) at 18 months corrected for age did not differ significantly between groups.

Blanken et al. (2013) reported on the findings of the multicenter, double-blind, randomized, placebo-controlled MAKI trial that allocated 429 otherwise healthy preterm infants born at a gestational age of 33 to 35 weeks to monthly palivizumab (n=214) or placebo (n=215) during RSV season.¹⁵ This trial was not included in the previously described 2013 Cochrane review. 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% (95% CI, 56% to 65%) relative decrease in the total number of wheezing days during the first year of life. Moreover, the effect of RSV prevention on the number of wheezing days persisted in the post prophylaxis 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 vs. 21.9% in the placebo group; p = 0.04).

Feltes et al. (2003) reported on the results of a double-blind RCT that randomized 1287 children with hemodynamically significant congenital heart disease.¹¹ Those receiving palivizumab had a 45% relative reduction in hospitalizations for RSV. Hospitalizations for RSV occurred in 5.3% (34/639) of the palivizumab group and in 9.7% (63/648) of the no prophylaxis group.

The IMpact-RSV Study (1998) reported on the results of a double-blind RCT that randomized 1,502 premature children (≤ 35 weeks) or children with bronchopulmonary dysplasia during the 1996 to 1997 RSV season to palivizumab or placebo.¹² The primary endpoint was hospitalization with confirmed RSV infection. Palivizumab resulted in a 55% reduction in RSV hospital admission (4.8% [48/1002] in the palivizumab group vs. 10.6% [53/500] in the no prophylaxis group). Similar reductions in other measures of RSV severity in breakthrough infections also were reported.

Nonrandomized Studies
Multiple nonrandomized studies have assessed the efficacy of palivizumab in preventing severe RSV infection in high-risk infants. For example, Farber et al. (2016) published results of a claims analysis that revealed healthy preterm infants (born at 29 to 36 weeks of gestation treated with at least 1 dose of palivizumab during their first RSV season occurring in 2012, 2013, or 2014) had only a minor absolute difference in RSV hospitalization rates (3.1%) compared with infants not treated with palivizumab (5.0%; p=0.04).¹⁶ However, the small absolute reduction in the rate of RSV-related hospitalizations favoring palivizumab was offset by increased hospitalizations for bronchiolitis without RSV diagnosis (3.3% vs. 1.9%, p=0.05).

Ozyurt et al. (2015) reported on the results of a case-control study, although the methods used were more consistent with a retrospective cohort study, that showed lower respiratory tract infection-related hospitalizations were less frequent in the palivizumab prophylaxis group (relative risk, 0.75; p<0.001) compared with those who did not receive palivizumab prophylaxis.¹⁷ Cohen et al. (2008) reported a cumulative incidence of RSV hospitalization of 1.9% among patients with congenital heart disease who received prophylaxis.¹⁸

Section Summary: High-Risk Infants
Several RCTs have demonstrated the effectiveness of palivizumab prophylaxis in reducing the risk of RSV-related infection and hospitalizations in infants at high-risk for RSV-related infection due to prematurity, chronic lung disease of prematurity, and congenital heart disease.

Cystic Fibrosis
Clinical Context and Therapy Purpose
The purpose of immune prophylaxis in infants with CF without other risk factors is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of immune prophylaxis for RSV improve the net health outcome in infants with CF without other risk factors for RSV?

The following PICO was used to select literature to inform this review.

Patients
The relevant populations of interest include infants with CF without other risk factors for RSV.

Interventions
The therapy being considered is immune prophylaxis for RSV. Currently, palivizumab (Synagis) is approved by the FDA for this indication. Treatment is administered once monthly for a maximum of 5 doses, during RSV season. In the U.S., RSV season typically has a median onset of mid-October and lasts until potentially early May. Monthly prophylaxis should be discontinued if an RSV infection or hospitalization occurs. Immune prophylaxis for RSV is administered in a clinician's office.

Comparators
The comparator is routine care without immune prophylaxis.

Outcomes
The general outcome of interest is the RSV hospitalization rate. Other outcomes include RSV infection rates and adverse events. Follow-up spans the RSV season, typically 5 months from November through March.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:  

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Sánchez-Solis et al. (2015) published a meta-analysis of palivizumab prophylaxis for RSV infection in CF patients.¹⁹ Literature was searched through June 2020 4 prospective and retrospective observational studies, a questionnaire, and a randomized trial included in a prior Cochrane review were selected (total n = 617 patients). Historical controls and nonprophylaxed cohorts from 3 other studies were also 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 (i.e., contemporaneous controls), the between-group difference was not statistically significant (weighted mean hospitalization rate, 0.024 [95% CI, 0.005 to 0.098] for palivizumab-treated patients versus 0.093 [95% CI, 0.037 to 0.218] for controls; p = 0.115).

Robinson et al. (2010) published a Cochrane review (updated in 2013, 2014 and 2016), which assessed the use of palivizumab in children with CF based on a literature search through May 2016^20,21,22,23 Reviewers identified a single RCT that randomized 186 infants (< 2 years old) with CF to palivizumab (n = 92) or placebo (n = 94). One member of each group was hospitalized for RSV within the 6 month follow-up. The incidence of adverse events was relatively high in both groups, with serious adverse events not differing significantly between the palivizumab (20.2%) and placebo (17.3%) groups. Robinson et al. noted that it was not possible to draw conclusions on the safety and tolerability of RSV immune prophylaxis in CF. Although the review 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. Reviewers called for additional randomized studies to establish the safety and efficacy of immune prophylaxis in children with CF.

Registry Studies
Groves et al. (2016) reported on a retrospective review of a CF registry of 92 children treated from 1997 to 2007, comparing outcomes of those treated before and after palivizumab prophylaxis became routine in 2002.²⁴ In addition to the study's primary objective (RSV-related hospitalization rates in pre- and post-2002 cohorts), the authors reported on lung function, growth parameters, and bacterial colonization in both cohorts at age 6. Forty-five patients were born after 2002, and all received palivizumab in their first year of life before RSV season. The overall rate of RSV-related hospitalizations was 13%. The risk of RSV infection among palivizumab nonrecipients was approximately 5 times that for palivizumab recipients (relative risk, 4.78; 95% CI, 1.1 to 20.7).

Section Summary: Cystic Fibrosis
Some evidence, summarized in systematic reviews, has demonstrated reductions in hospitalization rates in palivizumab-treated patients with CF when historical controls were involved in the analysis. However, analyses limited to studies that used contemporaneous controls have not demonstrated reductions in hospitalization rates. In the single RCT, event rates were low and did not differ statistically between palivizumab and placebo. Rates of adverse events were high in both groups, making it difficult to draw conclusions about the net benefit of palivizumab. A more recent nonrandomized study using noncontemporaneous controls found a reduced likelihood of RSV infections in palivizumab-treated compared with palivizumab-untreated patients. Additional studies are needed to establish the benefit of palivizumab in patients with CF.

Infants with Immunodeficiencies
Clinical Context and Therapy Purpose
The purpose of immune prophylaxis in infants with immunodeficiency syndromes is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of immune prophylaxis for RSV improve the net health outcome in infants with immunodeficiency syndromes without other risk factors for RSV?

The following PICO was used to select literature to inform this review.

Patients
The relevant populations of interest include infants with immunodeficiencies without other risk factors for RSV.

Interventions
The therapy being considered is immune prophylaxis for RSV. Currently, palivizumab (Synagis) is approved by the FDA for this indication. Treatment is administered once monthly for a maximum of 5 doses, during RSV season. In the U.S., RSV season typically has a median onset of mid-October and lasts until potentially early May. Monthly prophylaxis should be discontinued if an RSV infection or hospitalization occurs. Immune prophylaxis for RSV is administered in a clinician's office.

Comparators
The comparator is routine care without immune prophylaxis.

Outcomes
The general outcome of interest is the RSV hospitalization rate. Other outcomes include RSV infection rates and adverse events. Follow-up spans the RSV season, typically 5 months from November through March.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:  

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

The use of palivizumab in children with primary immunodeficiency syndrome has not been formally evaluated in clinical trials or in nonrandomized comparative studies. Lanari et al. (2014) published a literature review on RSV infection in infants with primary immunodeficiency disorders and speculated that the absence of RCTs assessing palivizumab prophylaxis in immunocompromised infants was attributable to "the low incidence of these disorders and the ethical controversies surrounding them."²⁵ In the absence of empirical data to support the use of palivizumab prophylaxis in immunocompromised infants, reviewers cited findings of a consensus panel of pediatric pulmonologists, as reported by Gaboli et al. (2014), who would consider off-label use of palivizumab in primary immunodeficiencies.²⁶ This recommendation was based on a case report by Manzoni et al. (2007) who discussed 2 infants with primary immunodeficiencies and 2 infants with acquired immunodeficiencies in whom palivizumab was used with good compliance and efficacy.²⁷

Section Summary: Immunodeficiencies
A relatively small body of literature has evaluated the use of palivizumab for RSV immunoprophylaxis in patients with primary or acquired immunodeficiency. Comparative evidence of efficacy is lacking.

Down Syndrome
Clinical Context and Therapy Purpose
The purpose of immune prophylaxis in infants with Down Syndrome is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of immune prophylaxis for RSV improve the net health outcome in infants with Down Syndrome?

The following PICO was used to select literature to inform this review.

Patients
The relevant populations of interest include infants with Down syndrome without other risk factors for RSV.

Interventions
The therapy being considered is immune prophylaxis for RSV. Currently, palivizumab (Synagis) is approved by the FDA for this indication. Treatment is administered once monthly for a maximum of 5 doses, during RSV season. In the U.S., RSV season typically has a median onset of mid-October and lasts until potentially early May. Monthly prophylaxis should be discontinued if an RSV infection or hospitalization occurs. Immune prophylaxis for RSV is administered in a clinician's office.

Comparators
The comparator is routine care without immune prophylaxis.

Outcomes
The general outcome of interest is the RSV hospitalization rate. Other outcomes include RSV infection rates and adverse events. Follow-up spans the RSV season, typically 5 months from November through March.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:  

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Yi et al. (2014) reported on a prospective cohort study that compared RSV infection and related hospitalization in a cohort of children younger than 2 years of age with Down syndrome who received palivizumab during the RSV season between 2005 and 2012 (n = 532) with a previously published, similarly untreated Down syndrome birth cohort (n = 233).²⁸ Overall 31 (9.9%) children were hospitalized for RSV (23 untreated, 8 treated). The adjusted risk of RSV-related hospitalizations was higher in untreated subjects than in palivizumab recipients (incidence rate ratio, 3.63; 95% CI, 1.52 to 8.67). The adjusted risk of hospitalization for all respiratory tract infection (147 events; 73 untreated vs. 74 treated) was similar (incidence rate ratio untreated vs. palivizumab, 1.11; 95% CI, 0.80 to 1.55). Use of a noncontemporaneous control from another country introduced potential bias due to different indications for hospitalization and different environmental factors that could have affected the severity of RSV infection. Therefore, these study design limitations preclude the interpretation of the study results.

Section Summary: Down Syndrome
One prospective cohort study, which used nonconcurrent controls, has reported reductions in RSV-related hospitalization risk in palivizumab-treated patients with Down syndrome. However, study methodology limited the conclusions that could be drawn.

Summary of Evidence
For individuals with high-risk indications for RSV in infancy who receive immune prophylaxis for RSV, the evidence includes several randomized controlled trials (RCTs) and systematic reviews. Relevant outcomes are overall survival (OS), symptoms, morbid events, and hospitalizations. Evidence from systematic reviews of RCTs has demonstrated that RSV prophylaxis with palivizumab is associated with reductions in RSV-related hospitalizations and length of intensive care unit stays. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals with cystic fibrosis without other risk factors for RSV in infancy who receive immune prophylaxis for RSV, the evidence includes an RCT, several prospective and retrospective cohort studies, and systematic reviews. Relevant outcomes are OS, symptoms, morbid events, and hospitalizations. Although some studies have demonstrated reductions in hospitalizations in palivizumab-treated patients, studies that used contemporaneous controls did not. In the available RCT, rates of adverse events were high in both the palivizumab and the placebo groups, making it difficult to draw conclusions about the net benefit of palivizumab. A more recent nonrandomized study using noncontemporaneous controls found fewer RSV infections in palivizumab-treated patients with cystic fibrosis. Additional studies are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with immunodeficiencies without other risk factors for RSV in infancy who receive immune prophylaxis for RSV, the evidence includes case series. Relevant outcomes are OS, symptoms, morbid events, and hospitalizations. Descriptive findings from a consensus panel and case reports of 2 infants with primary immunodeficiencies and 2 infants with acquired immunodeficiencies in whom palivizumab was used with good compliance and efficacy have been reported in the literature. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with Down syndrome without other risk factors for RSV in infancy who receive immune prophylaxis for RSV, the evidence includes a prospective cohort study. Relevant outcomes are OS, symptoms, morbid events, and hospitalizations. The available cohort study reported reduced rates of RSV-related hospitalization in treated patients but had methodologic limitations, including the use of a noncontemporaneous comparative cohort from a different country; such limitations introduce uncertainty into any conclusions that can be made. The evidence is insufficient to determine the effects of the technology on health outcomes.

Clinical Input From Physician Specialty Societies and Academic Medical Centers
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 received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received through 3 physician specialty societies (7 responders) while this policy was under review in 2009. Most providing input agreed with the policy statements; these statements concurred with the American Academy of Pediatrics (2009) guidelines.

Practice Guidelines and Position Statements
American Academy of Pediatrics
In 2014, the American Academy of Pediatrics (AAP) updated its guidelines on the use of palivizumab in high-risk infants.²⁹ In 2019, the AAP reviewed the guidelines and concluded that its recommendations should remain unchanged (Table 1).¹

Table 1. Guidelines on Use of Palivizumab Prophylaxis for Infants  

Recommendations for Using Palivizumab Prophylaxis

Prophylaxis recommended

Infants born before 29 weeks, 0 days of gestation, during first year of life

Infants born before 32 weeks, 0 days of gestation with chronic lung disease of prematurity, during first year of life

Children in the second year of life who require 28 or more days of supplemental oxygen and continue to require medical intervention during respiratory syncytial virus season

Prophylaxis may be considered

Infants with hemodynamically significant heart failure, during first year of life

Infants with a pulmonary abnormality or neuromuscular disease that impairs ability to clear secretions from lower airways, during first year of life

Children younger than 24 months who are profoundly immunocompromised during respiratory syncytial virus season

Prophylaxis not recommended

Healthy infants born at or after 29 weeks, 0 days of gestation

There is insufficient evidence for children with cystic fibrosis or Down syndrome without other risk factors

In 2014, the AAP also published guidelines on the diagnosis, management, and prevention of bronchiolitis (updating 2006 guidelines), and made the following recommendations about the use of palivizumab for RSV prevention (Table 2).³⁰ 

Table 2. Guidelines on the Diagnosis, Management, and Prevention of Bronchiolitis 

Recommendation	QOE	SOR
"Clinicians should not administer palivizumab to otherwise healthy infants with a gestational age of 29 weeks, 0 days or greater."	B	Strong
"Clinicians should administer palivizumab during the first year of life to infants with hemodynamically significant heart disease or chronic lung disease of prematurity defined as preterm infants <32 weeks 0 days' gestation who require >21% oxygen for at least the first 28 days of life."	B	Moderate
"Clinicians should administer a maximum 5 monthly doses (15 mg/kg/dose) of palivizumab during the respiratory syncytial virus season to infants who qualify for palivizumab in the first year of life."	B	Moderate

QOE: quality of evidence; SOR: strength of recommendation.

U.S. Preventive Services Task Force Recommendations
Not applicable.

Ongoing and Unpublished Clinical Trials
ClinicalTrials.gov in June 2020 did not identify any ongoing or unpublished trials that would likely influence this review.

References  

1. American Academy of Pediatrics. AAP publications reaffirmed. https://pediatrics.aappublications.org/content/144/2/e20191767. Accessed June 20, 2020
2. Munoz FM RS, Meissner HC. RSV Recommendations Unchanged after Review of New Data. AAP News 2017; http://www.aappublications.org/news/2017/10/19/RSV101917. Accessed June 15, 2020
3. Brady MT, Byington CL, Davies HD, et al. 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): e620-38. PMID 25070304
4. Rose EB, Wheatley A, Langley G, et al. Respiratory Syncytial Virus Seasonality - United States, 2014-2017. MMWR Morb Mortal Wkly Rep. Jan 19 2018; 67(2): 71-76. PMID 29346336
5. Hall CB, Weinberg GA, Iwane MK, et al. The burden of respiratory syncytial virus infection in young children. N Engl J Med. Feb 05 2009; 360(6): 588-98. PMID 19196675
6. Food and Drug Administration. Label: Synagis (Palivizumab) for Intramuscular Administration. 2017; https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8e35c4c8-bf56-458f-a73c-8f5733829788. Accessed June 15, 2020
7. Falloon J, Ji F, Curtis C, et al. A phase 1a, first-in-human, randomized study of a respiratory syncytial virus F protein vaccine with and without a toll-like receptor-4 agonist and stable emulsion adjuvant. Vaccine. May 27 2016; 34(25): 2847-54. PMID 27102821
8. Glenn GM, Fries LF, Thomas DN, et al. A Randomized, Blinded, Controlled, Dose-Ranging Study of a Respiratory Syncytial Virus Recombinant Fusion (F) Nanoparticle Vaccine in Healthy Women of Childbearing Age. J Infect Dis. Feb 01 2016; 213(3): 411-22. PMID 26259809
9. Homaira N, Rawlinson W, Snelling TL, et al. Effectiveness of Palivizumab in Preventing RSV Hospitalization in High Risk Children: A Real-World Perspective. Int J Pediatr. 2014; 2014: 571609. PMID 25548575
10. Andabaka T, Nickerson JW, Rojas-Reyes MX, et al. Monoclonal antibody for reducing the risk of respiratory syncytial virus infection in children. Cochrane Database Syst Rev. Apr 30 2013; (4): CD006602. PMID 23633336
11. 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): 532-40. PMID 14571236
12. 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): 531-7. PMID 9738173
13. Subramanian KN, Weisman LE, Rhodes T, et al. Safety, tolerance and pharmacokinetics of a humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia. MEDI-493 Study Group. Pediatr Infect Dis J. Feb 1998; 17(2): 110-5. PMID 9493805
14. Tavsu I, Gursoy T, Dirman S, et al. Palivizumab prophylaxis: does it have any influence on the growth and development of the infants?. Am J Perinatol. Sep 2014; 31(8): 667-72. PMID 24022378
15. Blanken MO, Rovers MM, Molenaar JM, et al. Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. N Engl J Med. May 09 2013; 368(19): 1791-9. PMID 23656644
16. Farber HJ, Buckwold FJ, Lachman B, et al. Observed Effectiveness of Palivizumab for 29-36-Week Gestation Infants. Pediatrics. Aug 2016; 138(2). PMID 27432850
17. Ozyurt A, Narin N, Baykan A, et al. Efficacy of palivizumab prophylaxis among infants with congenital heart disease: A case control study. Pediatr Pulmonol. Oct 2015; 50(10): 1025-32. PMID 25156973
18. 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): 382-7. PMID 17926087
19. Sanchez-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). May-Jun 2015; 43(3): 298-303. PMID 24231153
20. 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. Feb 17 2010; (2): CD007743. PMID 20166098
21. 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. Feb 15 2012; (2): CD007743. PMID 22336832
22. Robinson KA, Odelola OA, Saldanha IJ. Palivizumab for prophylaxis against respiratory syncytial virus infection in children with cystic fibrosis. Cochrane Database Syst Rev. May 22 2014; (5): CD007743. PMID 24851825
23. Robinson KA, Odelola OA, Saldanha IJ. Palivizumab for prophylaxis against respiratory syncytial virus infection in children with cystic fibrosis. Cochrane Database Syst Rev. Jul 20 2016; 7: CD007743. PMID 27439110
24. Groves HE, Jenkins L, Macfarlane M, et al. Efficacy and long-term outcomes of palivizumab prophylaxis to prevent respiratory syncytial virus infection in infants with cystic fibrosis in Northern Ireland. Pediatr Pulmonol. Apr 2016; 51(4): 379-85. PMID 26808981
25. Lanari M, Vandini S, Capretti MG, et al. Respiratory syncytial virus infections in infants affected by primary immunodeficiency. J Immunol Res. 2014; 2014: 850831. PMID 25089282
26. Gaboli M, de la Cruz OA, de Aguero MI, et al. Use of palivizumab in infants and young children with severe respiratory disease: a Delphi study. Pediatr Pulmonol. May 2014; 49(5): 490-502. PMID 23775884
27. Manzoni P, Leonessa M, Farina D, et al. Respiratory syncytial virus infection and prophylaxis with palivizumab in immunosuppressed children: the experience of a large Italian neonatal care setting. Pediatr Transplant. Jun 2007; 11(4): 456-7. PMID 17493231
28. Yi H, Lanctot KL, Bont L, et al. Respiratory syncytial virus prophylaxis in Down syndrome: a prospective cohort study. Pediatrics. Jun 2014; 133(6): 1031-7. PMID 24799541
29. Brady MT, Byington CL, Davies HD, et al. 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): 415-20. PMID 25070315
30. Ralston SL, Lieberthal AS, Meissner HC, et al. Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis. Pediatrics. Nov 2014; 134(5): e1474-502. PMID 25349312

Coding Section

Codes	Number	Description
CPT	90378	Respiratory syncytial virus, monoclonal antibody, recombinant, for intramuscular use, 50 mg, each
	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)
	V07.2	Prophylactic immunotherapy
	V46.2	Supplemental oxygen
ICD-10-CM (effective 10/01/15)	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 10/01/15)		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

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2014 Forward     

09/14/2022	Annual review, no change to policy intent.
09/01/2021	Annual review, no change to policy intent. Updating background, rationale and references.
09/01/2020	Annual review, no change to policy intent.
09/03/2019	Annual review, no change to policy intent.
09/18/2018	Annual review, adding some medical necessity criteria for infants/children with cystic fibrosis. Also rewriting not medically necessary portion of policy for clarification and specificity. Updating rationale and references.
09/11/2017	Annual review, no change to policy intent. Updating background, description, regulatory status, guidelines, rationale and references.
09/01/2016	Annual review, no change to policy intent. Updating background, description, rationale and references.
09/28/2015	Annual review, no change to policy intent. Updated background, description, rationale and references. Added coding.
09/29/2014	Annual review, significant changes in policy related to the 2014 American Academy of Pediatrics recommendations.