1Updated Guidance for Palivizumab Prophylaxis Among Infants and Young

DOI: 10.1542/peds.2014-1666; originally published online July 28, 2014; 2014;134;e620PediatricsCOMMITTEE

COMMITTEE ON INFECTIOUS DISEASES and BRONCHIOLITIS GUIDELINESInfection

Children at Increased Risk of Hospitalization for Respiratory Syncytial Virus Updated Guidance for Palivizumab Prophylaxis Among Infants and Young

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TECHNICAL REPORT

Updated Guidance for Palivizumab Prophylaxis AmongInfants and Young Children at Increased Riskof Hospitalization for Respiratory Syncytial VirusInfection

abstractGuidance from the American Academy of Pediatrics (AAP) for the use ofpalivizumab prophylaxis against respiratory syncytial virus (RSV) wasfirst published in a policy statement in 1998. Guidance initially wasbased on the result from a single randomized, placebo-controlled clin-ical trial conducted in 1996–1997 describing an overall reduction inRSV hospitalization rate from 10.6% among placebo recipients to 4.8%among children who received prophylaxis. The results of a secondrandomized, placebo-controlled trial of children with hemodynam-ically significant heart disease were published in 2003 and revealeda reduction in RSV hospitalization rate from 9.7% in control subjectsto 5.3% among prophylaxis recipients. Because no additional con-trolled trials regarding efficacy were published, AAP guidance hasbeen updated periodically to reflect the most recent literature regard-ing children at greatest risk of severe disease. Since the last update in2012, new data have become available regarding the seasonality of RSVcirculation, palivizumab pharmacokinetics, the changing incidence ofbronchiolitis hospitalizations, the effects of gestational age and otherrisk factors on RSV hospitalization rates, the mortality of childrenhospitalized with RSV infection, and the effect of prophylaxis onwheezing and palivizumab-resistant RSV isolates. These data enablefurther refinement of AAP guidance to most clearly focus on thosechildren at greatest risk. Pediatrics 2014;134:e620–e638

Palivizumab is a humanized mouse immunoglobulin (IgG1) monoclonalantibody produced by recombinant DNA technology. The antibody isdirected against a conserved epitope of the A antigenic site of thefusion (F) protein of respiratory syncytial virus (RSV) and demonstratesboth neutralizing and fusion inhibitory activity.1 The antibody consists of2 heavy chains and 2 light chains; 95% of the amino acid sequences(framework) are of human origin, and 5% (antigen binding sites) areof mouse origin. After intramuscular administration, palivizumab isdistributed hematogenously throughout the body, including the lowerrespiratory tract. When RSV encounters palivizumab in the lower re-spiratory tract, antibody binds to F protein and prevents the structural

COMMITTEE ON INFECTIOUS DISEASES and BRONCHIOLITISGUIDELINES COMMITTEE

KEY WORDSRSV, respiratory syncytial virus, palivizumab, bronchiolitis, infantsand young children, chronic lung disease, congenital heartdisease

ABBREVIATIONSAAP—American Academy of PediatricsCDC—Centers for Disease Control and PreventionCHD—congenital heart diseaseCI—confidence intervalCLD—chronic lung diseaseCOID—Committee on Infectious DiseasesFDA—US Food and Drug AdministrationHSCT—hematopoietic stem cell transplantKID—Kids’ Inpatient DatabaseNVSN—New Vaccine Surveillance NetworkPHIS—Pediatric Health Information SystemQALY—quality-adjusted life yearRSV—respiratory syncytial virusSOT—solid organ transplant

This document is copyrighted and is property of the AmericanAcademy of Pediatrics and its Board of Directors. All authorshave filed conflict of interest statements with the AmericanAcademy of Pediatrics. Any conflicts have been resolved througha process approved by the Board of Directors. The AmericanAcademy of Pediatrics has neither solicited nor accepted anycommercial involvement in the development of the content ofthis publication.

Technical reports from the American Academy of Pediatricsbenefit from expertise and resources of liaisons and internal(AAP) and external reviewers. However, technical reports fromthe American Academy of Pediatrics may not reflect the views ofthe liaisons or the organizations or government agencies thatthey represent.

The guidance in this report does not indicate an exclusivecourse of treatment or serve as a standard of medical care.Variations, taking into account individual circumstances, may beappropriate.

All technical reports from the American Academy of Pediatricsautomatically expire 5 years after publication unless reaffirmed,revised, or retired at or before that time.

(Continued on last page)

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conformational change that is neces-sary for fusion of the viral RSV envel-ope with the plasma membrane of therespiratory epithelial cell.2 Without fu-sion, the virus is unable to enter thecell and unable to replicate. In addition,palivizumab prevents cell-to-cell fusionof RSV-infected cells.2

BACKGROUND

Palivizumab was licensed by the USFood and Drug Administration (FDA)in June 1998, largely on the basis ofresults of the IMpact-RSV trial con-ducted during the 1996–1997 RSVseason. This randomized, placebo-controlled, double-blind trial involved1501 infants and young children bornpreterm (at or before 35 weeks’ ges-tation), some of whom had chroniclung disease (CLD) of prematurity.3

The IMpact-RSV trial demonstrated anRSV hospitalization rate of 10.6% inthe placebo arm and 4.8% amonghigh-risk infants who received pro-phylaxis, a reduction of 5.8% in RSVhospitalizations (P < .001).3 A secondrandomized, double-blind, placebo-controlled trial conducted from 1998to 2002 enrolled 1287 children withhemodynamically significant congeni-tal heart disease (CHD).4 This cardiactrial evaluated both the safety andefficacy of palivizumab prophylaxis anddemonstrated an RSV hospitalizationrate of 9.7% in the placebo arm and5.3% among recipients of palivizumabprophylaxis, a reduction in the RSVhospitalization rate of 4.4% (P < .003).No additional placebo-controlled trialsregarding the efficacy of palivizumabprophylaxis in any other subgroup havebeen published.

Palivizumab was licensed for the pre-vention of severe lower respiratorytract disease in pediatric patients atincreased risk of severe RSV disease.1

Recommendations from the AmericanAcademy of Pediatrics (AAP) for use ofprophylaxis have evolved since licensure

of palivizumab as additional informationhas become available.

In addition, peer-reviewed data havebeen published since preparation ofthe most recent guidance in 2012.5 Thistechnical report reviews the newerand older scientific literature to offerguidance on the most appropriate useof palivizumab prophylaxis, as publishedin the accompanying policy statement.6

Current guidance is risk stratified, tar-geting infants at greatest risk of se-vere disease and most likely to benefitfrom prophylaxis on the basis of evalu-ation of the published literature. There-fore, not all infants enrolled in the 2randomized trials are included in thecurrent guidance. Twenty-one AAP sec-tions and committees plus groups out-side the AAP have contributed to andconcur with the updated guidancepresented in the accompanying policystatement.

AAP guidance regarding the use ofpalivizumab was first published ina policy statement7 in 1998 and sub-sequently was revised in a 2003 policystatement,8 the 2006 Red Book,9 a 2009policy statement,10 and most recentlyin the 2012 Red Book.5 The AAP guid-ance for palivizumab prophylaxis isbeing updated at this time to reflectthe ongoing assessment by the Com-mittee on Infectious Diseases (COID) ofpeer-reviewed publications, as exem-plified in the following areas:

� Data regarding palivizumab phar-macokinetics11;

� Data on the seasonality of RSV cir-culation12,13;

� Data on overall declining incidenceof hospitalizations for bronchiolitisin the United States14;

� Data demonstrating that mortalityrates in children hospitalized withlaboratory-confirmed RSV are lowerthan previously estimated15;

� Data demonstrating a statisticallysignificant but clinically minimal

reduction of wheezing episodesamong recipients of palivizumabprophylaxis16,17;

� Reports indicating little benefit ofpalivizumab prophylaxis amongpatients with cystic fibrosis or Downsyndrome18–20;

� Reports describing palivizumabresistant RSV isolates from hospi-talized patients who receive pro-phylaxis21–23; and

� Independently conducted cost anal-yses demonstrating a high cost ver-sus limited benefit from palivizumabprophylaxis.24,25

In addition, the complexity of thecurrent guidance has resulted in lackof prophylaxis for some children whoqualify, whereas other children who donot qualify receive prophylaxis thatmay not be indicated.26,27 The goal ofthis updated guidance is to presentmore clearly the COID recommendationsfor palivizumab use for infants andyoung children who are most likely toderive benefit from prophylaxis and,in the process, to simplify guidancefor pediatricians and other clinicians.

It is important to note that usingthe same aggregate data, prophylaxisguidelines from other countries suchas the United Kingdom are more re-strictive than AAP guidance for theUnited States, and no evidence of ex-cess morbidity has been observed.28,29

Indications contained in a packagelabel reflect data from clinical trialsconducted by the sponsor and sub-mitted to the FDA for drug licensure.The FDA does not issue guidelines orrecommendations for drug use. Thepalivizumab package inserts states“Synagis is indicated for the pre-vention of serious lower respiratorytract disease caused by RSV in chil-dren at high risk of RSV disease.”1 Inthe absence of a specific definition of“high risk” by the FDA, the AAP hasendeavored since palivizumab was

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first licensed to provide more preciseguidance for determining those at in-creased risk.5,7,8,10 The same is truewith this revision.

ADMINISTRATION

Palivizumab is administered intramus-cularly at a dosage of 15 mg/kg oncea month. The drug is packaged in single-dose liquid solution vials at 50mg/0.5mLand 100 mg/1.0 mL and does not containpreservative. A vial cannot be storedonce it is opened, so a vial-sharingscheme is important to minimize wast-age. Anaphylaxis has occurred afterpalivizumab administration after initialexposure or reexposure, with somecases of severe hypersensitivity reac-tions reported.1

RSV IMMUNOPROPHYLAXIS ANDVACCINE ADMINISTRATION

Palivizumab does not interfere with theimmune response to live or inactivatedvaccines. The childhood immunizationschedule should be followed for allchildren, regardless of palivizumab use.1

GUIDANCE FOR PALIVIZUMABPROPHYLAXIS

Burden of RSV Disease

In the United States, RSV remains animportant cause of hospitalization inthe first months of life. Retrospectiveanalyses using national databases andInternational Classification of Diseases,Ninth Revision discharge diagnoseshave shown considerable variation inestimates of annual hospitalization ratesattributable to RSV for infants.30–33

More recent prospective population-based studies of laboratory confirmedcases demonstrate that RSV hospital-ization rates are approximately halfthe rates reported in retrospectivestudies, yet rates remain high.14,34–36

It is estimated that approximately 2.1million children younger than 5 years

require medical care as inpatients oras outpatients for RSV infection an-nually. Among outpatients, 60% (1.3million) are 2 through 5 years of age,and the remaining 40% are betweenbirth and 2 years of age.35 Approxi-mately 25% of RSV-infected childrenyounger than 5 years are assessedand treated in an emergency de-partment, and approximately 70% areassessed and treated in a pediatricoffice. It is estimated that each year,nearly 58 000 children in the first fewyears of life are hospitalized becauseof RSV infection.35 Infants in the sec-ond month after birth have the high-est RSV hospitalization rate, a ratethat is almost twice that of the nexthighest risk group (infants in the firstmonth after birth).34

Preterm Infants Without CLD

In 2012, 3.95 million births werereported in the United States. Preterminfants (singleton and multiple births)born at less than 37 weeks’ gestationrepresented 11.6% of all births.37

Preterm births of infants at less than28 weeks’ gestation accounted for0.7% of the annual birth cohort.37

Infants born from 32 weeks to 35weeks’ gestation represented approx-imately 9% of the birth cohort.

Beginning with the first AAP statementin 1998,7 the high cost of palivizumabinfluenced recommendations for useby the COID, leading to attempts toidentify risk factors for RSV hospital-ization among the large number ofmoderately preterm infants. The NewVaccine Surveillance Network (NVSN),sponsored by the Centers for DiseaseControl and Prevention (CDC) wasa prospective population-based sur-veillance program from 3 geographicallydiverse locations in the United Statesfor young children hospitalized withlaboratory-confirmed RSV respiratoryillness. Several studies were publishedsummarizing data from the NVSN. One

conducted during the RSV seasons from2000 through 2005 using multiplelogistic-regression analyses of datarevealed that some of the previouslyreported potential risk factors, in-cluding siblings in the household andchild care attendance, were not as-sociated with a significantly increasedrisk of RSV hospitalization.34 In thisstudy, only young chronologic age wassignificantly correlated with risk ofhospitalization for RSV illness. The as-sociation between preterm birth andincreased risk of severe illness was notspecific for RSV.35

In addition, data from the NVSN studyrevealed that for all preterm infants(<37 weeks’ gestation), the RSV hos-pitalization rate was 4.6/1000 children,which was not significantly differentfrom the hospitalization rate for terminfants, which was 5.3/1000 children(Table 1).34 Rates were derived from132 085 children born during thestudy period, among whom 2149 werehospitalized with acute respiratory ill-ness, and 559 of the hospitalized chil-dren had laboratory-confirmed RSV(Table 1). Infants born at <30 weeks’gestation experienced a higher RSVhospitalization rate (18.7/1000 chil-dren) than early preterm infants(30–33 weeks),34 although the smallnumber of infants born before 30weeks’ gestation limits the general-izability of this data. Late preterminfants were hospitalized significantlyless often than term infants for RSVinfection.34

An analysis of Tennessee Medicaiddata for children younger than 3 yearsconducted from July 1989 to June 1993(preimmunoprophylaxis era) included248 652 child-years of follow-up. Theretrospective cohort analysis wasconducted to determine RSV hospital-ization rates among infants with dif-ferent degrees of prematurity andother comorbidities.38 Within each agegroup, preterm infants had similar



rates of RSV hospitalization, regard-less of the degree of prematurity(Table 2). In this analysis, preterminfants with CLD were categorizedseparately to reduce confounding.

A historical cohort analysis fromRochester, New York, reported on RSVhospitalization rates among 1029 con-secutive preterm infants born before orat 32 weeks’ gestation during a 5-yearperiod.39 The RSV hospitalization rateincreased with decreasing gestationalage, with a breakpoint at ≤28 weeks’gestation (Table 3). Among infants bornat or before 26 weeks’ gestation, therisk of RSV-associated hospitalizationwas 13.9% vs 4.4% among childrenhospitalized at >30 to 32 weeks’ ges-tation. There was not a statisticallysignificant difference in RSV hospi-talization rates between infants withgestational ages of >28 to 30 weeksand infants with gestational ages of>30 to 32 weeks.

A retrospective cohort study of infantsenrolled in Medicaid in Texas and

Florida between 1999 and 2004 ex-amined RSV hospitalization rates inmoderately preterm infants 32 to 34weeks’ gestation40 Less than 20% ofeach cohort received palivizumab pro-phylaxis. In Florida, 71 (3.1%) of themoderately preterm infants were hos-pitalized compared with 1246 (1.5%) ofterm infants, and in Texas 164 (4.5%) ofthe preterm infants were hospitalizedcompared with 3815 (2.5%) of terminfants. Palivizumab prophylaxis wasassociated with decreased hospitali-zation in moderately preterm infantsin Texas but not in Florida. The risk ofRSV hospitalization in moderately pre-term infants was similar to 1-month-oldterm infants by 4.2 months in Florida(95% confidence interval [CI], 2.5–5.7)and by 4.5 months in Texas (95% CI,2.8–6.4).40

Choosing an appropriate cutoff forgestational age for which palivizumabprophylaxis may be considered forpreterm infants without other indica-tions is challenging. Data consistently

demonstrate the greatest increase inrisk for hospitalization is in preterminfants born before 29 weeks’ gesta-tion. These infants have hospitaliza-tion rates 2 to 4 times higher thanlater preterm infants (Tables 1, 2, and3). The consensus of the COID and theBronchiolitis Guidelines Committee isthat palivizumab prophylaxis may beconsidered for infants, without otherindications, whose gestational age isless than 29 weeks (28 weeks, 6 daysor fewer). The available data do notsupport universal recommendationsfor palivizumab prophylaxis for pre-term infants born at or after 29weeks’ gestation.

Data regarding the risk of RSV hospi-talization for most preterm infants donot support a benefit from prophylaxis.In recent large cohort studies of mod-erately preterm infants, the majority ofwhom did not receive palivizumab, 2.5%to 4.9% required hospitalization for RSVinfection during the RSV season in-dicating that more than 95% did notrequire hospitalization.40 The rate ofhospitalization among infants ≥35weeks’ gestation (5.1/1000) was nodifferent than the rate for terminfants (5.3/1000; Table 1). The hos-pitalization rate of infants ≥30 weeksto 35 weeks’ gestation indicate onlya slight increase in risk (less thantwofold; Tables 1, 2, and 3). Dataconcerning host or environmental riskfactors for hospitalization in preterminfants without CLD or CHD are in-consistent, with the exception of age

TABLE 1 Average RSV Hospitalization Rates Among Children Younger Than 24 Months (2000–2005)34

Children <24 mo N a RSV Hospitalization Rate/1000 95% CI

All infants regardless of gestational age 559b 5.2 4.8–5.7All term infants (≥37 wk gestation) 479 5.3 4.9–5.8All preterm infants (<37 wk gestation) 56 4.6 3.4–5.8≥35 wk gestation 494 5.1 4.7–5.532–34 wk gestation 23 6.9 4.3–10.129–31 wk gestation 6 6.3 2.0–12.4<29 wk gestation 12 19.3 8.4–34.0All very preterm (<30 wk gestation) 15c 18.7 10.0–30.0a Among 2149 enrolled hospitalized children from a birth cohort of 132 085 children.b The total of 559 children hospitalized with RSV includes 24 whose gestational age could not be verified.c Personal communication, Geoffrey A. Weinberg, MD.

TABLE 2 RSV Hospitalizations per 1000 Children From >248 000 Child-Years of Follow-up38

Age Stratum/Risk Group 0 to <6 mo 6 to <12 mo 12 to <24 mo IRR (95% CI) for 0 to <6 mo Adjusted IRR (95% CI) for first 12 mo

Low-risk infants 44.1 15.0 3.7 Comparator ComparatorInfants with CHD 120.8 63.5 18.2 2.7 (2.2–3.4) 2.8 (2.3–3.3)Infants with CLD 562.5 214.3 73.4 12.8 (9.3–17.2) 10.7 (8.4–13.6)≤28 wk gestation 93.8 46.1 30.0 2.1 (1.4–3.1) 2.4 (1.8–3.3)29 to <33 wk gestation 81.8 50.0 8.4 1.9 (1.4–2.4) 2.2 (1.8–2.7)33 to <36 wk gestation 79.8 34.5 10.8 1.8 (1.5–2.1) 1.8 (1.6–2.1)Other conditiona 122.3 55.2 24.1 2.8 (2.5–3.1) 2.3 (2.1–2.6)

IRR, incidence rate ratio.a Asthma, cystic fibrosis, cancer, HIV infection, immunodeficiency, steroid therapy, chronic renal disease, diabetes mellitus, congenital anomalies of the respiratory tract, or respiratorydistress syndrome.





younger than 3 months at the start ofthe RSV season, which has been as-sociated with an increased risk ofhospitalization.34

For all infants, particularly those whoare preterm, the environment shouldbe optimized to prevent RSV and otherviral respiratory infections by offeringbreast milk feeds, immunizing house-hold contacts with influenza vaccine,practicing hand and cough hygiene,and by avoiding tobacco or othersmoke exposure and attendance inlarge group child care during the firstwinter season, whenever possible.

Preterm Infants With CLD

Studies have documented that infantsand young children with CLD have in-creased rates of RSV hospitalization.38,39

Results from the IMpact-RSV trialevaluating all preterm infants with CLD(n = 762 randomized preterm infants)demonstrated that the RSV hospitali-zation rate among placebo recipientswas 12.8% and 7.9% among palivizumabrecipients (P = .038).3

Infants With HemodynamicallySignificant CHD

The results of an industry-funded mul-ticenter, randomized, double-blind,placebo-controlled trial of palivizumabprophylaxis among 1287 children (639palivizumab recipients, 648 placeborecipients) younger than 24 monthswith hemodynamically significant CHDwas published in 2003.4 Results fromthis study demonstrated a reductionin RSV hospitalization rates of 4.4%(9.7% among placebo recipients and5.3% among palivizumab recipients;

P = .003).4 The reduction in the num-ber of RSV hospitalizations betweenthe 2 study groups was 29 fewer RSVhospitalizations among palivizumabrecipients during the 4 years of thestudy.4 Prophylaxis with palivizumabappeared to have less benefit amongcyanotic children than among acya-notic children. Among children inthe cyanotic group, there were 23fewer RSV hospitalizations per 1000palivizumab recipients (7.9% vs 5.6%,P = .285). Among children in the acya-notic group, there were 68 fewer RSVhospitalizations per 1000 prophylaxisrecipients (11.8% vs 5.0%; P = .003).Despite enrolling 1287 subjects, the trialdid not have sufficient power to detectstatistically significant differences amongsubgroups of children with different car-diac lesions.

A retrospective analysis of the effect ofpalivizumab prophylaxis on RSV hos-pitalizations among children with he-modynamically significant CHD wasconducted in California. The authorsestimated a statewide 19% reductionin RSV hospitalization between 2000and 2002 (preprophylaxis era) and2004 and 2006 (prophylaxis era) afterthe licensure of palivizumab for chil-dren with CHD. The authors concludedthat in the state of California, 7 fewerRSV hospitalizations per year oc-curred among children younger than2 years with hemodynamically signifi-cant CHD following recommendationsfor palivizumabprophylaxis in this group.41

Other investigators describe rates ofRSV hospitalizations among patientswith hemodynamically significant CHD(2%–3%) who do not receive pro-

phylaxis as lower than the 9.7% ratereported in the placebo arm of thecardiac study.42–46 As the rate of RSVhospitalization decreases among chil-dren who do not receive prophylaxis,the cost to prevent 1 hospitalizationwith prophylaxis increases.

A retrospective analysis of childrenyounger than 3 years (248 652 child-years) in the Tennessee Medicaidprogram revealed that the RSV hos-pitalization rate for children with CHDin the second year of life (18.2/1000)was less than half the hospitalizationrate for low-risk infants in the first 5months after birth (44.1/1000), a groupfor whom palivizumab prophylaxis isnot recommended38 (Table 2). Thus,prophylaxis is not recommended dur-ing the second year of life.

Children With Anatomic PulmonaryAbnormalities or NeuromuscularDisorder

The risk of RSV hospitalization is notwell defined in children with neuro-muscular disorders that impair theability to clear secretions from theupper airway because of ineffectivecough, recurrent gastroesophagealtract reflux, pulmonary malformations,tracheoesophageal fistula, upper air-way conditions, or conditions requiringtracheostomy.

Studies suggest children and infantswith neuromuscular disease who arehospitalized with RSV infection tend tobe older compared with other groupsof patients hospitalized with RSV in-fection and are more likely to havepreexisting immunity to RSV.47,48 Thismay reflect the progressive nature ofneuromuscular disease, with suscep-tibility to respiratory disease tractincreasing with age.

Immunocompromised Children

Population-based data are not avail-able on the incidence or severity of RSVdisease among children who receive

TABLE 3 RSV Hospitalizations Among 1029 Infants Born at or Before 32 Weeks’ Gestation39

Gestational Age, wk No. of Infants No. of RSV Admissions % Admitted P vs 30–32 Weeks’ Gestation

≤26 165 23 13.9 <.00127–28 171 17 9.9 .007>28–30 240 18 7.5 .12>30–32 453 20 4.4 ComparatorTotal 1029 78 7.6 Not applicable



solid organ transplants (SOTs) or he-matopoietic stem cell transplants(HSCTs), children who receive che-motherapy, or children who are im-munocompromised because of otherconditions. Progression of RSV infectionfrom upper to lower respiratory tractdisease depends on the virulence of theRSV strain, as well as specific abnor-malities in the immunocompromisedhost’s immune response attributableto the underlying disease or to che-motherapy.

RSV infection in immunocompromisedchildren and adults can progress torespiratory failure and death.49,50 Lym-phopenia has been recognized as a riskfactor for disease progression in sev-eral studies of immunocompromisedpatients. One study in adults noted thatprogression of RSV to lower respiratorytract disease did not occur in patientswith a lymphocyte count greater than1000 cells/mm3 at time of onset of up-per respiratory tract infection.51 An ab-solute lymphocyte count of 100 cells/mm3

or less at the time of RSV upper tractinfection was associated with pro-gression to lower respiratory tractdisease. In contrast to lymphopenia,analysis of antibody concentration inthese adult HSCT recipients indicatedno correlation between preexistinganti-RSV antibody concentration andprogression from upper to lower re-spiratory tract disease.51

A retrospective report from 1 in-stitution described 58 immunocom-promised children with RSV infectionbetween 1997 and 2005.52 Sixty-fivepercent of the RSV-infected childrenwere managed as outpatients. Nodeaths occurred among 28 childreninfected with RSV who were receivingchemotherapy for acute lymphoblasticleukemia or among 11 immunosup-pressed SOT recipients. Five of 58patients with lower respiratory tractinfection died (8.6%), including 4 childrenwho were allogeneic HSCT recipients and

1 child with severe combined immunedeficiency. One of the deaths occurred ina 10-year-old child, and a second deathoccurred in a child with Aspergillusspecies coinfection. Profound lympho-penia (<100 cells/mm3) was associatedwith progression to lower respiratorytract disease.52

Another retrospective report from 1institution noted 5 deaths among117 RSV-infected, immunocompromisedpatients between 2006 and 2011 (2 withsevere combined immunodeficiency, 1with uncharacterized immunodeficiency,1 with chronic granulomatous disease,and 1 SOT recipient).53 The deaths oc-curred in children who presented withcommunity-acquired RSV lower re-spiratory tract infection. No deathsoccurred among children who wereHSCT recipients or those with leu-kemia or lymphoma.

A third retrospective review of RSVinfections in children with cancerwas conducted from 1998 to 2009.54

Among 57 patients, 37% experiencedprogression to lower respiratory tractdisease. Three patients died of re-spiratory failure within 60 days of RSVdiagnosis (1 had concomitant bacter-emia and fungemia and 1 had con-comitant herpes simplex pneumonia).

In a review of 208 viral respiratoryinfections among 166 patients overa 13-year period who received HSCTs,SOTs, or chemotherapy for malig-nancy, RSV infection accounted for43% of the infections.55 The meanand median ages of patients at thetime of infection were 6.1 years and4.3 years, with a range of 2 monthsto 21 years of age. Death occurredin 17 (8%) of patients with viral re-spiratory infection, including 6 of 88(7%) RSV-infected children who re-ceived allogeneic HSCTs or SOTs. Noinfection resulted in death amongpatients who received chemother-apy, despite being severely immu-nosuppressed. Mortality and morbidity

did not have a statistically significantcorrelation with the degree of immunesuppression.

Risk factors for a poor outcome afterRSV infection in an immunosuppressedhost include age younger than 2 years,presence of lower respiratory tractsymptoms at presentation (particu-larly in the absence of symptoms ofupper respiratory infection), cortico-steroid therapy, and varying degrees oflymphopenia. Underlying diagnosis,degree of immune suppression, RSVload in bronchoalveolar lavage, orspecific humoral immunity to RSV havenot been found to correlate with out-come.56 This inability to correlatedegree of immunosuppression withdisease severity indicates an incompleteunderstanding of the immune responseto viral respiratory infections in animmunocompromised host.

Antibody-based treatments, includingimmune globulin and palivizumab, havenot been associated with improvedoutcome in HSCT recipients.57 No dataare available to suggest benefit fromimmunoprophylaxis among immuno-compromised patients, and practicesvary nationwide.58,59 Further researchis required before definitive recom-mendations can be made for the useof palivizumab in this heterogeneousgroup of children.

Children With Down Syndrome

Several factors appear to place chil-dren with Down syndrome at in-creased risk of RSV lower respiratorytract disease than children withoutDown syndrome.18,19,60,61 CHD, with orwithout pulmonary hypertension, occursin approximately 45% of children withDown syndrome, and lesions includeatrioventricular canal, ventricular sep-tal defect, patent ductus arteriosus,and tetralogy of Fallot. Anatomic ab-normalities of the upper or lower re-spiratory tract, muscle dystonia, andintrinsic immune dysfunction may





contribute to viral respiratory diseasein this population.

One population-based cohort studyover an 11-year period in Coloradorevealed a statewide total of 85 RSVhospitalizations among 680 childrenwith Down syndrome during their first2 years of life. Concurrent risk factorswere present in 35 of the 85 (41%)hospitalized children, indicating theywould have qualified for prophylaxisfor other reasons. RSV hospitalizationrates were 67/1000 child-years forchildren with Down syndrome andother risk factors, 42/1000 child-yearsfor children with Down syndromewithout cardiopulmonary disease, and12/1000 child-years for children ina control group.61 These data suggestan estimated overall 7.7 RSV admis-sions per year (85 admissions per 11years) in the state of Colorado forchildren with Down syndrome. Usingthese figures, 4.6 RSV hospitalizationsper year occur among children withDown syndrome without concurrentfactors (50 admissions per 11 years)in Colorado. Assuming a 55% reductionin hospitalization, approximately 2 to 3hospitalizations per year might havebeen avoided from prophylaxis admin-istered to 680 children. Although chil-dren with Down syndrome were morelikely to experience a temperature>38°C, the median duration of stay forchildren younger than 1 year of agewith Down syndrome was 4 days, andfor children without Down syndromethe median was 3 days. No deaths werereported in this study.61 These datasuggest children with Down syndromehave a slightly higher hospitalizationrate, but the absolute number of RSVhospitalizations is small, and a numberof children with Down syndrome are atincreased risk because of qualifyingheart disease or other factors.

Another report described 39 of 395(9.9%) children with Down syndromehospitalized because of RSV infection

in the first 2 years of life.60 Amonghospitalized children, 38% had hemo-dynamically significant heart disease.This study had insufficient power todifferentiate among subgroups, mean-ing the increased RSV hospitalizationrate may have been explained by con-current risk factors and not Downsyndrome.60 Another study of 41 chil-dren with Down syndrome hospitalizedwith RSV infection noted that 51% hadunderlying CHD.18 An additional reportof 222 children with Down syndromehospitalized with RSV infection notedthe mean age of hospitalized children(1.3 years; range, 0–6.1 years) wassignificantly older than the age ofchildren hospitalized with RSV who didnot have Down syndrome. A similarfinding was noted in the Colorado re-port, with a mean age of 9.6 months atadmission for RSV infected patientswith Down syndrome and no other riskfactors. In this study, the age range forhospitalization extended through 17years.61 RSV prophylaxis for the firstyear of life would have limited effect onRSV hospitalization for children withDown syndrome without other riskfactors for RSV.19,61

Children With Cystic Fibrosis

Available studies indicate the in-cidence of RSV hospitalization in chil-dren with cystic fibrosis is uncommonand unlikely to be different fromchildren without cystic fibrosis. Ev-idence to support a benefit frompalivizumab prophylaxis in patients withcystic fibrosis is not available.20,62,63

A randomized clinical trial withpalivizumab prophylaxis included 186children with cystic fibrosis from 40centers. One subject in the untreatedgroup and 1 subject in the palivizumabgroup were hospitalized for RSV in-fection.64 Although this study was notpowered for efficacy, no clinicallymeaningful differences in outcomebetween the 2 groups were reported.

At the 12-month follow-up, there wasno significant difference between thetreated and untreated groups in num-ber of Pseudomonas colonizations orchange in weight-to height ratio. A case-control study of palivizumab in 75 chil-dren with cystic fibrosis noted a possi-ble trend toward a potential clinicalbenefit of palivizumab prophylaxis, butthe difference was not statistically sig-nificant.62

A large study of RSV hospitalizationsoccurring between 1997 and 2003 inDanish children with chronic medicalconditions identified 72 children withcystic fibrosis.65 There were 13 RSV-related hospitalizations, which resul-ted in an adjusted incidence rate ratiofor risk of RSV hospitalization of 4.32(95% CI, 2.42–7.71). The geometricmean ratio for duration of RSV hos-pitalization in these children withcystic fibrosis was 1.3 days (95% CI,0.81–2.11 days).

Two recent reviews20,66 of RSV in-fection in infants with cystic fibrosisacknowledged that infants with cysticfibrosis may have a slightly increasedrisk for hospitalization with RSV.However, they both stated that thereis insufficient evidence related tosafety and efficacy in infants withcystic fibrosis to support a recommen-dation of palivizumab prophylaxis.20,66

A survey of cystic fibrosis center di-rectors published in 2008 noted thatpalivizumab prophylaxis is not thestandard of care for patients withcystic fibrosis.67

Discontinuation of PalivizumabProphylaxis Among Children WhoExperience Breakthrough RSVHospitalization

RSV is classified into subgroups A andB, based on antigenic differences in thesurface G glycoprotein. Subgroups areclassified further into genotypes basedon genetic analysis. The ability of RSV tocause reinfections throughout life likely



is attributable both to strain variabilityand to an immune response that doesnot fully protect against subsequentinfection. Reinfections with both het-erologous and homologous strains oc-cur. More than 1 RSV strain may circulateconcurrently in a community. However,repeat RSV hospitalizations during 1season are rare.

One study identified 726 RSV lowerrespiratory tract infections among1560 children younger than 5 yearsover 8 successive RSV seasons in anoutpatient setting.68 Only 1 instance ofrepeat RSV infection occurred duringthe same season. Furthermore, it iswell established that repeat RSVinfections are associated with lesssevere clinical illness than the ini-tial RSV infection.69,70

In the blinded and randomized cardiactrial that involved 1287 childrenyounger than 24 months with hemo-dynamically significant CHD, a total of 5readmissions for a second RSV hos-pitalization occurred (a rate of lessthan 0.5%). Three of 648 children in theplacebo group and 2 of 639 childrenwho received palivizumab had morethan 1 RSV hospitalization over 4 years.4

In the Dutch trial of 429 preterminfants randomly assigned to receiveeither palivizumab prophylaxis or pla-cebo between April 2008 and December2010, infants were followed for re-current wheezing. No RSV reinfectionswere detected in either group, againindicating that repeat RSV infections inthe same year seldom occur.16

Use of Palivizumab in the SecondYear of Life

A prospective population-based sur-veillance study of 5067 children youngerthan 5 years evaluated 564 childrenhospitalized with laboratory-confirmedRSV infection. Among the childrenhospitalized with RSV infection, 75%were younger than 12 months. Less than20% of all pediatric RSV hospitalizations

occurred during the second year oflife.35

Limited safety data and no efficacydata are available regarding palivizumabprophylaxis in the second year oflife.71,72 Regardless of the presenceor absence of comorbidities, RSVhospitalization rates decline during thesecond RSV season for all children.34,38

In a retrospective cohort study con-ducted over 4 years and involving248 652 child-years, RSV hospitaliza-tion rates in the second year of lifefor children with comorbidities werelower than the rate for healthy terminfants in the first 12 months of life,a group for whom prophylaxis is notrecommended38 (Table 2).

Lack of Therapeutic Efficacy ofPalivizumab

Controlled studies have demonstratedthat monoclonal antibodies have notherapeutic benefit in the treatment ofRSV infected children. One randomizedstudy determined that intravenouspalivizumab administered to RSV-infected,intubated infants reduced the RSV viralload in the lower respiratory tract buthad no effect on RSV concentration in theupper respiratory tract.73 Despite a re-duction in viral load in the lower re-spiratory tract, no difference in diseaseseverity was found between palivizumabrecipients and placebo recipients. Aphase 2 therapeutic trial involving 118hospitalized, RSV infected infants eval-uated the outcome among recipients ofintravenous motavizumab at 30 mg/kgor at 100 mg/kg compared with pla-cebo.74 Motavizumab is an investigationalmonoclonal antibody with enhancedpotency relative to palivizumab. Nosignificant effect on RSV viral load inthe upper respiratory tract was detec-ted among motavizumab recipients. Nodifference in duration of hospitalization,requirement for supplemental oxygen,ICU admission, or need for mechanicalventilation between groups was detected.

Prevention of HealthCare-Associated RSV Disease

Strict infection-control practices, in-cluding restriction of visitors to theneonatal ICU during respiratory virusseason, will decrease health care-associated RSV disease. Evidence doesnot support the use of palivizumabamong hospitalized preterm infants toprevent health care-associated spreadof RSV.75,76 If an RSV outbreak occurs ina high-risk unit (eg, pediatric or neo-natal ICU or HSCT unit), primary em-phasis should be placed on properinfection-control practices, especiallyhand hygiene. No rigorous data exist tosupport palivizumab use in controllingoutbreaks of health care-associateddisease. Further, hospitalization ratesfor RSV infection do not differ amonginfants who receive inpatient palivizumabprophylaxis while in the neonatalICU compared with those who initi-ate prophylaxis at hospital dis-charge.77

CONSIDERATIONS AFFECTINGREVISION OF GUIDANCE

Risk Factors for RSV Hospitalization

Overall, approximately 2% to 3% ofinfants in the first 12 months of life arehospitalized with RSV infection eachyear in the United States. Children withcertain comorbidities are at increasedrisk of severe RSV disease relative tochildren without these comorbid-ities.35,38 Chronologic age is the singlemost important risk factor for RSVhospitalization on the basis of theobservation that more than 58% to64% of pediatric RSV hospitalizationsoccur in the first 5 months afterbirth.34,35,38 Most of these hospital-izations occur in the first 90 days afterbirth.22,34,40 Certain subgroups ofinfants with comorbidities such asprematurity, CLD, or hemodynamicallysignificant CHD have increased risksfor RSV hospitalization, although the





degree of risk varies among studies.30,78

The risk of RSV hospitalization associ-ated with most other risk factors hasbeen difficult to determine because oflow rates of occurrence. Most hostand environmental factors increasethe risk for RSV hospitalization by onlya small magnitude, so their contribu-tion to overall disease burden is lim-ited.79 In addition, these factors arenot identified consistently from studyto study. These inconsistencies likelyreflect variation in practice patterns indifferent countries, variation in livingconditions and climate, variation inhealth care coverage, yearly variationin disease severity, and incompletelyunderstood genetic factors. Differencesin study design may contribute to thesedifferences.

Reported host risk factors of limited(inconsistent) impact include the fol-lowing: congenital malformations, con-genital airway anomaly, neuromuscularimpairment, birth weight, gender, lackof breastfeeding, duration of breast-feeding, cord serum anti-RSV antibodyconcentration, small for gestational age,Down syndrome, epilepsy, cord bloodvitamin D concentration, family historyof atopy, viral load, malnutrition, mul-tiple births, and singletons versusmultiple birth subjects. Environmentalrisk factors of limited (variable)impact include the following: envi-ronmental pollution, crowded livingconditions, living at increased alti-tude, meteorological conditions, lowparental education, low socioeco-nomic status, child care attendance,size of child care facility, month ofbirth, smoke exposure, maternal smok-ing during pregnancy, and proximity tohospital care.30,35,38,47,48,60,65,78,80–94 Onepublication suggested that malforma-tions of the urinary tract increase therisk of RSV hospitalization.65

Multiple logistic-regression analysesof data from the 4-year population-based prospective study revealed that

of the evaluated risk factors (malegender, child care attendance, smokeexposure, lack of breastfeeding, andother children in the house), onlypreterm birth and young chronologicage independently correlated with moresevere RSV disease after adjusting forother covariates.35

RSV Seasonality

During the 6 RSV seasons from July2007 to January 2013, the medianduration of the RSV season rangedfrom 13 to 23 weeks, with median peakactivity from mid-December to earlyFebruary, with the exception of Floridaand Alaska (see later discussions foreach).12,13 Within the 10 Health andHuman Services Regions, in the fewregions when the RSV season began inOctober, the season ended in Marchor early April. In regions where theRSV season began in November orDecember, the season ended by Aprilor early May. Because 5 monthlydoses of palivizumab at 15 mg/kg perdose will provide more than 6 monthsof serum palivizumab concentrationsabove the desired serum concentra-tion for most infants, administrationof more than 5 monthly doses is notrecommended within the continentalUnited States.11 Children who qualifyfor 5 monthly doses of palivizumabprophylaxis should receive the firstdose at the time of onset of the RSVseason. For qualifying infants bornduring the RSV season, fewer than5 doses will be needed to provideprotection until the RSV seasonends in their region (maximum of5 doses).

A small number of sporadic RSV hos-pitalizations occur before or after themain season in many areas of theUnited States,79,95 but maximum ben-efit from prophylaxis is derived duringthe peak of the season and not whenthe incidence of RSV hospitalization islow.

Prophylaxis for Alaska Native/American Indian Children andTiming of Palivizumab Initiation

Hospitalization rates for all causesof bronchiolitis as high as 484 to590/1000 infants have been describedin isolated Inuit populations.96–99 AlaskaNative infants in southwestern Alaskaexperience higher RSV hospitalizationrates and a longer RSV season. On thebasis of the epidemiology of RSV inAlaska, particularly in remote regions,the selection of infants eligible forprophylaxis may differ from the re-mainder of the United States. Clini-cians may wish to use RSV surveillancedata generated by the state of Alaskato assist in determining onset and endof the RSV season for appropriate tim-ing of palivizumab administration.100

Two published studies have docu-mented a bronchiolitis hospitalizationrate in Navajo populations that was91.3 to 96.3/1000 infants younger than1 year.101,102 This rate was similar tothose seen with high-risk groups,such as infants born preterm andthose with CLD. There are no data onefficacy of palivizumab in this pop-ulation. However, if local data supporta high burden of RSV disease in selectAmerican Indian populations, selec-tion of infants eligible for prophylaxismay differ from the remainder of theUnited States for infants in the firstyear of life.

Timing of Prophylaxis for the Stateof Florida

Variation in the onset and offset ofthe RSV season in different regionsof Florida may affect the timing ofpalivizumab administration. Florida De-partment of Health data may be usedto determine the appropriate timingfor administration of the first doseof palivizumab for qualifying infants.Despite varying onset and offset datesof the RSV season in different regionsof Florida, a maximum of 5 monthly



doses of palivizumab will be adequatefor qualifying infants for most RSVseasons in Florida. Even if the first of 5monthly doses is administered in July,protective serum concentrations ofpalivizumab will be present for mostinfants and young children for at least 6months and likely into February. Morethan 5 monthly doses are not recom-mended, despite the detection of a smallnumber of cases of RSV infection outsidethis time window. A small number ofsporadic RSV hospitalizations occurbefore or after the main season in manyareas of the United States, but maximumbenefit from prophylaxis is derivedduring the peak of the season and notwhen the incidence of RSV hospitaliza-tion is low.

Pharmacokinetics of Palivizumab

A threshold protective serum palivizumabconcentration in humans has notbeen established. On the basis ofstudies of palivizumab prophylaxis withthe cotton rat, serum concentrations of25 to 30 mcg/mL produced a mean re-duction in pulmonary RSV concen-trations of 99% (2 log10).103,104 Becauseof the reliability of the cotton rat modelto predict results in humans, this se-rum concentration became the targettrough concentration in the randomizedclinical trials.3,4 The package labelstates “palivizumab serum concen-trations of greater than or equal to40 mcg/mL have been shown to re-duce pulmonary RSV replication inthe cotton rat model of RSV infectionby 100 fold.”1

Palivizumab pharmacokinetic datapublished by the manufacturer in 2012demonstrate that after 5 monthly doses,serum concentrations of palivizumabremain at or above protective levelsfor most children for at least 6 months(>24 weeks).11 There is seldom justi-fication to administer more than 5doses within the continental UnitedStates. These data were derived from

a computer model based on 22 clini-cal trials.

Weight dosing at 15 mg/kg resulted insimilar palivizumab concentrations inhealthy term infants as well as pre-term infants.11

Race and Sex

Data from the NVSN demonstrate thatthe overall rate of RSV hospitalizationdoes not differ between African Americanand white children younger than 24months of age (5.4/1000 for AfricanAmerican children and 4.7/1000 forwhite children).34 Among infantsyounger than 6 months, RSV hospi-talization rates for African Americanand white children were not signif-icantly different.34 Another reportfrom NVSN evaluated 564 childrenhospitalized with RSV infection. Nei-ther race nor ethnic group wasfound to be an independent riskfactor for hospitalization.35 A thirdCDC report revealed rates of RSVcoded illness in African Americanand white children to be similar at5.3/1000 (95% CI, 3.7–6.9/1000) and5.3/1000 (95% CI, 4.3–6.3/1000), re-spectively.33 Hospitalization ratesdid not differ during the years ofthis study (1997–1999 and 2004–2006) by African American or whiterace. In this study, hospitalizationrates for RSV-coded illness were7.5/1000 boys (95% CI, 5.9–9.1) and5.9/1000 girls (95% CI, 4.5–7.3).

Another population-based study eval-uated racial disparities between AfricanAmerican and white children whowere hospitalized because of RSV in-fection in 3 large United States coun-ties.105 No disparity was found in anycounty for any of the 7 years studiedamong children in the first 12 monthsof life or between infants 0 to 2months or infants 3 to 5 months ofage. Because of small numbers, reli-able estimates for other race groupsare not available.33 RSV hospitalization

rates among boys exceed that of girlsin some, but not all studies.34,35

Mortality Rates Among HospitalizedChildren With RSV Infection

Using 2 national databases (the Pedi-atric Health Information System [PHIS]data for 2004–2011 and the HealthCost and Utilization Project Kids’ In-patient Database [KID] for 2009),mortality rates associated with hos-pitalized infants with RSV infectionwere lower than previously estimated.The PHIS data set from 44 children’shospitals identified 33 deaths per year(13.7 deaths/10 000 RSV admissionsduring the RSV season), but only 8.5deaths/10 000 admissions were codedwith RSV as the primary diagnosis,suggesting that other comorbiditieswere involved. In the KID data set frommore than 4000 hospitals in 44 states,RSV was estimated to account for 121deaths annually in the United States(9/10 000 RSV admissions) with 84deaths per year occurring during thetypical RSV season. In addition, assuggested by the PHIS database,nearly 80% of deaths occurred inchildren with complex chronic medi-cal conditions. The mean age at timeof death was 7.5 months for infants inthe PHIS data set and 6.2 months inthe KID data set.15

An industry-sponsored meta-analysisof published reports of fatality ratesattributable to RSV infection in chil-dren suggested higher rates of deathbased on estimates from earlier years,likely because supportive care receivedin intensive care units was less effectivein earlier years.106

A statistically significant reduction inRSV mortality has not been demon-strated in any randomized clinical trialwith palivizumab or motavizumab.Thus, inclusion of mortality reductionor life years saved is difficult to justifyin a cost analysis of palivizumab pro-phylaxis.





Motavizumab

Motavizumab is a second-generationmonoclonal antibody that differsfrom palivizumab by 13 amino acids.Motavizumab was developed by affinitymaturation of the complementaritydetermining regions of palivizumab toimprove binding affinity to F protein. Incell culture, motavizumab has ap-proximately 10-fold greater neutraliz-ing activity than palivizumab againstRSV clinical isolates of both A andB subtypes.107 Unlike palivizumab,motavizumab may reduce RSV vial loadin the upper respiratory tract, as wellas the lower respiratory tract.108

Data from several clinical trials, in-cluding a noninferiority trial betweenpalivizumab and motavizumab, were sub-mitted to the FDA as part of the licens-ing application for motavizumab.109–111

In August 2010, the FDA rejected thelicense application for motavizumab.Among a number of concerns notedby the FDA was lack of greater clin-ical efficacy from motavizumab anda threefold increase in hypersensi-tivity reactions among motavizumabrecipients relative to palivizumabrecipients.107,109,112 Methodologic con-cerns were raised by the FDA inregard to laboratory testing proce-dures and geographic variation inresults from the noninferiority trial.Specifically, the generalizability of themain study finding was uncertain,because the results of the primaryend point differed when stratified bygeographic location. The results didnot reach the noninferiority thresholdfor the northern hemisphere, whereapproximately 90% of subjects wereenrolled.107

The overall RSV hospitalization ratewas 4.8% among palivizumab recipi-ents in the IMpact-RSV trial comparedwith a 1.9% RSV hospitalization rateamong palivizumab recipients in thepalivizumab-motavizumab noninferioritytrial. It was concluded that the non-

inferiority trial may have been con-ducted in a population with lesscomorbidity than the IMpact-RSV study.The FDA requested an additional clin-ical trial to support a satisfactory risk–benefit profile in populations for whichprophylaxis is being considered.107

RSV-specific outpatient medically atten-ded lower respiratory tract infectionswere reported to be significantly loweramong motavizumab recipients rela-tive to palivizumab recipients in thenoninferiority trial. However, this out-come was determined in a subset ofpatients from selected study sites,making the risk of bias high, as notedin the FDA report.107

Outpatient visits among RSV-infectedchildren exceed the number of out-patient visits attributable to influenzainfection by more than twofold.113 Onestudy of acute respiratory infection inchildren younger than 8 years esti-mated children from birth through 23months of age experienced overallemergency department visits attrib-utable to RSV infection at a rate of64.4/1000 (95% CI, 45.4–91.3) com-pared with a rate of 15.0/1000 (95% CI,4.4–50.6) among influenza-infectedchildren (27% had received influenzavaccine) during 2 respiratory virusseasons between 2003 and 2005.113

The impact of immunoprophylaxis onoutpatient medically attended eventsattributable to RSV infection is animportant consideration but remainsunknown because of lack of evalua-tion in a rigorous, controlled fashion.

Palivizumab-Resistant Isolates

Palivizumab and motavizumab bind toa highly conserved epitope (antigenicsite A) on the extracellular domain ofthe mature F protein that encom-passes amino acids 262 to 275. Afterantibody binding, viral entry into therespiratory epithelial cell is blocked,as is cell-to-cell fusion of infectedcells.2 RSV escape mutants resistant

to palivizumab have been isolatedfrom approximately 5% of childrenhospitalized with breakthrough RSVinfection while receiving monthlypalivizumab prophylaxis.1, 21,22,23,114

RSV isolates resistant to palivizumabcontain mutations in codons encodingthe amino acids between 262 and 275of the F protein. Amino acid sequencevariations outside antigenic site A donot appear to confer palivizumab re-sistance.

Effect of Palivizumab Prophylaxison Subsequent Wheezing

Numerous studies have documentedthat infants hospitalized with virallower airway disease are more likelyto experience recurrent wheezingcompared with infants who do notexperience severe bronchiolitis.68,115–119

The possible effect of avoidance ofRSV lower respiratory tract infectionearly in life with palivizumab pro-phylaxis on recurrent wheezing wasaddressed in 3 industry-sponsoredstudies.16,17,120

One trial among preterm infantswithout CLD describes physician-diagnosed recurrent wheezing in 8%of prophylaxis recipients and in 16% ofthe control group. This trial was con-ducted at 27 sites, and the patientswere followed for up to 24 months.Participants were not prospectivelyrandomized, the groups were notbalanced for birth weight, degree ofprematurity or known RSV risk factors,and families were not blinded to studymedication, making the results of un-certain significance.120

A nonrandomized observational reportfrom Japan compared the incidence ofwheezing between 349 preterm infants(33–35 weeks’ gestation) who re-ceived palivizumab prophylaxis in thefirst 6 months of life with 95 infantswho did not receive prophylaxis. Theprimary end point of the study wasphysician-diagnosed wheezing during



a 3-year follow-up. Twenty-two of 345infants (6.4%) who received immuno-prophylaxis experienced wheezing,whereas 18 of 95 infants (18.9%) whodid not receive prophylaxis developedrecurrent wheezing (P < .001) duringthe 3-year follow-up period.17 No dif-ference in hospitalization rates attrib-utable to respiratory disease betweenthe 2 groups was found. Concerns withthis study design include the lack ofrandomization and blinding and theabsence of standardized enrollmentcriteria at the 52 participating sites,each of which may have led to en-rollment bias, and no information wasprovided on the severity of thewheezing episodes. In addition, a his-tory of smokers in the household andfamily history of allergy was signifi-cantly more common in the untreatedgroup.

A double-blind placebo-controlled trialconducted in the Netherlands addressedpalivizumab prophylaxis and recurrentwheezing using a different study de-sign.16 Parent-reported wheezing in429 otherwise healthy late preterminfants during the first year of life wasevaluated in 214 infants who receivedmonthly prophylaxis with palivizumabcompared with 215 infants who re-ceived placebo. During the first yearof life, infants and young children inthe placebo group experienced 2309days with wheezing from a total51 726 patient days (4.5%), whereasthose in the palivizumab group had 930days of wheezing of 53 075 patient days(1.8%; P = .01). This represents an ab-solute 2.7 fewer days of wheezing per100 patient days (17.5 wheezing days/1000 days vs 44.6 wheezing days/1000days or 27.1 fewer wheezing days/1000days) among infants who receivedmonthly palivizumab in contrast tothose who did not receive prophylaxis.16

Reliance on parent reporting of wheez-ing was identified as a potential limi-tation. The wheezing episodes were not

medically attended events but parent-reported wheezing of unknown sever-ity.16 The proportion of infants usingbronchodilators in the placebo groupwas 23% and 13% among palivizumabrecipients.

Cost Analyses

Financial stewardship is a conceptthat acknowledges a physician’s re-sponsibility to advocate “for a justand cost-effective distribution of fi-nite resources.”121,122 Use of noncost-effective interventions contribute tomaladies within the health care sys-tem, including huge deficits, lowerquality of care, and inequitable ac-cess to health care.123 Financialstewardship has become an essen-tial component of successful reformof the existing health care system.

A number of economic analyses fromdifferent countries have evaluatedimmunoprophylaxis use in differentage groups, among children withvarying comorbidities and from boththe payer and the societal perspective.24

Economic evaluations sponsored by themanufacturer of palivizumab suggestcost neutrality or even cost savings.124–134

In contrast, analyses conducted byindependent investigators consis-tently demonstrate the cost ofpalivizumab prophylaxis far exceedsthe economic benefit of hospitalavoidance, even among infants athighest risk.24,25,39–42,46,90,135–143 Varia-tion in results are explained bydifferences in study methodology anddifferent base case assumptions usedin the model, such as incidence ofRSV hospitalization for different riskgroups, effectiveness of prophylaxis inreducing hospitalization rate by riskgroup, estimates of cost of prophylaxisand RSV hospitalizations avoided, num-ber of doses administered, estimatedage and weight of infants, and inclusionof a theoretical benefit on mortalityreduction.

The CDC has recommended quality-adjusted life years (QALYs) saved asan optimal approach to evaluate thebenefit of an intervention. One analysisusing this methodology for hypotheti-cal cohorts of infants without CLD bornat 26 to 32 weeks’ gestation revealedthe incremental cost-effectiveness ra-tio to be greater than $200 000 perQALY saved for all gestational ages,a figure not considered to be cost-effective.135

An economic analysis funded by themanufacturer of palivizumab andpublished in the Journal of MedicalEconomics also examined incrementalcost-effectiveness ratios per QALYgained in 4 groups of preterm infantswithout CLD and revealed the cost oftreatment with palivizumab for infants32 to 35 weeks’ gestation with ≤1 riskfactor was $464 476, using an averagecost for palivizumab for private andpublic payers. Medicaid discountswere reported to have resulted inan “approximate 40% reduction inpalivizumab cost for approximately 60%of palivizumab recipients.”129 None-theless, in most state Medicaid pro-grams, palivizumab is one of the mostcostly medication expenditures.

Cost was considered during deliber-ations by the COID and the Bronchio-litis Guidelines Committee, but the finalguidance as presented in the accom-panying Policy Statement is driven bythe limited clinical benefit derivedfrom palivizumab prophylaxis.

The American College of PhysiciansClinical Guidelines Committee outlinesprinciples to help clinicians definehigh-value health care by consideringkey concepts: benefits, harms and costof the intervention, downstream coststhat occur as a result of the in-tervention, and finally, the incrementalcost-effectiveness ratio.144 On the ba-sis of these principles, the minimalclinical reduction in RSV hospital-izations and reduction in wheezing





episodes associated with palivizumabprophylaxis are not of sufficient clinicaland societal importance to justify thecost. Although some RSV hospital-izations may be severe and pro-longed, the majority of hospitalizationsgenerally last 2 to 3 days. The high costof palivizumab prophylaxis becomesa cost-inefficient way to prevent a fewshort hospitalization stays and a smallnumber of longer hospital stays, espe-cially in the absence of evidence ofsignificant long-term benefit and nomeasurable effect on mortality.144

Health expenditures should not be basedonly on cost and benefit but rather onthe assessment of the benefit of theintervention relative to the expenditure.High-cost interventions may be appro-priate if highly beneficial.144 Because thehigh cost of palivizumab prophylaxis isassociated with minimal health benefit,this intervention cannot be consideredas high-value health care for any groupof infants.

Control Measures

A critical aspect of RSV preventionamong all infants is education ofparents and other caregivers aboutthe importance of decreasing expo-sure to and transmission of RSV.Preventive measures include limit-ing, where feasible, exposure to con-tagious settings (eg, child care centers)and emphasis on hand hygiene in allsettings, including the home and theneonatal ICU, especially during periodswhen contacts of children at high riskhave respiratory tract infections. For allchildren, the importance of breastfeed-ing, avoidance of crowds, and absence ofexposure to tobacco smoke, includingsecond-hand and third-hand exposure,should be emphasized.

Future Possibilities

Continued evaluation of the impact ofpalivizumab prophylaxis should in-clude other groups considered to be

at increased risk of disease to evaluatereductions in RSV hospitalizations, aswell as the effect of prophylaxis onmedically attended outpatient visits.

Investigation of other types of passiveimmunoprophylaxis including anti-Gmonoclonal antibodies, should con-tinue not only in prophylaxis but intreatment studies to modulate RSVdisease severity.145 Modification of theFc fragment of the motavizumab mol-ecule appears to prolong the half-lifeand theoretically may enable adminis-tration of fewer doses of motavizumabper season, although an increasedrisk of adverse effects remains a con-cern.107,146 Nanobodies are antibody-derived proteins consisting of functionalheavy-chain antibodies that lack lightchains and were initially found incamels and llamas. Nanobodies di-rected against the RSV fusion proteinhave demonstrated RSV-neutralizingactivity in experimental models.147

Ribavirin was licensed in 1986 andremains the only FDA-licensed antivi-ral agent for therapy but seldom isused because of limited efficacy, cum-bersome delivery (aerosol), and highcost.5 Interest continues in developingmore broadly effective antiviral agentsincluding fusion inhibitors and smallinterfering RNA.148,149

Development of a safe and effectiveRSV vaccine remains a high prior-ity.150–153 Progress has been ach-ieved with live-attenuated intranasalvaccines,154 but ensuring adequateattenuation while maintaining im-munogenicity remains a challenge.Early experience with a formalin-inactivated whole virus vaccine resul-ted in enhanced RSV disease in youngchildren in the 1960s, which hascomplicated development of inacti-vated RSV vaccines.150,155 The demon-stration of the effectiveness of passiveprophylaxis with an anti-F monoclonalprovides reassurance that antibodyto the F protein is protective. New

subunit vaccines and particularly vac-cines directed against the F proteinadministered intramuscularly or in-tranasally continue to be explored.150,155

A vaccine against a “prefusion” config-uration of the F protein may offer in-creased efficacy with less risk ofdisease enhancement.156 F protein viral-like particle vaccines administeredduring the latter half of pregnancymight offer passive protection foryoung children through the firstmonths of life.157,158

SUMMARY

The vast majority of RSV hospital-izations occur among healthy terminfants. Immunoprophylaxis remainsan option for a very small number ofchildren, but palivizumab immuno-prophylaxis will continue to have onlya minimal effect on the burden ofRSV disease. Effort should be madeto avoid prophylaxis among infantsand young children who do notqualify for prophylaxis, as outlinedin the accompanying AAP policystatement.6

COMMITTEE ON INFECTIOUSDISEASES, 2013–2014Michael T. Brady, MD, FAAP – Chairperson, RedBook Associate EditorCarrie L. Byington, MD, FAAPH. Dele Davies, MD, FAAPKathryn M. Edwards, MD, FAAPMary Anne Jackson, MD, FAAP – Red BookAssociate EditorYvonne A. Maldonado, MD, FAAPDennis L. Murray, MD, FAAPWalter A. Orenstein, MD, FAAPMobeen H. Rathore, MD, FAAPMark H. Sawyer, MD, FAAPGordon E. Schutze, MD, FAAPRodney E. Willoughby, MD, FAAPTheoklis E. Zaoutis, MD, FAAP

EX OFFICIOHenry H. Bernstein, DO, MHCM, FAAP – Red BookOnline Associate EditorDavid W. Kimberlin, MD, FAAP – Red BookEditorSarah S. Long, MD, FAAP – Red Book AssociateEditor



H. Cody Meissner, MD, FAAP – Visual Red BookAssociate Editor

LIAISONSMarc A. Fischer, MD, FAAP – Centers for DiseaseControl and PreventionBruce G. Gellin, MD, MPH – National VaccineProgram OfficeRichard L. Gorman, MD, FAAP – National Institutesof HealthLucia H. Lee, MD, FAAP – Food and Drug AdministrationR. Douglas Pratt, MD – Food and Drug AdministrationJennifer S. Read, MD, MS, MPH, DTM&H FAAP– Food and Drug AdministrationJoan L. Robinson, MD – Canadian Pediatric SocietyMarco Aurelio Palazzi Safadi, MD – SociedadLatinoamericana de Infectologia PediatricaJane F. Seward, MBBS, MPH, FAAP – Centers forDisease Control and PreventionJeffrey R. Starke, MD, FAAP – American ThoracicSocietyGeoffrey R. Simon, MD, FAAP – Committee onPractice Ambulatory MedicineTina Q. Tan, MD, FAAP – Pediatric InfectiousDiseases Society

CONTRIBUTORSJoseph A. Bocchini, MD, FAAPW. Robert Morrow, MD, FAAP – Chairperson,Section on CardiologyLarry K. Pickering, MD, FAAP

Geoffrey L Rosenthal, MD, PhD, FAAP – Sectionon CardiologyDan L. Stewart, MD, FAAP – Committee on Fetusand NewbornAlmut Winterstein, PhD

STAFFJennifer M. Frantz, MPH

SUBCOMMITTEE ON BRONCHIOLITISShawn L. Ralston, MD, FAAP – Chairperson;Pediatric HospitalistAllan S. Lieberthal MD, FAAP – Chairperson;General Pediatrician with expertise in pulmo-nologyH. Cody Meissner, MD, FAAP – Pediatric In-fectious Disease Physician; AAP Committee onInfectious Diseases RepresentativeBrian K. Alverson, MD, FAAP – Pediatric Hospi-talist; AAP Section on Hospital Medicine Rep-resentativeJill E. Baley, MD, FAAP – Neonatal-PerinatalMedicine, AAP Committee on Fetus and New-born RepresentativeAnne M. Gadomski, MD, MPH, FAAP – GeneralPediatrician and Research ScientistDavid W. Johnson, MD, FAAP – Pediatric Emer-gency Medicine PhysicianMichael J. Light, MD, FAAP – Pediatric Pulmo-nologist; AAP Section on Pediatric PulmonologyRepresentative

Nizar F. Maraqa, MD, FAAP – Pediatric InfectiousDisease Physician; AAP Section on InfectiousDiseases RepresentativeEneida A. Mendonca, MD, PhD, FAAP, FACMI– Informatician/Academic Pediatric IntensiveCare Physician; Partnership for Policy Imple-mentation RepresentativeKieran J. Phelan, MD, MSc – General Pedia-tricianJoseph J. Zorc, MD, MSCE, FAAP – PediatricEmergency Physician; AAP Section on Emer-gency Medicine RepresentativeDanette Stanko-Lopp, MA, MPH – Methodologist,EpidemiologistSinsi Hernández-Cancio, JD – Parent/ConsumerRepresentative

LIAISONSMark A. Brown, MD – Pediatric Pulmonologist;American Thoracic Society LiaisonIan Nathanson, MD, FAAP – Pediatric Pulmonolo-gist; American College of Chest Physicians LiaisonElizabeth Rosenblum, MD – Academic FamilyPhysician, American Academy of Family Physi-cians LiaisonStephen Sayles III MD, FACEP – EmergencyMedicine Physician; American College of Emer-gency Physicians Liaison

STAFFCaryn Davidson, MA

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DOI: 10.1542/peds.2014-1666; originally published online July 28, 2014; 2014;134;e620PediatricsCOMMITTEE

COMMITTEE ON INFECTIOUS DISEASES and BRONCHIOLITIS GUIDELINESInfection

Children at Increased Risk of Hospitalization for Respiratory Syncytial Virus Updated Guidance for Palivizumab Prophylaxis Among Infants and Young

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