Bronchiolitis and Synagis

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Bronchiolitis and Synagis
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Pretest

• Which of the following children should receive
  RSV prophylaxis during RSV season?
• A. 5 month former 34 weeker who attends day care
  and has a 5 yo brother
• B. 11 month former 27 weeker
• C. 7 month former 31 weeker
• D. 18 month patient with cystic fibrosis on home
  02
• E. 14 month Tetrology of Fallot patient
• F. 22 month former 32 weeker with BPD who
  required diuretics and steroids in October

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Background

• Respiratory syncytial virus (RSV) is the primary
  cause of lower respiratory tract illness in young
  children.
• Generally resolves uneventfully in otherwise
  healthy children.
• High risk populations may develop severe and
  sometimes fatal lower respiratory tract
  infections.

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Background

• RSV infection annually contributes up to 126,300
  pediatric hospitalizations in the U.S.
• Estimated annual hospitalization costs for RSV
  pneumonia in children lt4 years 300 - 400
  million (1998 ), now much greater.
• Annual mortality due to RSV in infants and
  children is estimated to range from 200 to over
  2,700.

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Microbiology Basics

• RSV is single-stranded RNA virus of
  Paramyxoviridae family
• Two subtypes, A and B
• A subtypes cause more disease
• Within subtypes are several genotypes
• Strains have shifts each year, accounting for
  re-infections

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Prematurity

• Prematurity increases risk of severe RSV
  infection.

RSV Hospitalization Rate by Gestational Age at
Birth
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Epidemiology

• Worldwide RSV epidemics occur yearly
• United States November April
• Peak January March (most areas)
• Peak 2 3 months earlier (Southeast)
• 80 RSV admissions occur within 4 months of
  discharge from NICU.

Respiratory Illness Hospitalization Rate by
Month of Discharge from NICU in Infants lt 32
Weeks GA
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Transmission

• Inoculation of nasal or ocular membranes after
  contact with virus containing secretions or
  fomites
• Virus can survive for several hours on hands and
  fomites (WASH HANDS!!!)
• Direct contact most common, large aerosol drops
  also implicated
• Incubation is 2-8 days
• Patients usually shed 3-8 days but can shed up to
  4 weeks in young infants

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Immunity

• Almost everyone has been infected with RSV by age
  3
• Does not convey total protection against
  reinfection
• Can be infected more than once in same RSV season
  but usually 2d infection milder
• Transplacental Ab does not protect completely
  against infection but high Abs imply milder
  disease and usually is only in upper respiratory
  tract

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Pathologic findings

• Necrosis of epithelial cells
• Proliferation of bronchiolar epithelium
• Infiltrates of monocytes and T cells around
  arterioles
• Neutrophils between vasculature and small airways
• Leads to airway obstruction, air trapping,
  increased airway resistance
• Increased incidence of wheezing as children grow
  older

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Hospital therapy for RSV

• Care is mainly supportive (fluids, respiratory
  support)
• Trial (one dose) of beta-agonist if bronchospasm.
  D/C if not improvement
• Steroids not recommended
• Ribavirin not recommended unless severe LRT
  infection
• Neither RSVIG nor Synagis is effective in
  treatment of hospitalized children

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RSVIG

• Was developed as hyperimmune globulin from donors
  with high titers of RSV antibody
• In trials reduced hospitalizations in high risk
  infants by 41-63
• Increased morbidity and mortality in CHD patients
• Interfered with immune response to live vaccines
  (MMR and varicella)
• No longer used frequently

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Palivizumab (Synagis)

• Is monoclonal antibody (not blood product)
  against RSV F glycoprotein
• Easier to administer than RSVIG
• Does not interfere with response to live vaccines
• A newer but similar product is MEDI-524 or Numax
• More potent in animal trials
• Currently undergoing clinical evaluation

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Synagis

• Synagis is available in 50 and 100 mg vials
• The cost is 725 per 50 mg and 1370 per 100 mg
  vial
• Synagis has a shelf life of 6 hours making drug
  wastage nearly inevitable

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Dosing of Synagis

• 15 mg/kg IM once per month for 5 doses
• Begin before RSV season begins, October or
  November
• Once dosing begins, continue even if patient is
  past age of indication
• Continue even if breakthrough
• infection

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Efficacy

• IMpact-RSV trial in BPD pts and preemies
• 55 reduction in RSV-associated hospitalizations
  vs placebo
• Trial in CHD pts
• 45 fewer hospitalizations
• 73 fewer hospital days needing O2
• 56 fewer total hospital days
• Trial in 421 preemies without CLD who received
  Synagis or placebo
• 50 fewer infants in Synagis group had recurrent
  wheezing
• Shows that prevention of RSV LRTI may reduce risk
  of recurrent wheezing in preemies without CLD

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Risk factors for severe disease

• Less than 6 months
• Born during first half of RSV season
• Attending daycare
• Underlying lung disease
• Born before 35 weeks
• Congenital heart disease
• Immunocompromised patients
• SCIDS, leukemia, BM transplant
• Significant asthma (any age)
• Living at altitudes greater than 8000 feet
• Institutionalized elderly

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Adverse Reactions

• Extremely safe, no serious adverse events in two
  consecutive seasons seen
• Severe hypersensitivity (less than 1 per 100,000)
• About 1 per 100 children will have anti-Synagis
  antibodies and antibody response declines with
  continued dosing
• No resistance to Synagis by RSV seen
• Doesnt interfere with immunizations

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Specific Recommendations

• BPD- younger than 2 yo needing medical therapy
  for lungs who required medical therapy within 6
  mos of RSV season
• CHD under 2 who have hemodynamically
  significant CHD
• Prematurity
• 28 weeks, younger than 1 yr at start of season
• 29-35 wks, younger than 6 mos
• 32-35 consider for infants lt6 mos if 2 risk
  factors (day care attendance, congenital
  abnormalities, NMD, school-aged sibs)
• Immunocompromised no controlled studies but
  seems apparent that those with SCIDS or HIV with
  low CD4 undergoing chemotherapy or
  post-transplant would benefit
• Structural or functional lung disease (such as
  CF) are at increased risk no data on
  effectiveness

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Medicaid and Synagis

• Synagis is a benefit under the Comprehensive Care
  Program
• Administered by a Synagis provider
• Eligibility for children under 2 the same except
• Hemodynamically significant heart disease is
  defined as including
• Pulmonary hypertension
• Digoxin or diuretics
• Oxygen
• Lung disease qualifies if
• On steroids, diuretics, ventilator or 02
• Transplants patients qualify

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RSV Vaccine

• Many challenges for effective vaccine
• Immature immunity
• Possible suppression of immune response by
  maternal antibody
• Several antigenically divergent strains
• Live attenuated vaccines are being tested
• Must be very attenuated in this young group
• However, lessens chance of detectable Ab response

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Post-test

• Which of the following children should receive
  RSV prophylaxis during RSV season?
• A. 5 month former 34 weeker who attends day care
  and has a 5 yo brother
• B. 11 month former 27 weeker
• C. 7 month former 31 weeker
• D. 18 month patient with cystic fibrosis on home
  02
• E. 14 month Tetrology of Fallot patient
• F. 22 month former 32 weeker with BPD who was
  required diuretics and steroids in October

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Answer to Pretest Question
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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References

• Up To Date, Treatment and Prevention of RSV
• AAP Clinical Practice Guidelines, Diagnosis and
  Management of Bronchiolitis, PEDIATRICS Volume
  118, Number 4, October 2006
• AAP Policy Statement, Revised Indications for the
  Use of Palivizumab and Respiratory Syncytial
  Virus Immune Globulin Intravenous for the
  Prevention of Respiratory Syncytial Virus
  Infections