Bronchiolitis and Synagis

CONTINUITY CLINIC Pretest Which of the following children should receive RSV prophylaxis during RSV season? 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

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

CONTINUITY CLINIC Background RSV infection annually contributes up to 126,300 pediatric hospitalizations in the U.S. RSV infection annually contributes up to 126,300 pediatric hospitalizations in the U.S. Estimated annual hospitalization costs for RSV pneumonia in children <=4 years: $300 - $400 million (1998 $), now much greater. Estimated annual hospitalization costs for RSV pneumonia in children <=4 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. Annual mortality due to RSV in infants and children is estimated to range from 200 to over 2,700.

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

CONTINUITY CLINIC Prematurity Prematurity increases risk of severe RSV infection. Prematurity increases risk of severe RSV infection. RSV Hospitalization Rate by Gestational Age at Birth

CONTINUITY CLINIC Epidemiology Worldwide RSV epidemics occur yearly Worldwide RSV epidemics occur yearly United States: November – April United 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 of discharge from NICU. 80% RSV admissions occur within 4 months of discharge from NICU. Respiratory Illness Hospitalization Rate by Month of Discharge from NICU in Infants <= 32 Weeks GA

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

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

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

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

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

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

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

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

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

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

CONTINUITY CLINIC Adverse Reactions Extremely safe, no serious adverse events in two consecutive seasons seen Extremely safe, no serious adverse events in two consecutive seasons seen Severe hypersensitivity (less than 1 per 100,000) 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 About 1 per 100 children will have anti-Synagis antibodies and antibody response declines with continued dosing No resistance to Synagis by RSV seen No resistance to Synagis by RSV seen Doesn’t interfere with immunizations Doesn’t interfere with immunizations

CONTINUITY CLINIC Specific Recommendations BPD- younger than 2 yo needing medical therapy for lungs who required medical therapy within 6 mos of RSV season 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 CHD – under 2 who have hemodynamically significant CHD Prematurity Prematurity ≤ 28 weeks, younger than 1 yr at start of season ≤ 28 weeks, younger than 1 yr at start of season wks, younger than 6 mos wks, younger than 6 mos consider for infants <6 mos if 2 risk factors (day care attendance, congenital abnormalities, NMD, school-aged sibs) consider for infants <6 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 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 Structural or functional lung disease (such as CF) are at increased risk; no data on effectiveness

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

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

CONTINUITY CLINIC Post-test Which of the following children should receive RSV prophylaxis during RSV season? 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

CONTINUITY CLINIC 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

CONTINUITY CLINIC References Up To Date, “Treatment and Prevention of RSV” 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 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 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