Bronchiolitis and Bronchiolitis and SynagisSynagis

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PretestPretest

Which of the following children should Which of the following children should receive RSV prophylaxis during RSV season?receive RSV prophylaxis during RSV season?A. 5 month former 34 weeker who attends day care A. 5 month former 34 weeker who attends day care

and has a 5 yo brotherand has a 5 yo brother

B. 11 month former 27 weeker B. 11 month former 27 weeker

C. 7 month former 31 weekerC. 7 month former 31 weeker

D. 18 month patient with cystic fibrosis on home 02D. 18 month patient with cystic fibrosis on home 02

E. 14 month Tetrology of Fallot patientE. 14 month Tetrology of Fallot patient

F. 22 month former 32 weeker with BPD who F. 22 month former 32 weeker with BPD who required diuretics and steroids in Octoberrequired diuretics and steroids in October

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BackgroundBackground Respiratory syncytial virus (RSV) Respiratory syncytial virus (RSV)

is the primary cause of lower is the primary cause of lower respiratory tract illness in young respiratory tract illness in young children.children.

Generally resolves uneventfully in Generally resolves uneventfully in otherwise healthy children. otherwise healthy children.

High risk populations may develop High risk populations may develop severe and sometimes fatal lower severe and sometimes fatal lower respiratory tract infections.respiratory tract infections.

:)

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BackgroundBackground

RSV infection annually contributes up RSV infection annually contributes up to 126,300 pediatric hospitalizations to 126,300 pediatric hospitalizations in the U.S.in the U.S.

Estimated annual hospitalization costs Estimated annual hospitalization costs for RSV pneumonia in children <=4 for RSV pneumonia in children <=4 years: $300 - $400 million (1998 $), years: $300 - $400 million (1998 $), now much greater.now much greater.

Annual mortality due to RSV in infants Annual mortality due to RSV in infants and children is estimated to range and children is estimated to range from 200 to over 2,700.from 200 to over 2,700.

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Microbiology BasicsMicrobiology Basics

RSV is single-stranded RNA virus of RSV is single-stranded RNA virus of Paramyxoviridae familyParamyxoviridae family

Two subtypes, A and BTwo subtypes, A and B A subtypes cause more diseaseA subtypes cause more disease Within subtypes are several genotypesWithin subtypes are several genotypes

Strains have shifts each year, Strains have shifts each year, accounting for re-infectionsaccounting for re-infections

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PrematurityPrematurity Prematurity increases risk of Prematurity increases risk of

severe RSV infection.severe RSV infection.

20.60%

14.60%

11.30%

6.40%

0%

5%

10%

15%

20%

25%

Percent RSV Hospitalization

=< 26 W. 27 - 28 W. > 28 - 30 W. > 30 - 32 W.

Gestational Age at Birth

RSV Hospitalization Rate by Gestational Age at Birth

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EpidemiologyEpidemiology Worldwide RSV epidemics occur yearlyWorldwide RSV epidemics occur yearly

United States: November – AprilUnited States: November – April Peak: January – March (most areas)Peak: January – March (most areas) Peak: 2 – 3 months earlier (Southeast) Peak: 2 – 3 months earlier (Southeast)

80% RSV admissions occur within 4 months 80% RSV admissions occur within 4 months of discharge from NICU.of discharge from NICU.

42%

27%

15%

41%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

Probability of hospitalization

Jan. Feb. - Apr. May - Aug. Sept. - Dec.

Month of Discharge

Respiratory Illness Hospitalization Rate by Month of Discharge from NICU in Infants <= 32 Weeks GA

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TransmissionTransmission Inoculation of nasal or ocular membranes Inoculation of nasal or ocular membranes

after contact with virus containing after contact with virus containing secretions or fomitessecretions or fomites

Virus can survive for several hours on Virus can survive for several hours on hands and fomites (WASH HANDS!!!)hands and fomites (WASH HANDS!!!)

Direct contact most common, large Direct contact most common, large aerosol drops also implicatedaerosol drops also implicated

Incubation is 2-8 daysIncubation is 2-8 days Patients usually shed 3-8 days but can Patients usually shed 3-8 days but can

shed up to 4 weeks in young infantsshed up to 4 weeks in young infants

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ImmunityImmunity

Almost everyone has been infected with Almost everyone has been infected with RSV by age 3RSV by age 3

Does not convey total protection against Does not convey total protection against reinfectionreinfection

Can be infected more than once in same Can be infected more than once in same RSV season but usually 2d infection RSV season but usually 2d infection mildermilder

Transplacental Ab does not protect Transplacental Ab does not protect completely against infection but high Ab’s completely against infection but high Ab’s imply milder disease and usually is only in imply milder disease and usually is only in upper respiratory tractupper respiratory tract

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Pathologic Pathologic findingsfindings

Necrosis of epithelial cellsNecrosis of epithelial cells Proliferation of bronchiolar epitheliumProliferation of bronchiolar epithelium Infiltrates of monocytes and T cells Infiltrates of monocytes and T cells

around arteriolesaround arterioles Neutrophils between vasculature and Neutrophils between vasculature and

small airwayssmall airways Leads to airway obstruction, air trapping, Leads to airway obstruction, air trapping,

increased airway resistanceincreased airway resistance Increased incidence of wheezing as Increased incidence of wheezing as

children grow olderchildren grow older

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Hospital therapy for RSVHospital therapy for RSV

Care is mainly supportive (fluids, Care is mainly supportive (fluids, respiratory support)respiratory support)

Trial (one dose) of beta-agonist if Trial (one dose) of beta-agonist if bronchospasm. D/C if not bronchospasm. D/C if not improvementimprovement

Steroids not recommendedSteroids not recommended Ribavirin not recommended unless Ribavirin not recommended unless

severe LRT infectionsevere LRT infection Neither RSVIG nor Synagis is effective Neither RSVIG nor Synagis is effective

in treatment of hospitalized childrenin treatment of hospitalized children

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RSVIGRSVIG

Was developed as hyperimmune globulin Was developed as hyperimmune globulin from donors with high titers of RSV from donors with high titers of RSV antibodyantibody

In trials reduced hospitalizations in high In trials reduced hospitalizations in high risk infants by 41-63%risk infants by 41-63%

Increased morbidity and mortality in CHD Increased morbidity and mortality in CHD patientspatients

Interfered with immune response to live Interfered with immune response to live vaccines (MMR and varicella)vaccines (MMR and varicella)

No longer used frequentlyNo longer used frequently

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Palivizumab (Synagis)Palivizumab (Synagis)

Is monoclonal antibody (not blood Is monoclonal antibody (not blood product) against RSV F glycoproteinproduct) against RSV F glycoprotein

Easier to administer than RSVIGEasier to administer than RSVIG Does not interfere with response to Does not interfere with response to

live vaccineslive vaccines A newer but similar product is A newer but similar product is

MEDI-524 or NumaxMEDI-524 or Numax More potent in animal trialsMore potent in animal trials Currently undergoing clinical evaluationCurrently undergoing clinical evaluation

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Synagis Synagis

Synagis is available in 50 and Synagis is available in 50 and

100 mg vials100 mg vials The cost is $725 per 50 mg and The cost is $725 per 50 mg and

$1370 per 100 mg vial $1370 per 100 mg vial Synagis has a shelf life of 6 hours Synagis has a shelf life of 6 hours

making drug wastage nearly making drug wastage nearly inevitable inevitable

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Dosing of SynagisDosing of Synagis 15 mg/kg IM once per month for 5 15 mg/kg IM once per month for 5

dosesdoses Begin before RSV season begins, Begin before RSV season begins,

October or NovemberOctober or November Once dosing begins, continue even if Once dosing begins, continue even if

patient is past age of indicationpatient is past age of indication Continue even if breakthroughContinue even if breakthrough

infectioninfection

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EfficacyEfficacy

IMpact-RSV trial in BPD pts and preemiesIMpact-RSV trial in BPD pts and preemies 55% reduction in RSV-associated 55% reduction in RSV-associated

hospitalizations vs placebohospitalizations vs placebo Trial in CHD pts Trial in CHD pts

45% fewer hospitalizations45% fewer hospitalizations 73% fewer hospital days needing O273% fewer hospital days needing O2 56% fewer total hospital days 56% fewer total hospital days

Trial in 421 preemies without CLD who Trial in 421 preemies without CLD who received Synagis or placeboreceived Synagis or placebo 50% fewer infants in Synagis group had 50% fewer infants in Synagis group had

recurrent wheezingrecurrent wheezing Shows that prevention of RSV LRTI may Shows that prevention of RSV LRTI may

reduce risk of recurrent wheezing in preemies reduce risk of recurrent wheezing in preemies without CLDwithout CLD

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Risk factors for severe Risk factors for severe diseasedisease

Less than 6 monthsLess than 6 months Born during first half of RSV seasonBorn during first half of RSV season Attending daycareAttending daycare

Underlying lung diseaseUnderlying lung disease Born before 35 weeksBorn before 35 weeks Congenital heart diseaseCongenital heart disease Immunocompromised patientsImmunocompromised patients

SCIDS, leukemia, BM transplantSCIDS, leukemia, BM transplant Significant asthma (any age)Significant asthma (any age) Living at altitudes greater than 8000 feetLiving at altitudes greater than 8000 feet Institutionalized elderlyInstitutionalized elderly

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Adverse ReactionsAdverse Reactions

Extremely safe, no serious adverse Extremely safe, no serious adverse events in two consecutive seasons seenevents in two consecutive seasons seen

Severe hypersensitivity (less than 1 per Severe hypersensitivity (less than 1 per 100,000)100,000)

About 1 per 100 children will have anti-About 1 per 100 children will have anti-Synagis antibodies and antibody Synagis antibodies and antibody response declines with continued response declines with continued dosingdosing

No resistance to Synagis by RSV seenNo resistance to Synagis by RSV seen Doesn’t interfere with immunizationsDoesn’t interfere with immunizations

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Specific Specific RecommendationsRecommendations

BPD- younger than 2 yo needing medical therapy BPD- younger than 2 yo needing medical therapy for lungs who required medical therapy within 6 for lungs who required medical therapy within 6 mos of RSV seasonmos of RSV season

CHD – under 2 who have hemodynamically CHD – under 2 who have hemodynamically significant CHDsignificant CHD

PrematurityPrematurity ≤ ≤ 28 weeks, younger than 1 yr at start of season28 weeks, younger than 1 yr at start of season 29-35 wks, younger than 6 mos29-35 wks, younger than 6 mos 32-35 consider for infants <6 mos if 2 risk factors (day 32-35 consider for infants <6 mos if 2 risk factors (day

care attendance, congenital abnormalities, NMD, school-care attendance, congenital abnormalities, NMD, school-aged sibs)aged sibs)

Immunocompromised – no controlled studies but Immunocompromised – no controlled studies but seems apparent that those with SCIDS or HIV seems apparent that those with SCIDS or HIV with low CD4 undergoing chemotherapy or post-with low CD4 undergoing chemotherapy or post-transplant would benefittransplant would benefit

Structural or functional lung disease (such as CF) Structural or functional lung disease (such as CF) are at increased risk; no data on effectivenessare at increased risk; no data on effectiveness

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Medicaid and SynagisMedicaid and Synagis Synagis is a benefit under the Synagis is a benefit under the

Comprehensive Care ProgramComprehensive Care Program Administered by a Synagis providerAdministered by a Synagis provider Eligibility for children under 2 the same Eligibility for children under 2 the same

except:except: Hemodynamically significant heart disease is Hemodynamically significant heart disease is

defined as including:defined as including: Pulmonary hypertensionPulmonary hypertension Digoxin or diureticsDigoxin or diuretics OxygenOxygen

Lung disease qualifies if:Lung disease qualifies if: On steroids, diuretics, ventilator or 02On steroids, diuretics, ventilator or 02

Transplants patients qualifyTransplants patients qualify

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RSV VaccineRSV Vaccine Many challenges for effective vaccineMany challenges for effective vaccine

Immature immunityImmature immunity Possible suppression of immune response Possible suppression of immune response

by maternal antibodyby maternal antibody Several antigenically divergent strainsSeveral antigenically divergent strains

Live attenuated vaccines are being Live attenuated vaccines are being testedtested Must be very attenuated in this young Must be very attenuated in this young

groupgroup However, lessens chance of detectable Ab However, lessens chance of detectable Ab

responseresponse

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Post-testPost-test

Which of the following children should Which of the following children should receive RSV prophylaxis during RSV season?receive RSV prophylaxis during RSV season?A. 5 month former 34 weeker who attends day care A. 5 month former 34 weeker who attends day care

and has a 5 yo brotherand has a 5 yo brother

B. 11 month former 27 weeker B. 11 month former 27 weeker

C. 7 month former 31 weekerC. 7 month former 31 weeker

D. 18 month patient with cystic fibrosis on home 02D. 18 month patient with cystic fibrosis on home 02

E. 14 month Tetrology of Fallot patientE. 14 month Tetrology of Fallot patient

F. 22 month former 32 weeker with BPD who was F. 22 month former 32 weeker with BPD who was required diuretics and steroids in Octoberrequired diuretics and steroids in October

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Answer to Pretest Answer to Pretest QuestionQuestion

There is evidence for lack of benefit in the 7 month old 31 weeker

No evidence for benefit in cystic fibrosis patient but is reasonable to consider

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ReferencesReferences

Up To Date, “Treatment and Prevention of Up To Date, “Treatment and Prevention of RSV”RSV”

AAP Clinical Practice Guidelines, “Diagnosis AAP Clinical Practice Guidelines, “Diagnosis and Management of Bronchiolitis”, and Management of Bronchiolitis”, PEDIATRICS Volume 118, Number 4, October PEDIATRICS Volume 118, Number 4, October 20062006

AAP Policy Statement, AAP Policy Statement, Revised Indications Revised Indications for the Use of Palivizumab and for the Use of Palivizumab and Respiratory Syncytial Virus Immune Respiratory Syncytial Virus Immune Globulin Intravenous for the Prevention Globulin Intravenous for the Prevention of Respiratory Syncytial Virus Infectionsof Respiratory Syncytial Virus Infections