Palivizumab (Synagis)

Number: 0318

Policy

Note: Requires Precertification:

Precertification of palivizumab (Synagis) is required of all Aetna participating providers and members in applicable plan designs. For precertification of palivizumab call (866) 752-7021, or fax (866) 267-3277.

1. Criteria for Initial Approval

   Aetna considers palivizumab (Synagis) medically necessary for up to 5 doses per respiratory syncytial virus (RSV) season for the prevention of serious lower respiratory tract disease caused by RSV when a member has any of the following diagnoses and when associated criteria are met:

   1. Prematurity

      When all of the following criteria are met:

      1. Member's gestational age is less than 29 weeks, 0 days; and
      2. Member's chronological age at the start of RSV season is less than 12 months;

   2. Chronic Lung Disease (CLD) of Prematurity

      When all of the following criteria are met:

      1. Member’s gestational age is less than 32 weeks, 0 days; and
      2. Requirement is for greater than 21% oxygen for at least the first 28 days after birth; and
      3. Member meets either of the following criteria:
         
         
         1. Member’s chronological age at the start of their first RSV season is less than 12 months; or
         2. Member’s chronological age at the start of the subsequent RSV season is less than 24 months and the member continues to require medical support (e.g., chronic corticosteroids, diuretic therapy, supplemental oxygen) during the 6-month period prior to the start of the RSV season;

   3. Congenital Heart Disease (CHD)

      When all of the following criteria are met:

      1. CHD is hemodynamically significant; and
      2. Member meets either of the following criteria:
         
         
         1. Member’s chronological age at the start of RSV season is less than 12 months; or
         2. Member’s chronological age at the start of RSV season is between 12 to 24 months and the member will be undergoing cardiac transplantation during the RSV season;

   4. Congenital Airway Abnormality

      When all of the following criteria are met:

      1. The condition compromises handling of respiratory secretions; and
      2. Member’s chronological age at the start of RSV season is less than 12 months;

   5. Neuromuscular Condition

      When all of the following criteria are met:

      1. The condition compromises handling of respiratory secretions; and
      2. Member’s chronological age at the start of RSV season is less than 12 months;

   6. Immunocompromised Children

      When all of the following criteria are met:

   1. Member is profoundly immunocompromised during the RSV season (e.g., SCID, stem cell transplant, bone marrow transplant); and
   2. Member’s chronological age at the start of the RSV season is less than 24 months;

   7. Cystic Fibrosis

      When either of the following criteria is met:

      1. Member’s chronological age at the start of the RSV season is less than 12 months and the member has evidence of CLD or nutritional compromise; or
      2. Member’s chronological age at the start of RSV season is between 12 to 24 months and the member has manifestations of lung disease (e.g., hospitalizations for pulmonary exacerbations) or weight for length less than the 10th percentile.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).  

2. Other

   For all off-season Synagis requests, authorization of 1 dose per request, up to a maximum of 5 doses per RSV season, may be granted if the RSV activity for the requested region is greater than or equal to 10% (with rapid antigen testing) or greater than or equal to 3% (with real-time polymerase chain reaction (PCR) test) within 2 weeks of the intended dose according to the CDC National Respiratory and Enteric Virus Surveillance System (NREVSS). The local health department or the CDC NREVSS will be consulted to assess the RSV activity for that region, see CDC Respiratory Syncytial Virus (RSV) Surveillance.

   Aetna considers Synagis season to be from November 1^st to March 31^st. Other health plans may differ. For 2021/2022, RSV Season will be extended to start in September 2021. If providers choose to begin Synagis earlier in the year, please be aware that American Academy of Pediatrics has not released guidance to provide more than 5 Synagis doses per season.

Dosage and Administration

The dosage and administration information are based on the FDA-approved Prescribing Information. See Appendix A for recommendations from the American Academy of Pediatrics (AAP).

Palivizumab is available as Synagis for injection as 50 mg per 0.5 mL and 100 mg per 1 mL single-dose liquid solution vials for intramuscular use.

The recommended dose of Synagis is 15 mg per kg of body weight given monthly by intramuscular injection. The first dose of Synagis should be administered prior to commencement of the RSV season and the remaining doses should be administered monthly throughout the RSV season. Children who develop an RSV infection should continue to receive monthly doses throughout the RSV season. In the northern hemisphere, the RSV season typically commences in November and lasts through April, but it may begin earlier or persist later in certain communities. Synagis serum levels are decreased after cardio-pulmonary bypass. Children undergoing cardio-pulmonary bypass should receive an additional dose of Synagis as soon as possible after the cardio-pulmonary bypass procedure (even if sooner than a month from the previous dose). Thereafter, doses should be administered monthly as scheduled. The efficacy of Synagis at doses less than 15 mg per kg, or of dosing less frequently than monthly throughout the RSV season, has not been established.

Source: Swedish Orphan Biovitrum AB, 2020

Experimental and Investigational

Aetna considers palivizumab experimental and investigational for all other indications (not an all-inclusive list):

• Asthma
• Down syndrome
• Childhood interstitial lung disease (chILD)
• Prevention of health-care associated RSV disease
• Prophylaxis against RSV in immunocompromised adults
• Treatment of RSV.

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

Synagis is indicated for the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in pediatric patients:

• with a history of premature birth (less than or equal to 35 weeks gestational age) and who are 6 months of age or younger at the beginning of RSV season,
• with bronchopulmonary dysplasia (BPD) that required medical treatment within the previous 6 months and who are 24 months of age or younger at the beginning of RSV season,
• with hemodynamically significant congenital heart disease (CHD) and who are 24 months of age or younger at the beginning of RSV season.

Limitations of Use:

The safety and efficacy of Synagis have not been established for treatment of RSV disease.

Compendial Uses

• RSV prophylaxis in infants with congenital abnormalities of the airway or neuromuscular disease that compromise handling of respiratory secretions
• RSV prophylaxis in immunocompromised pediatric patients
• RSV prophylaxis in pediatric patients with cystic fibrosis who have evidence of chronic lung disease or nutritional compromise in the first year of life

Palivizumab is available as Synagis (Swedish Orphan Biovitrum AB). Palivizumab is a humanized monoclonal antibody (IgG1k) produced by recombinant DNA technology, directed to an epitope in the A antigenic site of the F protein of respiratory syncytial virus. Palivizumab exhibits neutralizing and fusion‐inhibitory activity against respiratory syncytial virus (RSV). The populations at highest risk are premature babies and children with congenital heart disease, patients with chronic lung disease, or immunodeficient patients.

Synagis label carries warnings and precautions for anaphylaxis and anaphylactic shock (including fatal cases), and other severe acute hypersensitivity reactions have been reported. As with any intramuscular injection, Synagis should be given with caution to children with thrombocytopenia or any coagulation disorder. Palivizumab may interfere with immunological-based RSV diagnostic tests such as some antigen detection-based assays. Adverse reactions occurring greater than or equal to 10% and at least 1% more frequently than placebo include fever and rash (Swedish Orphan Biovitrum AB, 2020).

Physicians should arrange for drug administration within six hours after opening a vial as this product does not contain a preservative.

Synagis (palivizumab) received FDA approval in June 1998 for the prevention of serious lower respiratory tract disease caused by RSV in pediatric patients at high risk of RSV disease. Safety and efficacy were established in infants with bronchopulmonary dysplasia (BPD), infants with a history of premature birth (≤5 weeks gestational age), and children with hemodynamically significant congenital heart disease (CHD).

Randomized placebo controlled clinical trials have demonstrated the safety and efficacy of palivizumab (Impact RSV Study, 1998) in reducing hospitalizations due to RSV infection, and in producing reductions in other measures of severity of RSV infection for a very specific group of infants and children. Epidemiologic data indicate that the risk of severe RSV infection most likely to require hospitalization is greater in the presence of risk factors.

In a phase I/II, multi-center, randomized, double-blind, placebo-controlled, escalating dose clinical trial, Saez-Llorens and colleagues (2004) described the safety, tolerance, pharmacokinetics and clinical outcome of a single intravenous dose of palivizumab in previously healthy children hospitalized with acute RSV infection.  A total of 59 subjects less than or equal to 2 years of age received study drug – 16 children received 5 mg/kg of palivizumab (n = 8) or placebo (n = 8); 43 received 15 mg/kg of palivizumab (n = 22) or placebo (n = 21).  Adverse events judged to be related to study drug were seen in one 5-mg/kg palivizumab patient and one 15-mg/kg palivizumab patient.  These events were transient or consistent with progression of RSV disease.  No discontinuations of study drug infusion because of adverse events occurred.  Mean serum concentrations of palivizumab in the 5- and 15-mg/kg groups, respectively, were 61.2 and 303.4 microg/ml at 60 mins and 11.2 and 38.4 microg/ml after 30 days.  There were no significant differences in clinical outcomes between placebo and palivizumab groups for either dose.

There is no adequate evidence that immune globulins (palivizumab or RSV-IVIG) are effective for treatment of RSV infections.  A Cochrane systematic evidence review found no studies demonstrating statistically significant benefits of treatment with immune globulins added to supportive care compared with supportive care alone (Fuller and Del Mar, 2006).

Fernandez and colleagues (2010) stated that RSV is an important pathogen causing annual epidemics of bronchiolitis and pneumonia among infants worldwide.  High-risk infants currently receive RSV prophylaxis with palivizumab, a humanized RSV monoclonal antibody (MAb).  In pre-clinical in vitro and in vivo (cotton-rat model) studies, motavizumab, a new RSV MAb, was shown to have greater anti-RSV activity than palivizumab.  Motavizumab is currently under review for licensing approval.  Since both MAbs may be available concurrently, these researchers evaluated their safety and tolerability when administered sequentially during the same RSV season.  Between April 2006 and May 2006, 260 high-risk infants were randomly assigned 1:1:1 to receive monthly intra-muscular injections: 2 doses of motavizumab followed by 3 doses of palivizumab (M/P); 2 doses of palivizumab followed by 3 doses of motavizumab (P/M); or 5 doses of motavizumab (control).  Adverse events (AEs, serious AEs [SAEs]), development of anti-drug antibody (ADA), and serum drug trough concentrations were assessed.  Most children received all 5 doses (246/260 [94.6 %]) and completed the study (241/260 [92.7 %]).  While overall AE rates were similar (mostly level 1 or 2 in severity), SAEs and level 3 AEs occurred more frequently in the M/P group (SAEs: 22.9 % M/P, 8.4 % P/M, 11.8 % motavizumab only; level 3 AEs: 15.7 % M/P, 6.0 % P/M, 6.5 % motavizumab only).  This trend in AE rates occurred before and after switching from motavizumab to palivizumab, suggesting a cause other than the combined regimen.  Frequencies of AEs judged by the investigator to be related to study drug were similar among groups.  Two deaths occurred on study (both in the M/P group, before palivizumab administration); neither was considered by the site investigator to be related to study drug.  Mean serum drug trough concentrations were comparable among groups; ADA detection was infrequent (5.1 % or less of any group).  The authors stated that conclusions drawn from this study are limited by the small sample size per group.  However, within this small study, overall AE rates, serum drug trough concentrations, and development of ADA associated with administering motavizumab and palivizumab sequentially to high-risk children appear comparable to administering motavizumab alone during the same RSV season.

Results from clinical trials indicate that palivizumab trough serum concentrations greater than 30 days after the fifth dose will be well above the protective concentration for most infants.  If the first dose is administered in November, 5 monthly doses of palivizumab will provide substantially more than 20 weeks of protective serum antibody concentrations for most of the RSV season, even with variation in season onset and end.

The American Academy of Pediatrics (AAP) stated children who qualify for palivizumab prophylaxis for the entire RSV season should receive palivizumab only during the 5 months following the onset of RSV season in their region (maximum of 5 doses), which should provide coverage during the peak of the season, when prophylaxis is most effective. "Because 5 monthly doses of palivizumab at 15 mg/kg per dose will provide more than 6 months (>24 weeks) of serum palivizumab concentrations above the desired level for most children, administration of more than 5 monthly doses is not recommended within the continental United States. For qualifying infants who require 5 doses, a dose beginning in November and continuation for a total of 5 monthly doses will provide protection for most infants through 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, which will provide protection for most infants through March. If prophylaxis is initiated in December, the fifth and final dose should be administered in April, which will provide protection for most infants through May. Variation in the onset and offset of the RSV season in different regions of Florida may affect the timing of palivizumab administration. Data from the Florida Department of Health may be used to determine the appropriate timing for administration of the first dose of palivizumab for qualifying infants. Despite varying onset and offset dates of the RSV season in different regions of Florida, a maximum of 5 monthly doses of palivizumab should be adequate for qualifying infants for most RSV seasons in Florida. On the basis of the epidemiology of RSV in Alaska, particularly in remote regions where the burden of RSV disease is significantly greater than the general US population, the selection of Alaska Native infants eligible for prophylaxis may differ from the remainder of the United States. Clinicians may wish to use RSV surveillance data generated by the state of Alaska to assist in determining onset and end of the RSV season for qualifying infants. Limited information is available concerning the burden of RSV disease among American Indian populations. However, special consideration may be prudent for Navajo and White Mountain Apache infants in the first year of life" (AAP, 2014).

The American Academy of Pediatrics (AAP) issued updated guidelines regarding the use of immune prophylaxis for RSV in the AAP Red Book (2014; reaffirmed in 2019). The AAP Red Book was developed by members of the AAP Committee on Infectious Diseases in conjunction with the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), and other leading institutions. A summary of the AAP (2014) RSV guidance is as follows:

• In the first year of life, palivizumab prophylaxis is recommended for infants born before 29 weeks, 0 days' gestation.
• Palivizumab prophylaxis is not recommended for otherwise healthy infants born at or after 29 weeks, 0 days' gestation.
• In the first year of life, palivizumab prophylaxis is recommended for preterm infants with CLD of prematurity, defined as birth at <32 weeks, 0 days' gestation and a requirement for >21% oxygen for at least 28 days after birth.
• Clinicians may administer palivizumab prophylaxis in the first year of life to certain infants with hemodynamically significant heart disease.
• 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 in the first year of life. Qualifying infants born during the RSV season may require fewer doses. For example, infants born in January would receive their last dose in March.
• Palivizumab prophylaxis is not recommended in the second year of life except for children who required at least 28 days of supplemental oxygen after birth and who continue to require medical intervention (supplemental oxygen, chronic corticosteroid, or diuretic therapy).
• Monthly prophylaxis should be discontinued in any child who experiences a breakthrough RSV hospitalization.
• Children with pulmonary abnormality or neuromuscular disease that impairs the ability to clear secretions from the upper airways may be considered for prophylaxis in the first year of life.
• Children younger than 24 months who will be profoundly immunocompromised during the RSV season may be considered for prophylaxis.
• Insufficient data are available to recommend palivizumab prophylaxis for children with cystic fibrosis or Down syndrome.
• The burden of RSV disease and costs associated with transport from remote locations may result in a broader use of palivizumab for RSV prevention in Alaska Native populations and possibly in selected other American Indian populations.
• Palivizumab prophylaxis is not recommended for prevention of health care-associated RSV disease.

According to AAP (2014; reaffirmed in 2019), "mean decrease in palivizumab serum concentration of 58% was observed after surgical procedures that involve cardiopulmonary bypass, for children who are receiving prophylaxis and who continue to require prophylaxis after a surgical procedure, a postoperative dose of palivizumab (15 mg/kg) should be considered after cardiac bypass or at the conclusion of extracorporeal membrane oxygenation for infants and children younger than 24 months. Children younger than 2 years who undergo cardiac transplantation during the RSV season may be considered for palivizumab prophylaxis".

Palivizumab prophylaxis is not recommended in the second year of life on the basis of a history of prematurity alone. A second season of palivizumab prophylaxis is recommended only for preterm infants born at <32 weeks, 0 days’ gestation who required at least 28 days of oxygen after birth and who continue to require supplemental oxygen, chronic systemic corticosteroid therapy, or bronchodilator therapy within 6 months of the start of the second RSV season.

Palivizumab reportedly does not interfere with response to vaccines.  At this time, the available data do not support the need for supplemental doses of any routinely administered vaccines.

Chronic Lung Disease of Prematurity or Childhood Interstitial Lung Disease (chILD)

Children with more severe chronic lung disease who require medical therapy may benefit from prophylaxis for 2 RSV seasons.  Children with less severe underlying disease may benefit only for the first season. The literature also suggests that infants born before 29 weeks of gestation without chronic lung disease of prematurity (CLD) may also benefit from RSV prophylaxis.  In these infants, major risk factors to consider are gestational age and chronologic age at the start of the RSV season.  Infants born at 28 weeks of gestation or earlier may benefit from prophylaxis up to 12 months of age.

The AAP (2014; reaffirmed in 2019) states that during the second year of life, consideration of palivizumab prophylaxis is recommended only for infants who satisfy the definition of CLD of prematurity and continue to require medical support (chronic corticosteroid therapy, diuretic therapy, or supplemental oxygen) during the 6-month period before the start of the second RSV season. For infants with CLD who do not continue to require medical support in the second year of life prophylaxis is not recommended. CLD of prematurity is defined as gestational age <32 weeks, 0 days and a requirement for >21% oxygen for at least the first 28 days after birth.

Drummond et al (2016) noted that there is a lack of evidence concerning the effectiveness of immunoprophylaxis with palivizumab in children with childhood interstitial lung disease (chILD).  In this retrospective study, these researchers evaluated the effectiveness of palivizumab for decreasing the rate of RSV-related hospitalizations in children under the age of 24 months with chILD treated with corticosteroids.  A retrospective national study was conducted in France.  Patients born between 2007 and 2013, diagnosed with chILD and on corticosteroid treatment were identified through the French online database for pediatric interstitial lung disease (Respirare^®).  Data were collected for the etiology and severity of chILD, risk factors and preventive measures for bronchiolitis, palivizumab immunoprophylaxis, and hospitalizations for bronchiolitis and RSV-bronchiolitis.  These investigators evaluated 24 children during their first 2 RSV seasons, corresponding to 36 patient-seasons.  The observed rate of RSV-related hospitalization (305/1,000 patient-seasons), and the median length of stay (7 days), were higher than those for the general population.  However, RSV-related hospitalization rates did not differ significantly between children with and without palivizumab prophylaxis (5/16 versus 4/18, respectively, p = 0.70).  The authors concluded that children with chILD on corticosteroid treatment are at high risk of hospitalization for RSV-bronchiolitis, which tends to be more severe in these children than in the general population.  Moreover, they stated that the effectiveness of palivizumab prophylaxis in this population remains to be demonstrated.

Congenital Heart Disease

Palivizumab is FDA-approved for prevention of serious lower respiratory tract disease caused by respriatory synctial virus (RSV) in pediatric patients with hemodynamically significant congenital heart disease (CHD) and who are 24 months of age or younger at the beginning of RSV season (Medimmune, 2017).

Chang and Chen (2010) evaluated the impact of palivizumab prophylaxis on RSV hospitalizations among children with hemodynamically significant CHD.  In 2003, the AAP revised the bronchiolitis policy statement and recommended palivizumab in children less than 24 months old with hemodynamically significant CHD (HS-CHD).  California statewide hospital discharge data from years 2000 to 2002 (pre-AAP policy revision) were compared to those from years 2004 to 2006 (post-AAP policy revision).  Hospitalizations due to RSV bronchiolitis for children less than 2 years of age were identified by IDC-9 CM codes 4661.1, 480.1, and 079.6 as the principal diagnosis.  Children with CHD and children with HS-CHD were identified by the co-diagnoses.  The overall RSV hospitalization rate was 71 per 10,000 children less than 2 years of age.  Of all RSV hospitalizations, 3.0 % were among children with CHD, and 0.50 % among children with HS-CHD. HS-CHD patients accounted for 0.56 % of RSV hospitalizations in 2000 to 2002, compared to 0.46 % RSV hospitalizations in 2004 to 2006.  That represents a 19 % reduction in RSV hospitalizations among HS-CHD patients after 2003.  The 19 % decrease in RSV hospitalizations equates to 7 fewer hospitalizations (76 hospital days) per year among HS-CHD patients.  The authors concluded that since the recommendation of palivizumab for children with HS-CHD in 2003, the impact on RSV hospitalizations in California among HS-CHD patients has been limited.  Considering the high cost of palivizumab administration, the cost-benefit of RSV prophylaxis with palivizumab warranted further investigation.

A multi-center, prospective, controlled clinical trial demonstrated that palivizumab significantly reduced the rate of hospitalizations, hospital days, and days of increased oxygen usage in children with serious CHD.  Children born with serious CHD who have decreased cardiac or pulmonary reserve appear to be at highest risk of serious RSV infection.  These children have been shown to require intensive care and use mechanical ventilation more frequently than children who do not have CHD.  A 4-year, double-blind, placebo-controlled study was designed to assess the safety and efficacy of palivizumab in children less than 2 years of age with serious CHD.  The study was conducted at 76 centers in North America and Europe, and involved 1,287 children who were randomized to receive 5 monthly intramuscular injections (15 mg/kg) of either palivizumab or placebo during the RSV season.  Compared to placebo, the palivizumab group had 45 % fewer hospitalizations due to RSV (p = 0.003).  The data showed significantly fewer RSV-related hospital days (p = 0.003) and fewer days of increased oxygen usage (p = 0.014) in the treated group than in the placebo group.  The proportions of subjects in the placebo and palivizumab groups who experienced any adverse events were similar. 

A multi‐center, prospective, controlled, clinical trial demonstrated that palivizumab significantly reduced the rate of hospitalizations, hospital days, and days of increased oxygen usage in children with serious CHD. The data showed significantly fewer RSV‐related hospital days and fewer days of increased oxygen usage, in the treated group than in the placebo group. The proportions of subjects in the placebo and palivizumab groups who experienced any adverse events were similar. Infants and children with hemodynamically insignificant heart disease were not included in this study, as they are not considered to be at increased risk from RSV. Paired palivizumab serum levels were available for 139 children before and after cardiopulmonary bypass surgery. Mean serum concentrations were reduced by 58% (98 mcg/ml [ ±52], to 41.4 mcg/ml [ ±33]) after bypass. Based on this observation, the authors recommended that another dose of palivizumab be administered following cardiopulmonary bypass (Feltes, 2003).

According to the AAP Committee on Infectious Diseases, decisions regarding the use of palivizumab prophylaxis in children with congenital heart disease should be made on the basis of the degree of physiological cardiovascular impairment.  Infants most likely to benefit from immunoprophylaxis include those receiving medication to control congestive heart failure, those with moderate to severe pulmonary artery hypertension, and infants with cyanotic heart diseases. 

A decrease in the serum concentration of palivizumab by a mean of 58 % has been reported after surgical procedures that use cardiopulmonary bypass.  Thus, after surgical procedures that use cardiopulmonary bypass, the AAP recommends a post-operative dose of palivizumab (15 mg/kg) be considered for children 2 years of age or less who continue to require prophylaxis as soon as the patient is medically stable. 

The AAP (2014; reaffirmed in 2019) reported that certain children who are 12 months or younger with hemodynamically significant CHD may benefit from palivizumab prophylaxis. The children with CHD who are most likely to benefit from prophylaxis, according to the AAP, include infants with acyanotic heart disease who are on medication to control congestive heart failure and will require cardiac surgical procedures and infants with moderate to severe pulmonary hypertension. In regards to infants with cyanotic heart defects in the first year of life, the AAP states that decisions regarding palivizumab prophylaxis may be made in consultation with a pediatric cardiologist. These AAP recommendations apply to qualifying infants in the first year of life who are born within 12 months of onset of the RSV season.

Decisions regarding prophylaxis with palivizumab in children with CHD should be made on the basis of the degree of physiologic cardiovascular compromise. The AAP Red Book (2014; reaffirmed in 2019) guidelines suggest that the following groups of infants are not at increased risk from RSV and generally should not receive immunoprophylaxis:

• 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);
• Infants with lesions adequately corrected by surgery, unless they continue to require medication for congestive heart failure;
• Infants with mild cardiomyopathy who are not receiving medical therapy for the condition;
• Children in the second year of life.

Cystic Fibrosis

Routine use of palivizumab prophylaxis in patients with cystic fibrosis, including neonates diagnosed with cystic fibrosis by newborn screening, is not recommended unless other indications are present. An infant with cystic fibrosis and clinical evidence of CLD and/or nutritional compromise in the first year of life may be considered for prophylaxis. Continued use of palivizumab prophylaxis in the second year may be considered for infants with manifestations of severe lung disease (previous hospitalization for pulmonary exacerbation in the first year of life or abnormalities on chest radiography or chest computed tomography that persist when stable) or weight for length less than the 10th percentile.

Giebels and colleagues (2008) stated that in CF patients, RSV infection is associated with significant morbidity.  Although passive prophylaxis with palivizumab lowers hospitalization rate for RSV infection in populations at risk of severe infection, its use is not recommended in infants with CF disease.  In a retrospective study, these researchers examined the effect of palivizumab prophylaxis on hospitalization for acute respiratory illness in young children with CF during the first RSV season following the diagnosis of CF.  Medical records of patients diagnosed with CF between the years 1997 and 2005 inclusively and on whom the diagnosis was made before 18 months of age were reviewed.  Collected data included age at diagnosis, palivizumab prophylaxis, occurrence of hospitalization for acute respiratory tract illness during the RSV season and identification of RSV infection.  A diagnosis of CF was made in 76 young children and data collected from 75 children.  Of those, 40 did not receive RSV prophylaxis while 35 received palivizumab injection monthly during the RSV season.  Among non-recipient children, 7 out of 40 were hospitalized for acute respiratory illness during the RSV season.  Of these 7 patients, RSV detection was positive in naso-pharyngeal secretions in 3 patients, negative in 1 patient and not requested in the others.  Among palivizumab recipients, 3 out of 35 children were hospitalized for acute respiratory illness (p > 0.05 compared to non-recipients group).  In these 3 palivizumab recipients, RSV detection was negative in naso-pharyngeal secretions.  Palivizumab recipients experienced fewer hospital days per patient for acute respiratory illness (mean +/- SD: 0.8 +/- 3.07 days) as compared to non-recipients (mean +/- SD: 1.73 +/- 4.27 days); but this difference did not reach statistical significance.  The authors concluded that CF infants may benefit from RSV immunoprophylaxis with palivizumab.

Speer and associates (2008) noted that the Palivizumab Outcomes Registry collected data on 19,548 high-risk infants who received 1 or more dose(s) of palivizumab and followed prospectively from 2000 through 2004.  A total of 91 children with CF were identified who received palivizumab off-label.  None of the infants with CF who received prophylaxis was hospitalized as a result of RSV lower respiratory tract infection.  The authors concluded that evaluations of palivizumab use in infants with CF could be warranted.

The Cystic Fibrosis Foundation's evidence-based guidelines for management of infants with CF (2009) noted that 2 studies have addressed the use of palivizuma in infants with CF.  A chart review of hospitalized infants found that fewer children who received palivizumab were hospitalized and their length of stay was shorter, although these differences did not reach statistical significance.  Extrapolation of data from other populations suggested that there could be benefit from the use of RSV prophylaxis in infants with CF.  Thus, the Foundation recommended the use of palivizumab be considered for prophylaxis of RSV for infants with CF under 2 years of age (Certainty: low; Benefit: moderate; consensus recommendation).  The committee made consensus recommendations for topics not included in the evidence review, for topics where prior guidelines were available, and for topics for which there was limited or no evidence, but the potential benefit was assessed as at least moderate.

A Cochrane review initially published in 2010 and updated in 2014 assessed the use of palivizumab in infants with cystic fibrosis. One randomized controlled trial met the inclusion criteria for both reviews. The study compared 5 monthly doses of palivizumab to placebo in infants up to 2 years of age with cystic fibrosis. The authors of the review concluded that the overall incidence of adverse events was similar in both groups and it was not possible to draw conclusions on the safety and tolerability of RSV prophylaxis and palivizumab in infants with cystic fibrosis because the trial did not specify how adverse events were classified and additional randomized studies are needed.

In a Cochrane review, Robinson et al (2012) examined the safety and effectiveness of palivizumab compared with placebo, no prophylaxis or other prophylaxis, in preventing hospitalization and mortality from RSV infection in children with CF.  These investigators searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register and scanned references of the eligible study and related reviews.Date of last search: October 25, 2011.  Randomized and quasi-randomized studies were searched.  The authors independently extracted data and assessed risk of bias.  One study (186 infants up to 2 years old) comparing 5 monthly doses of palivizumab (n = 92) to placebo (n = 94) over 1 RSV season was identified and met inclusion criteria.  At 6 months follow-up, 1 participant in each group was hospitalized due to RSV; there were no deaths in either group.  In the palivizumab and placebo groups, 86 and 90 children experienced any adverse event, while 5 and 4 children had related adverse events, respectively.  A total of 19 children receiving palivizumab and 16 receiving placebo suffered serious adverse events; 1 participant receiving palivizumab discontinued due to this.  At 12 months follow-up, there were no significant differences between groups in number of Pseudomonas bacterial colonisations or change in weight-to-height ratio.  The authors identified 1 randomized controlled trial comparing 5 monthly doses of palivizumab to placebo in infants up to 2 years old with CF.  While the overall incidence of adverse events was similar in both groups, it is not possible to draw conclusions on the safety and tolerability of RSV prophylaxis with palivizumab in infants with CF because the trial did not specify how adverse events were classified.  Six months after treatment, the authors reported no clinically meaningful differences in outcomes; however no data were provided.  The authors stated that additional randomized studies are needed to establish the safety and efficacy of palivizumab in children with CF.

Winterstein and colleagues (2013) evaluated palivizumab effectiveness in children with cystic fibrosis by utilizing Medicaid Extract files provided by the Centers for Medicare and Medicaid Services. A cohort was established consisting of children 0–2 years of age from 27 states with a cystic fibrosis (CF) diagnosis between 1999 and 2006. Eligible children entered the cohort after CF diagnosis and after RSV season onset, and were followed until season end, second birthday, death, or hospitalizations for reasons other than a study outcome. The primary endpoint was hospitalization for RSV‐related infections (RSV‐ha). The secondary endpoint was based on hospitalization for acute respiratory illness (ARI‐ha). Palivizumab exposure was defined based on pharmacy or procedure claims. Both primary and secondary outcomes were examined in a Cox regression model, adjusting for RSV risk factors and CF severity via exposure propensity score. The matched cohort included 1974 infants (2875 infant seasons), who experienced 32 RSV‐ha and 212 ARI‐ha (3.9 and 26.2/1000 season months, respectively). Compared to periods of no use, the adjusted hazard ratio for current use was 0.57 (95% confidence interval [CI]: 0.20–.60) for RSV‐related hospitalization and 0.85 (95% CI: 0.59–.21) for ARI‐related hospitalization. Each month of increasing age reduced the ARI‐ha by 5.8%. The authors concluded that adjusted and unadjusted RSV‐hospitalization incidence rates suggested potentially positive effects of palivizumab, but results were inconclusive due to small event rates. The authors also reported that age greatly affected infection risk with incidence rates for 1‐2 year olds reduced to half when compared to 0‐1 year old infants.

The AAP (2014; reaffirmed in 2019) recommended palivizumab for prevention of RSV in an infant with cystic fibrosis (CF) who has clinical evidence of chronic lung disease (CLD) and/or nutritional compromise in the first year of life. Continued use of palivizumab prophylaxis in the second year may be considered for infants with manifestations of severe lung disease (previous hospitalization for pulmonary exacerbation in the first year of life or abnormalities on chest radiography or chest computed tomography that persist when stable) or weight for length less than the 10th percentile.

Sanchez-Solis et al (2015) noted that infections by RSV are more severe in patients with CF, and many CF units use palivizumab as prophylaxis; however, information about the effectiveness of palivizumab in CF patients is almost lacking.  These investigators performed a literature search up to December 2012 on the morbidity of RSV bronchiolitis in CF patients and on the safety and effectiveness of palivizumab in those patients.  A random-effects meta-analysis was conducted for those studies meeting pre-specified search criteria.  Historical controls were allowed.  The number of patients who received palivizumab was 354 and the hospital admission rate was 0.018 (95 % CI: 0.0077 to 0.048).  The corresponding number in the non-treated groups was 463 patients with an admission rate of 0.126 (95 % CI: 0.086 to 0.182) (Q = 13.9; p < 0.001).  The authors concluded that palivizumab may have a role in the prevention of severe lower airway infection by RSV in CF patients.

However, the updated Cochrane review on "Palivizumab for prophylaxis against respiratory syncytial virus infection in children with cystic fibrosis" (Robinson et al, 2013) still maintained that additional randomized studies are needed to establish the safety and effectiveness of palivizumab in children with CF.

In a Cochrane review, Robinson et al (2014) determined the safety and effectiveness of palivizumab compared with placebo, no prophylaxis or other prophylaxis, in preventing hospitalization and mortality from RSV infection in children with CF.  The authors concluded that they identified 1 randomized controlled trial (RCT) comparing 5 monthly doses of palivizumab to placebo in infants up to 2 years old with CF.  While the overall incidence of adverse events was similar in both groups, it is not possible to draw firm conclusions on the safety and tolerability of RSV prophylaxis with palivizumab in infants with CF.  They reported no clinically meaningful differences in outcomes 6 months after treatment.  They stated that additional randomized studies are needed to establish the safety and effectiveness of palivizumab in children with CF.

In a Cochrane review, Robinson and colleagues (2016) evaluated the safety and effectiveness of palivizumab (Synagis) compared with placebo, no prophylaxis or other prophylaxis, in preventing hospitalization and mortality from RSV infection in children with CF.  The authors identified 1 RCT comparing 5 monthly doses of palivizumab to placebo in infants up to 2 years old with CF.  While the overall incidence of AEs was similar in both groups, it is not possible to draw firm conclusions on the safety and tolerability of RSV prophylaxis with palivizumab in infants with CF.  The authors reported no clinically meaningful differences in outcomes 6 months after treatment.  They stated that additional randomized studies are needed to establish the safety and effectiveness of palivizumab in children with CF.

McGirr and associates (2017) evaluated the cost-effectiveness of palivizumab (PMB) prophylaxis in CF children less than 2 years of age from the Canadian healthcare payer's perspective.  In 2014, a Markov cohort model of CF disease and infant RSV infections in the Canadian setting was developed based on literature data.  Infants were treated with monthly PMB injections over the 5-month RSV season.  Lifetime health outcomes, quality-adjusted life years (QALYs) and 2013 $CAD costs, discounted at 5 %, were estimated.  Findings are summarized as incremental cost-effectiveness ratios (ICERs) and budget impact.  Deterministic sensitivity analysis was conducted to assess parameter uncertainty.  Implementation of a hypothetical Canadian RSV prophylaxis program resulted in ICERs of C$652,560 (all CF infants) and C$157,332 (high-risk CF infants) per QALY gained and an annual budget impact of C$1,400,000 (all CF infants) and C$285,000 (high-risk CF infants).  The analysis was highly sensitive to the probability of severe RSV, the degree of lung deterioration following infection, and the cost of PMB.  The authors concluded that these findings suggested that PMB is not cost-effective in Canada by commonly used thresholds.  However, given the rarity of CF and relatively small budget impact, consideration may be given for the selective use of PMB for immunoprophylaxis of RSV in high-risk CF infants on a case-by-case scenario basis.

Buchs and colleagues (2017) noted that RSV infections may worsen CF lung disease and favor Pseudomonas aeruginosa (Pa) or Staphylococcus aureus (Sa) acquisition, which is of particular importance in the youngest patients.  These researchers determined the effectiveness of palivizumab (PVZ) on microbiological outcomes in young children with CF.  They conducted a retrospective case-control study to compare these outcomes in children who systematically received PVZ (PVZ+; n = 40) or not (PVZ-; n = 140); 1 case was matched with at least 3 same-gender controls born the same year and month.  Median (range) age at first Pa isolation was not statistically different between PVZ- (12.3 [3.8 to 32.6] months) and PVZ+ (10.4 [1.2 to 33.0] months; p = 0.953) patients.  A similar trend was found for Sa (PVZ+: 6.4 [2.0 to 59.0] months; PVZ-: 3.8 [0.1 to 74.1] months; p = 0.191).  The proportion of Pa isolations by 3 years of age did not differ between groups (PVZ+ 40 % versus PVZ- 41.4 %), but this proportion was higher for Sa in the PVZ+ group (97 %) than in the PVZ- group (85 %; p = 0.001).  Healthcare consumption and growth outcomes did not significantly differ between groups.  The authors concluded that systematic PVZ use did not delay key pathogen acquisition in young children with CF.  Whether or not palivizumab is useful in infants with CF remains controversial.  Palivizumab did not delay key pathogens (Pseudomonas aeruginosa, Staphylococcus aureus) first isolation in young children with CF; it did not reduce healthcare consumption or improve growth during the first 3 years of life of young children with CF.

Kua and associates (2017) stated that RSV is a common pathogen in infants with CF.  The use of PVZ prophylaxis for RSV infection as the standard of care for infants with CF remains controversial.  These investigators evaluated the efficacy of PVZ in reducing the incidence of RSV hospitalization in children with CF who are younger than 2 years.  Four electronic databases (PubMed, Embase, CINAHL, and CENTRAL) were searched from inception until January 31, 2017, for clinical studies investigating the use of PVZ in infants with CF aged less than 2 years.  The primary outcome was hospitalization rate due to RSV infection.  Secondary outcomes included hospitalization for respiratory illness, length of hospital stay, safety (adverse effects), and cost-effectiveness of PVZ prophylaxis.  The review included a total of 10 studies (6 cohort studies, 2 before-and-after studies, 1 cross-sectional study, and 1 RCT) involving 3,891 patients with CF; 7 studies reported that PVZ prophylaxis had a positive impact on the rate of RSV hospitalization; 5 studies (n = 3,404) reported that PVZ prophylaxis significantly reduced the rate of hospitalization due to RSV infection compared to no prophylaxis.  One study (n = 5) demonstrated patients with CF who received PVZ had no RSV hospitalization.  Another study showed infants with CF receiving PVZ (n = 117) had a lower risk of hospitalization for RSV infection compared with premature infants (gestational age less than 35 completed weeks) who received PVZ (n = 4,880).  The authors concluded that evidence from the literature suggested that PVZ may have a potential role in reducing RSV hospitalization in children aged less than 2 years with CF.  moreover, they stated that given the lack of overall data, additional research is needed to better understand the safety and efficacy of prophylactic PVZ in infants with CF.

Fink and colleagues (2019) noted that the AAP does not recommend routine use of palivizumab prophylaxis for infants with CF but recommends consideration in infants with clinical evidence of chronic lung disease or nutritional compromise. However, the beneficial impact of palivizumab on longer-term outcomes is uncertain. These researchers used Cystic Fibrosis Foundation Patient Registry data to assess the association of receiving palivizumab during the first 2 years of life with longer-term outcomes, including lung function at 7 years old, time to first positive Pseudomonas respiratory culture, and pulmonary-related hospitalizations during the first 7 years of life. Eligible infants were born from 2008 to 2015 and diagnosed with CF during the first 6 months of life. Demographic and clinical confounders of association between palivizumab receipt and outcomes were explored. They created propensity scores to adjust for potential confounding by indication (i.e., sicker infants were more likely to receive palivizumab). For each outcome, these investigators performed regression analyses adjusted by propensity scores. The sample included 4,267 infants; 1,588 (37 %) received palivizumab. Mean percent forced expiratory volume in 1 second (FEV1) predicted at 7 years old was similar among those who did (98.2; 95 % CI: 96.9 to 99.5) and did not (97.3; 95 % CI: 96.1 to 98.5) received palivizumab, adjusting for propensity scores. Time to first positive Pseudomonas aeruginosa culture and annual risk of hospitalization were similar among those who did and did not receive palivizumab. The authors concluded that at the population level, palivizumab receipt was not associated with improved longer-term outcomes in children with CF.

Down Syndrome

The available limited data indicates a slight increase in RSV hospitalization rates for children with Down syndrome. However, the AAP (2014) reports: "data are insufficient to justify a recommendation for routine use of prophylaxis in children with Down syndrome unless a qualifying heart disease, CLD, airway clearance issues, or prematurity (<29 weeks, 0 days' gestation) is present."

Hematopoietic Stem Cell Transplants (HSCTs)

Boeckh et al (2001) stated that intravenous palivizumab (15 mg/kg) was investigated in 2 phase I studies among recipients of hematopoietic stem cell transplants (HSCTs).  Study 1 included 6 HSCT patients without active RSV infection.  Study 2 included 15 HSCT patients with RSV upper respiratory tract infection (URTI; n = 3) or RSV interstitial pneumonia (IP; n = 12), all of whom also received aerosolized ribavirin.  Peak serum concentrations of palivizumab in the 2 studies were similar.  The mean serum half-life was 22.4 days in study 1, which mainly included autologous HSCT recipients, and 10.7 days in study 2, which mainly included allogeneic HSCT recipients.  No antibodies to palivizumab were detected in study 1.  No adverse events were attributed to palivizumab in the 2 studies.  In study 2, all 3 patients with RSV URTI recovered without progression to lower respiratory tract disease, and 10 (83 %) of the 12 patients with RSV IP survived the 28-day study period.  Thus, palivizumab appears to be safe and well-tolerated in HSCT recipients.  Well-designed studies are needed to validate the findings of these phase I studies.

Shah and Chemaly (2011) noted that RSV is a common cause of seasonal respiratory viral infection in patients who have undergone HSCT.  Respiratory syncytial virus usually presents as an URTI in this patient population but may progress rapidly to lower respiratory tract infection. Available therapies that have been used for the treatment of RSV infections are limited to ribavirin, intravenous immunoglobulin (IVIG), and palivizumab.  The use of aerosolized ribavirin, alone or in combination with either palivizumab or IVIG, remains controversial.

Seo et al (2013) evaluated the effect of transplant and treatment factors on overall survival, mortality from respiratory failure, and pulmonary function among 82 HSCT recipients who had RSV lower respiratory tract disease (LRD) between 1990 and 2011.  All patients received aerosolized ribavirin.  In multi-variable analyses, only the use of marrow or cord blood as graft source (adjusted hazard ratio [aHR], 4.1; 95 % confidence interval [CI]: 1.8 to 9.0; p < 0.001) and oxygen requirement (aHR, 3.3; 95 % CI: 1.5 to 6.7; p = 0.003) remained independently associated with overall mortality and death due to respiratory failure (aHR, 4.7; 95 % CI: 1.8 to 13; p = 0.002 and aHR, 5.4; 95 % CI: 1.8 to 16; p = 0.002, respectively).  Antibody-based treatments, including IVIG and palivizumab, were not independently associated with improved outcome and did not alter the associations of the graft source and oxygen requirements in statistical models.  The authors concluded that use of peripheral blood stem cells as graft source and lack of oxygen requirement at diagnosis appear to be important factors associated with improved survival of HSCT recipients with RSV LRD.  These results may explain differences in outcomes reported from RSV infection over time and may guide the design of future interventional trials.

Immunocompromised Adults

Hynicka and Ensor Pharmd (2012) reviewed the literature regarding current strategies and strategies under active development for the prevention and treatment of RSV infections in immunocompromised adults.  The MEDLINE/PubMed, EMBASE, and Cochrane databases were queried from January 1980 to December 2011 for articles in English using these associated search terms: respiratory syncytial virus, ribavirin, intravenous immunoglobulin, IVIG, palivizumab, motavizumab, lung, pneumonia, transplantation, bone marrow, cancer, malignancy, and vaccine.  All relevant original studies, meta-analyses, systematic reviews, and review articles were assessed for inclusion.  References from pertinent articles were examined for additional content not found during the initial search.  Respiratory syncytial virus in the immunocompromised adult can lead to significant morbidity and mortality.  Treatment of RSV-infected adults is limited to anti-viral therapy with ribavirin (aerosolized, oral, intravenous) as well as immunomodulation with intravenous immunoglobulins, corticosteroids, and palivizumab.  Existing literature is predominantly case reports, small trials, and retrospective reviews of patients infected with RSV who have undergone lung or hematopoietic stem cell transplantation (HSCT).  Palivizumab may be a viable option for prophylaxis against RSV in high-risk adults.  Ribavirin is the most studied treatment option and should remain the backbone of multi-drug regimens.  Of the routes of administration, aerosolized ribavirin carries the preponderance of evidence and, though challenging, is preferred to limit systemic toxicities in the infected patient.  Addition of an immunomodulator to ribavirin may provide a survival benefit over ribavirin alone; however, this has only been studied in a subset of HSCT patients with lower respiratory tract RSV infection.  The authors concluded that research most strongly supports the use of aerosolized ribavirin as the treatment strategy for immunocompromised adults with RSV.  Addition of an immunomodulator may provide a survival benefit over ribavirin alone.  Strategies and supportive data for the prevention of RSV infection in the high-risk adult are critically needed.

Immunocompromised Children

Palivizumab prophylaxis has not been evaluated in randomized trials in immunocompromised children.  Although specific recommendations for immunocompromised patients can not be made, the literature indicates that children with severe immunodeficiencies (e.g., severe combined immunodeficiency or severe acquired immunodeficiency syndrome) may benefit from prophylaxis.

No population based data are available on the incidence of RSV hospitalization in children who undergo solid organ or hematopoietic stem cell transplantation. Severe and even fatal disease attributable to RSV is recognized in children receiving chemotherapy or who are immunocompromised because of other conditions, but the efficacy of prophylaxis in this cohort is not known. Prophylaxis may be considered for children younger than 24 months of age who are profoundly immunocompromised during the RSV season.

Cortez and colleagues (2002) studied whether RSV‐IVIg provided sufficient RSV immune prophylaxis to prevent RSV pneumonia in 54 individuals undergoing stem‐cell transplantation. The authors reported a low incidence of RSV infection in the 54 RSV‐IVIg subjects, as well as in 31 others not enrolled in the study, but could not determine the preventive effect of RSVIVIg. Hynicka and Ensor (2012), in a literature review, reported that data are limited on RSV prophylaxis in immunocompromised adults.

Santos et al (2012) presented the findings of 2 children with acute lymphocytic leukemia (ALL) and persistent RSV infection while receiving chemotherapy.  Patient A is a 4-year old male with Down syndrome, ALL, and persistent RSV infection for at least 3 months.  Patient B is a 3-year old female with pre-B cell ALL whose chemotherapy intensification phase was delayed due to a month-long RSV infection.  Respiratory syncytial virus infections were determined by using real-time polymerase chain reaction assays from nasopharyngeal swabs before intravenous (IV) palivizumab therapy; patient A was positive for RSV at 36 cycles and patient B was positive for RSV at 29 cycles.  Respiratory syncytial virus infection was cleared in both patients within 72 hours after receiving IV palivizumab (patient A: 16 mg/kg; patient B: 15 mg/kg).  The authors stated that intravenous palivizumab may be a treatment option for persistent RSV infection among immune-compromised patients.

The AAP (2014; reaffirmed in 2019) recommends palivizumab for immunocompromised children who are younger than 24 months of age who are profoundly immunocompromised during the RSV season. 

Preterm Infants

According to the AAP (2014; reaffirmed in 2019), palivizumab prophylaxis may be given to preterm infants born before 29 weeks, 0 days gestation who are younger than 12 months at the beginning of the RSV season. For infants born during the RSV season, less than 5 monthly doses will be needed. Available data has demonstrated that the greatest increased risk for hospitalization is in preterm infants born before 29 weeks gestation. For infants born at 29 weeks, 0 days gestation or later, a definite cutoff of gestational age for which RSV prophylaxis may be beneficial has not been demonstrated. Infants born at 29 weeks, 0 days gestation or later are not generally recommended by the AAP to receive prophylaxis, unless they qualify to receive it based on other conditions, such as CHD or CLD. Additionally, palivizumab prophylaxis is not recommended by the AAP in the second year of life based on a history of prematurity alone.

Preterm infants who develop CLD of prematurity defined as gestational age <32 weeks, 0 days and a requirement for >21% oxygen for at least the first 28 days after birth may be considered for palivizumab prophylaxis during the RSV season in the first year of life. During the second year of life prophylaxis is recommended by the AAP only for infants who meet the definition of CLD of prematurity and continue to require medical support (chronic corticosteroid therapy, diuretic therapy, or supplemental oxygen) during the 6‐month period prior to the start of the second RSV season. For infants with CLD who do not continue to require medical support in the second year of life, the AAP does not recommend prophylaxis.

Prevention of Health Care Associated RSV Disease

Respiratory syncytial virus is known to be transmitted in the hospital setting and to cause serious disease in high-risk infants.  In high-risk hospitalized infants, the major means to prevent RSV disease is strict observance of infection control practices, including the use of rapid means to identify and cohort RSV-infected infants.  If an RSV outbreak is documented in a high-risk unit (e.g., pediatric intensive care unit), accepted guidelines indicate that primary emphasis should be placed on proper infection control practices.  The need for and efficacy of prophylaxis in these situations has not been evaluated.

The AAP Red Book (2014; reaffirmed in 2019) includes the following statement regarding the use of palivizumab in controlling outbreaks of health care associated disease: No rigorous data exist to support palivizumab use in controlling outbreaks of health care‐associated disease, and palivizumab use is not recommended for this purpose. Infants in a neonatal unit who qualify for prophylaxis because of CLD, prematurity, or CHD may receive the first dose 48 to 72 hours before discharge to home or promptly after discharge.

Strict adherence to infection‐control practices is the basis for reducing health care‐associated RSV disease.

RespiGam Respiratory Syncytial Virus Immune Globulin (RSV-IVIG)

On October 1, 2003, MedImmune and Massachusetts Public Health & Biologics Laboratory (MPHBL), the manufacturers of RespiGam, announced that production of RespiGam will be discontinued.  As of March 15, 2004 all current inventory levels of RespiGam had been depleted and no product is available for sale from MedImmune or MPHBL.

RSV Infection in Mechanically Ventilated Pediatric Patients

In a retrospective, single-center cohort study, Helmink and colleagues (2016) compared outcomes among pediatric patients with RSV infection who received IV palivizumab and standard of care (SOC) versus SOC alone.  This study was conducted between November 2003 and October 2013.  Pediatric patients with active RSV infection treated with IV palivizumab after initiation of mechanical ventilation were matched 1:1 to a control selected from ventilated patients who received SOC.   The primary end-point evaluated the duration of mechanical ventilation between groups.  Secondary end-points included hospital length of stay, ICU length of stay, duration of respiratory support over baseline, time to RSV microbiologic cure, duration of antibiotic therapy, and in-hospital mortality.  A total of 22 patients with a median age of 3 months were included in the study.  Patients in the treatment group received a median of 2 doses of IV palivizumab, with a mean dose of 14.2 mg/kg.  All patients received bronchodilators and corticosteroids, with the exception of 1 patient in the control group, and only 1 treatment group patient received IV ribavirin.  Duration of mechanical ventilation was longer in the treatment group (18.9 ± 9.5 versus 14.3 ± 9.3 days; p = 0.26).  No statistically significant differences were observed between groups for any of the secondary end-points.  The authors concluded that pediatric patients who received IV palivizumab in addition to SOC for the treatment of RSV infection following initiation of mechanical ventilation experienced similar outcomes to those who received SOC alone.  They stated that further studies are needed to evaluate the potential benefit of IV palivizumab in addition to current SOC.

RSV Season

The Center for Disease Control and Prevention (CDC) National Respiratory and Enteric Virus Surveillance System (NREVSS) is a laboratory-based system that monitors temporal and geographic patterns associated with the detection of RSV and other viruses.  Annual summaries and alerts based on NREVSS data have been published periodically in CDC's Morbidity and Mortality Weekly Report at RSV Seasonal Trends, or RSV State Trends. CDC surveillance summaries of weekly RSV laboratory test result data for each region of the United States are posted at: RSV State Trends.

Meissner et al (2004) cited evidence supporting the AAP position that 5 monthly doses of palivizumab will provide effective protection during the RSV season, even with variations in the onset and end of the season: "The recommendation for 5 monthly doses of palivizumab was derived from the design of clinical trials with both RespiGam and palivizumab.  In the IMpact-RSV trial and in the trial involving children with hemodynamically significant congenital heart disease, 5 monthly doses of palivizumab resulted in serum concentrations 30 µg/ml for over 20 weeks in almost all subjects.  A serum palivizumab concentration 30 µg/ml is the proposed serologic correlate of protection, derived from animal models, in which this concentration results in a decrease in pulmonary RSV replication by more than 100-fold.  One month after the fourth monthly dose of palivizumab, the mean serum trough concentration was 72 µg/ml among subjects in the IMpact-RSV trial and 90 µg/ml in subjects in the cardiac trial, indicating that the trough serum level more than 30 days after the fifth dose will be greater than 30 µg/ml for most children.  Thus, for most infants, 5 monthly doses of palivizumab will provide substantially over 20 weeks of serum antibody levels, which should be protective and cover most of the RSV season even with variation in season onset and end."

Meissner et al (2004) stated that "it is important to remember that results from antigen detection assays do not provide an adequate basis for determination of onset and offset of the RSV season."  Meissner et al explained that RSV antigen detection assays may overestimate the risk of RSV outside of the RSV season, as the positive predictive value of a test decreases as disease incidence goes down.  Because the sensitivity and specificity of antigen-detection assays are low both at the onset and the end of the season, the risk to the child in these periods will be less than that predicted by RSV detection using antigen-based assays.

Although there have been reports of year-round prevalence of RSV in certain localities (e.g., Chattanooga, TN, South Florida), these reports are based on antigen detection assays, which are only reliable during periods of extremely high population prevalence (Meissner, 2005).  During periods of relatively low RSV prevalence, antigen detection assays are associated with false positive rates greater than 50 %, and no good correlation with actual disease prevalence in the community or with clinical risk to patients. 

Midgley et al (2017) state that in the U.S., the seasonality of RSV has been defined on the basis of weeks during which antigen-based tests detect RSV in greater than 10% of specimens; however, PCR-based reports are increasingly relevant for RSV surveillance and determining the seasonality of RSV. The authors assessed antigen- and PCR-based RSV reports submitted to the National Respiratory and Enteric Virus Surveillance System during July 2005–June 2015. To characterize RSV seasons by using PCR-based reports, they assessed the traditional 10% threshold; subsequently, they developed 3 methods based on either PCR-based detections or the percentage of positive test results. The authors found that the annual number of PCR-based reports increased 200-fold during 2005–2015, while the annual number of antigen-based reports declined. The weekly percentage of specimens positive for RSV by PCR was less than that for antigen-detection tests; accordingly, the 10% threshold excluded detections by PCR and so was imprecise for characterizing RSV seasons. Among our PCR-specific approaches, the most sensitive and consistent method captured 96%–98% of annual detections within a season, compared with 82%–94% captured using the traditional method. The authors developed a method that defined season onset as the first of 2 consecutive weeks when the weekly percentage of tests positive for RSV was >3%. They chose this threshold because the national and regional percentage of tests positive for RSV throughout the summer months was typically <3%; once the 3% threshold was exceeded, the percentage of tests yielding RSV continued to increase rapidly. This third method provided a simple approach that accounted for the number of tests performed. Based on the 3% threshold, national season onsets during July 2009–June 2015 were between weeks 42 and 46.The authors concluded that PCR-specific methods provide a more comprehensive understanding of RSV trends, particularly in settings where testing and reporting are most active. Diagnostic practices will vary by locality and should be understood before choosing which method to apply. The PCR-specific approach, the 3% threshold, incorporates the RSV tests performed to determine the weekly percentage of tests positive for RSV, as was used traditionally for antigen-based reports. This simple approach might allow for a reasonable estimation of RSV season in public health jurisdictions where RSV testing is not performed or reported throughout the year.

The Centers for Disease Control Morbidity and Mortality Weekly Report (MMWR, 2018) for RSV seasonality in the U.S. from 2014 to 2017 states, "nationally, across the three seasons, the median RSV onset occurred at surveillance week 41 (mid-October), and lasted 31 weeks until surveillance week 18 (early May). The median national peak occurred at week 5 (early February). When Florida and Hawaii are excluded, the national onset occurred 1 week later and the season duration decreased by 1 week. Median onset for the 10 HHS regions (excluding Florida and Hawaii) ranged from week 37 to week 48 (mid-September to early December) and offset ranged from week 15 to week 21 (mid-April to late May). The median season peaks ranged from week 52 to week 7 (late December to mid-February), and the median duration ranged from 22 to 37 weeks (Table 2). Region 9 had the shortest season (median = 22 weeks), and Region 4 had the longest (37 weeks). The median onset for Florida occurred at week 37 (mid-September), and the season continued through week 16 (mid-April)".  

Per the Centers for Disease Control and Prevention (CDC, 2020), "for 2016 to 2017, the RSV season onset ranged from mid-September to mid-November, season peak ranged from late December to mid-February, and season offset ranged from mid-April to mid-May in all 10 U.S. Department of Health and Human Services (HHS) regions, except Florida. Florida has an earlier RSV season onset and longer duration than most regions of the country. Seasonal patterns remain consistent with previous years".

According to the AAP Red Book 2021, "during the 3 RSV seasons from July 2014 to June 2017, the Centers for Disease Control and Prevention reported the median peak of RSV activity occurred in early February (with median onset mid-October and median offset mid-May). Data regarding RSV circulation are obtained from 10 different US Department of Health and Human Services regions within the United States and are reported separately for Florida because patterns of RSV circulation there can be different from regional and national patterns. During these 3 years, the season onset ranged from early September to early December, demonstrating that determination of onset of the RSV season should be based on local activity. Season onset can be determined in real time by identifying the first week of 2 consecutive weeks that RSV RT-PCR test positivity is 3% or greater or antigen detection positivity is 10% or greater".

Appendix

Appendix A: Recommended Use of Synagis for Prevention of RSV Infection

Recommendations from the American Academy of Pediatrics (AAP) for the prevention of RSV infection with Synagis are summarized in Table below. Synagis should be administered intramuscularly at a dose of 15 mg/kg once per month beginning prior to the onset of the RSV season, which typically occurs in November. Because 5 monthly doses of Synagis will provide more than 6 months of serum Synagis concentrations above the desired serum concentration for most infants, administration of more than 5 monthly doses is not recommended within the continental United States.

Table: Recommended Use of Synagis for Prevention of RSV Infection

Prematurity	Preterm infants born < 29 weeks, 0 days of gestation who are younger than 12 months at the start of the RSV season
Congenital Heart Disease	Infants and children < 12 months of age with hemodynamically significant CHD Those most likely to benefit from prophylaxis include: 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 and children < 24 months of age who undergo cardiac transplantation during the RSV season
Chronic Lung Disease of Prematurity	For the first RSV season during the first year of life: Preterm infants who develop CLD of prematurity defined as: Gestational age < 32 weeks, 0 days AND Requirement for > 21% oxygen for at least the first 28 days after birth For the second RSV season during the second year of life: Preterm infants who: Satisfy the above definition of CLD of prematurity AND Continue to require medical supportFootnote1* for CLD during the 6-month period prior to the start of the second RSV season
Congenital Abnormality of the Airway/ Neuromuscular Condition	Infants who have either a significant congenital abnormality of the airway or a neuromuscular condition that compromises handling of respiratory secretions for the first year of life
Immunocompromised children	Children younger than 24 months of age who are profoundly immunocompromised during the RSV season
Cystic Fibrosis	For the first year of life, children with clinical evidence of CLD and/or nutritional compromise For the second year of life, children with manifestations of severe lung disease (previous hospitalization for pulmonary exacerbation in the first year of life or abnormalities on chest radiography or chest computed tomography that persist when stable) OR weight for length less than the 10th percentile.

Abbreviations: CHD = congenital heart disease; CLD = chronic lung disease (formerly bronchopulmonary dysplasia); RSV = respiratory syncytial virus.

Footnote1* Medical support includes supplemental oxygen, diuretic therapy, or chronic corticosteroid therapy

Source: AAP (2014; reaffirmed in 2019)

Appendix B: Examples of Congenital Heart AnomaliesFootnote2**

• Atrial or ventricular septal defect 
• Patent ductus arteriosus
• Coarctation of aorta 
• Tetralogy of Fallot  
• Pulmonary or aortic valve stenosis  
• D-Transposition of great arteries
• Hypoplastic left/right ventricle
• Truncus arteriosus
• Total anomalous pulmonary venous return
• Tricuspid atresia 
• Ebstein’s anomaly
• Pulmonary atresia 
• Single ventricle
• Double-outlet right ventricle

Footnote2** Must be hemodynamically significant. See Table Recommended Use of Synagis for Prevention of RSV Infection (above) for examples of infants and children who are most likely to benefit from Synagis.

Source: Bernstein, 2020

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
90378	Respiratory syncytial virus, monoclonal antibody recombinant, for intramuscular use, 50 mg each
Other CPT codes related to the CPB:
33120	Excision of intracardiac tumor, resection with cardiopulmonary bypass
33305	Repair of cardiac wound; with cardiopulmonary bypass
33315	Cardiotomy, exploratory (includes removal of foreign body, atrial or ventricular thrombus); with cardiopulmonary bypass
33322	Suture repair of aorta or great vessels; with cardiopulmonary bypass
33335	Insertion of graft, aorta or great vessels; with cardiopulmonary bypass
33390 - 33391	Valvuloplasty, aortic valve, open, with cardiopulmonary bypass
33405	Replacement, aortic valve, with cardiopulmonary bypass; with prosthetic valve other than homograft or stentless valve
33406	Replacement, aortic valve, with cardiopulmonary bypass; with allograft valve (freehand)
33410	Replacement, aortic valve, with cardiopulmonary bypass; with stentless tissue valve
33422	Valvotomy, mitral valve; open heart, with cardiopulmonary bypass
33425	Valvuloplasty, mitral valve, with cardiopulmonary bypass
33426	Valvuloplasty, mitral valve, with cardiopulmonary bypass; with prosthetic ring
33427	Valvuloplasty, mitral valve, with cardiopulmonary bypass; radical reconstruction, with or without ring
33430	Replacement, mitral valve, with cardiopulmonary bypass
33460	Valvectomy, tricuspid valve, with cardiopulmonary bypass
33465	Replacement, tricuspid valve, with cardiopulmonary bypass
33474	Valvotomy, pulmonary valve, open heart; with cardiopulmonary bypass
33496	Repair of non-structural prosthetic valve dysfunction with cardiopulmonary bypass (separate procedure)
33500	Repair of coronary arteriovenous or arteriocardiac chamber fistula; with cardiopulmonary bypass
33504	Repair of anomalous coronary artery from pulmonary artery origin; by graft, with cardiopulmonary bypass
33641	Repair atrial septal defect, secundum, with cardiopulmonary bypass, with or without patch
33702	Repair sinus of Valsalva fistula, with cardiopulmonary bypass
33710	Repair sinus of Valsalva fistula, with cardiopulmonary bypass; with repair of ventricular septal defect
33720	Repair sinus of Valsalva aneurysm, with cardiopulmonary bypass
33736	Atrial septectomy or septostomy; open heart with cardiopulmonary bypass
33814	Obliteration of aortopulmonary septal defect; with cardiopulmonary bypass
33853	Repair of hypoplastic or interrupted aortic arch using autogenous or prosthetic material; with cardiopulmonary bypass
33858	Ascending aorta graft, with cardiopulmonary bypass, includes valve suspension, when performed; for aortic dissection
33859	for aortic disease other than dissection (eg, aneurysm)
33860	Ascending aorta graft, with cardiopulmonary bypass, includes valve suspension, when performed
33864	Ascending aorta graft, with cardiopulmonary bypass with valve suspension, with coronary reconstruction and valve sparing aortic root remodeling (e.g., David Procedure, Yacoub Procedure
33870	Transverse arch graft, with cardiopulmonary bypass
33871	Transverse aortic arch graft, with cardiopulmonary bypass, with profound hypothermia, total circulatory arrest and isolated cerebral perfusion with reimplantation of arch vessel(s) (eg, island pedicle or individual arch vessel reimplantation)
33875	Descending thoracic aorta graft, with or without bypass
33877	Repair of thoracoabdominal aortic aneurysm with graft, with or without cardiopulmonary bypass
33910	Pulmonary artery embolectomy; with cardiopulmonary bypass
33916	Pulmonary endarterectomy, with or without embolectomy, with cardiopulmonary bypass
33922	Transection of pulmonary artery with cardiopulmonary bypass
33926	Repair of pulmonary artery arborization anomalies by unifocalization; with cardiopulmonary bypass
33946 - 33986	Extracorporeal membrane oxygenation (ECMO)/extracorporeal life support (ECLS) provided by physician
33987	Arterial exposure with creation of graft conduit (eg, chimney graft) to facilitate arterial perfusion for ECMO/ECLS (List separately in addition to code for primary procedure)
33988	Insertion of left heart vent by thoracic incision (eg, sternotomy, thoracotomy) for ECMO/ECLS
33989	Removal of left heart vent by thoracic incision (eg, sternotomy, thoracotomy) for ECMO/ECLS
87252	Virus isolation; tissue culture inoculation, observation, and presumptive identification by cytopathic effect
87420	Infectious agent antigen detection by immunoassay technique, (eg, enzyme immunoassay [EIA], enzyme-linked immunosorbent assay [ELISA], immunochemiluminometric assay [IMCA]) qualitative or semiquantitative, multiple-step method; respiratory syncytial virus
87634	Infectious agent detection by nucleic acid (DNA or RNA); respiratory syncytial virus, amplified probe technique
96372	Therapeutic, prophylactic or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met:
S9562	Home injectable therapy, palivizumab, including administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
ICD-10 codes covered if selection criteria are met:
C91.00 - C91.02	Acute lymphoblastic leukemia [ALL] [children younger than 24 months who will be profoundly immunocompromised during the RSV season]
C92.00 - C92.02, C92.40 - C92.92	Acute myeloid leukemia [children younger than 24 months who will be profoundly immunocompromised during the RSV season]
D80.0 - D89.9	Certain disorders involving the immune mechanism [severe combined immunodeficiency or severe acquired immunodeficiency syndrome in children younger than 24 months who will be profoundly immunocompromised during the RSV season]
E84.0 - E84.9	Cystic fibrosis [for infants with clinical evidence of CLD and/or nutritional compromise in the first year of life and for continued in the second year for infants who have manifestations of severe lung disease (previous hospitalization for pulmonary exacerbation in the first year of life or abnormalities on chest radiography or chest computed tomography that persist when stable) or weight for length less than the 10th percentile] [ Not covered for routine use of palivizumab prophylaxis in infants and children with cystic fibrosis, including neonates diagnosed with cystic fibrosis by newborn screening, is considered experimental and investigational unless other indications are present]
G70.00 - G73.7	Disease of myoneural junction and muscle [that impair the ability to clear secretions from the upper airways because of ineffective cough]
I27.0 - I27.9	Other pulmonary heart disease [chronic lung disease] [infants with moderate to severe pulmonary hypertension]
I50.20 - I50.9	Congestive heart failure [infants receiving medication for control and will require cardiac surgical procedures]
J40 - J44.9, J47.0 - J47.9	Chronic lower respiratory disease [chronic lung disease]
P07.20 - P07.26	Extreme immaturity of newborn, gestational age less than 28 completed weeks
P07.30 - P07.35	Preterm [premature] newborn[other] [when a risk factor is present] [less than 33 weeks completed]
P27.1	Bronchopulmonary dysplasia originating in the perinatal period [chronic lung disease (CLD) of prematurity]
P29.30 - P29.38	Persistent fetal circulation [primary pulmonary hypertension of newborn] [infants with moderate to severe pulmonary hypertension]
Q20.0 - Q28.9	Congenital malformations of the circulatory system [congenital heart disease
Q33.0 - Q33.9	Congenital malformation of lung [anatomic pulmonary abnormalities that impair the ability to clear secretions from the upper airways because of ineffective cough]
T59.5X1+ - T59.894+	Toxic effect of other specified gases, fumes, or vapors [exposure to indoor air pollutants]
Z23	Encounter for immunization [respiratory syncytial virus (RSV)] [not covered for prevention of health-care associated RSV disease] [not covered for prophylaxis against RSV in immunocompromised adults]
Z48.21, Z94.1	Heart transplant status [for children younger than 2 years who undergo cardiac transplantation during the RSV season]
Z94.81	Bone marrow transplant status [postoperative dose of palivizumab (15 mg/kg) is considered medically necessary after cardiac bypass for infants and children younger than 24 months who are receiving palivizumab prophylaxis and who continue to require palivizumab prophylaxis]
Z94.84	Stem cells transplant status [children younger than 24 months who will be profoundly immunocompromised during the RSV season]
ICD-10 codes not covered for indications listed in the CPB:
B97.4	Respiratory syncytial virus as the cause of disease classified elsewhere
J12.1	Respiratory syncytial virus pneumonia
J21.0	Acute bronchiolitis due to respiratory syncytial virus
J45.20 - J45.998	Asthma
J84.848	Other interstitial lung diseases of childhood [child]
P07.36 - P07.39	Preterm newborn, gestational age 33 - 36 completed weeks
Q21.0 - Q21.9	Congenital malformations of cardiac septa
Q22.1	Congenital pulmonary valve stenosis
Q23.0	Congenital stenosis of aortic valve
Q25.0	Patent ductus arteriosus
Q25.1	Coarctation of aorta (preductal) (postductal)
Q90.0 - Q90.9	Down syndrome

The above policy is based on the following references: