1. RSV Bronchiolitis Mark A. Brown, M.D. Professor of Clinical Pediatrics Pediatric Pulmonary Section University of Arizona

2. Bronchiolitis: Definition Viral infection of the lower respiratory tract characterized by acute inflammation, edema, and necrosis of epithelial cells lining small airways, increased mucus production, and bronchospasm AHRQ Evidence Report

4. Epidemiology Bronchiolitis statistics –90% of children 0-2 yrs. are infected with RSV –20% have lower respiratory infection –3% hospitalized –0.002% mortality Age at presentation –Peak age 2-5 months –Rare in 1 st month of life

5. Viral causes of bronchiolitis Respiratory syncytial virus (RSV): 70% Metapneumovirus10-20% –Newly identified paramyxovirus –Similar seasonality and course to RSV Parainfluenza Influenza 10-20% Adenovirus Bocavirus ? }

7. Seasonality Bronchiolitis RSV Isolates Year Hall, NEJM 2001

8. RSV  Prime Cause of LRTI in Young Child Hospitalization for RSV Bronchiolitis: 38% of all LRTI in first year of life 22% of all LRTI in  5 years of age 31 / 1,000 children < 12 mos each year Economic Burden Costs for LRTI hospitalizations: $2.25 billion for infants, 14 to 26% from RSV $3.73 billion for first 5 years of life, 10  16% from RSV Shay ’99 Stang ’01

9. Clinical course of bronchiolitis Incubation period: 2-8 days Upper respiratory infection: 1-3 days Worsening lower airway disease: 3-5 days Full recovery: 2-8 weeks Percent Days of symptoms Swingler et al. 2000

10. Clinical course Severity Days

11. Risk Factors for Hospitalization with RSV 1708 Hospitalized Infants in Rochester, NY Prematurity Chronic Disease Age < 6 wks 1 or more Risk Factors Percent with:

12. RSV Roentgenographic Findings Diffuse interstitial pneumonitis most common in all lobes Hyperaeration > 50% Lobar or segmental consolidation 20  50%; RUL, RML most common Peribronchial thickening

14. Therapy for RSV Oxygen, administered by means of a small tent, gives these patients with cyanosis definite relief, and is the treatment upon which we have to rely for the most severely ill infants.  J. Adams, Lancet 1945

15. Therapies Supportive care –Airway clearance –Hydration –Oxygen Bronchodilators

16. Supportive Care Administer humidified oxygen Nasal suctioning to clear upper airway Monitor for apnea, hypoxemia, and impending respiratory failure Normalize body temperature Rehydrate with oral or intravenous fluids Monitor hydration status

17. Supportive Care Quittell LM, et al. Am Rev Respir Dis. 1988;137:406A; Chest Physiotherapy (CPT) –Little evidence to confirm enhancement of mucociliary clearance

18. Bronchodilators Multiple studies of bronchodilators –Albuterol Beta 2 adrenergic effects –Racemic epinephrine Beta 2 adrenergic effects Alpha adrenergic effects - ? vasoconstriction –Anticholinergics No evidence for benefit in bronchiolitis

19. Effect on clinical score: Cochrane meta-analysis Hartling et al. Cochrane Review 2004

20. Odds of improvement Hartling et al. Cochrane Review 2004

21. Effect on hospitalization Hartling et al. Cochrane Review 2004

22. Bronchodilators Evidence for modest short-term improvement –Overall, 57% improved vs. 43% for placebo –1 infant will benefit for every 7 treated Mild side effects common: tachycardia, hypoxemia No impact on overall course of disease in inpatients AlbuterolDobson et al. Pediatrics. 1998; 101:361-368. EpinephrineWainwright et al, N Eng J Med 2003; 49:27-35. Studies comparing epinephrine vs. albuterol mixed

23. Hartling et al. Cochrane Review 2004

24. Bronchodilators and bronchiolitis Bronchodilators have variable effects on infants with bronchiolitis… Some improve…some get worse…and the rest stay the same Unknown

25. Therapies Supportive Care Suctioning/Airway Clearance –Upper airway congestion can contribute to symptoms –No evidence for role of deep suctioning –One RCT suggests benefit for using 3% saline with nebs Sarrell, et al. Chest 2002; 122:2015-2020. Chest physiotherapy –One small RCT found no benefit of routine Chest PT Webb et al. Arch Dis Child 1985; 60:1078- 1079. Hydration –Assess and follow I/Os (potential for SIADH)

26. Oxygen Pulse oximetry detects hypoxemia not apparent on PE Significance of mild hypoxemia (> 90%) unclear –Variability in saturation due to plugging / mismatch –Indication for starting oxygen unclear –Oxygen requirement associated with worse outcomes Increased risk of need for ventilation Wang et al. J Peds 1995; 126:212-219. 4 x increased inpatient LOS Wainwright et al. 2003 –? Continuous pulse oximetry vs. spot checking

28. Protection against lower respiratory infection Natural immunity to RSV Antibody to F and G surface proteins protect against LRI Humoral immunity controls and terminates infection Reinfections with RSV Usually limited to URI Healthcare workers at risk Significant cause of illness in elderly

29. Prevention Non-Specific Measures –Avoidance –Hygiene –Nutrition Passive Immunization –Palivizumab (Synagis ® )

30. RSV immunoprophylaxis Attempts to provide immunity to RSV Vaccine in 1960s worsened course of infection New intra-nasal vaccine undergoing trials Passive immunity via hyperimmune globulin Monoclonal antibody to F protein (palivizumab) –55%  hospitalizations for preterm/chronic lung disease –45%  hospitalizations for congenital heart disease

31. The IMpact-RSV Study Group. Pediatrics. 1998;102(3):531-7; Palivizumab Outcomes Study Group. Pediatric Pulm. 2003;35:484-9; Hudak et al. J Perinatol. 2002;22:619, abstract P32; Data on file, MedImmune Inc. Reduction in RSV Hospitalization Rate IMpact-RSV study based on active collection of hospital data; Outcomes Registry based on passive reporting 8.1 11 9.8 12.8 4.8 1.8 5.8 2 7.9 2.9 2.1 4.5 1.6 5.8 1.5 1.2 1.7 1.3 2.2 1.1 1.2 1.6 1.9 10.6 0.7 0 2 4 6 8 10 12 14 All PatientsPremature w/o CLD All <32 weeks GA All 32-35 weeks Patients with CLD RSV Hosp Rate 1996-1997 IMpact-RSV Trial-Placebo 1996-1997 IMpact-RSV Trial-Synagis 2000-2001 Synagis Outcomes Registry2001-2002 Synagis Outcomes Registry 2002-2003 Synagis Outcomes Registry

32. *Receiving medical therapy for CLD within 6 months Guidelines for RSV Prophylaxis Premature, no CLD, no CHD 29-32 wks GA Palivizumab if ≤6 months at start of RSV season ≤28 wks GA Palivizumab if ≤12 months at start of RSV season 32-35 wks GA Palivizumab if ≤6 months at start of RSV season with two risk factors present Chronic Lung Disease* (CLD) Hemodynamically Significant CHD Palivizumab if ≤2 years old at start of RSV season

33. Apnea and RSV Apnea reported in 20% of hospitalized infants with RSV Risk factors for apnea –Age < 2-3 months –Prematurity May be presenting symptom but usually follows URI/LRI Recurrence rate 50% Mortality < 2% Levine et al. 2004

34. RSV and asthma link 40-50% of hospitalized bronchiolitics will wheeze again –Increased risk if > 12 months, atopy, eosinophilia Martinez FD, Godfrey S, 2003 Reijonen 1997 Ehlenfield 2000

35. Otitis media Otitis media a common complication –Cohort study of 42 infants with bronchiolitis 62% acute OM (tympanocentesis confirmed) 24% otitis media with effusion 14% normal throughout course Andrade et al. 1998 –Usual guidelines for AOM and OME apply

36. May there never develop in me the notion that my education is complete, but give me the strength and leisure and zeal continually to enlarge my knowledge. Moses Maimonides