1. Bronchiolitis Epidemiology, Testing, & Management Jesse Sturm, MD Fellow, Pediatric Emergency Medicine Emory University November 5, 2008

2. Outline DefinitionsEpidemiology Clinical Manifestations Testing and Diagnosis Non-pharmacologic management Pharmacologic options – what’s the evidence? Guidelines Interesting Studies

3. Definitions Bronchiolitis – clinical description –Acute respiratory illness –Inflammation of small airways → wheezing –Typically: first episode of wheezing in child younger than 2yo with signs of viral URI & no other explanation for wheezing such as pneumonia or atopy Respiratory syncytial virus (RSV) is principal agent –Para influenza, human metapneumovirus, adenovirus, influenza, rhinovirus, coronavirus, mycoplasma

4. RSV specific RNA virus In infants < 2yo, 60% of lower respiratory tract infections due to RSV Invades epithelial cells of nasopharynx to mucosa of lower airway –Moves by cell to cell transfer –RSV kills resident cells –Mononuclear cells, mucous, sloughed epithelium clump in airway –Causes turbulent airflow, wheezing, hyperinflation, atelectasis, V/Q mismatch

5. Infection of epithelial cells in respiratory tract. Recombinant RSV expressing green fluorescence.

6. RSV Epidemiology Primarily between 2-8 months –50% of all children during first 2y of life –95% have seroconversion by 3yo Overall seasonal pattern Nov – March –Peak in Jan-Feb, duration of 15-16 weeks –Southern US slightly earlier onset –Year round illness in equatorial regions

7. Epidemiology ~ 5% of children with bronchiolitis require hospitalization Infants < 6 months account for 57% of hospitalizations Increasing hospitalization rate –Among children < 1yo bronchiolitis accounted for 16.4% of admission in 1996 (compared to 5.4% in 1980) Mortality rates 2/100,000 live births in US –Deaths 200-500 annually –Unchanged mortality rate in last 20 years –Increased risk of death if low birthweight, congenital heart disease, large family, unmarried mother, tobacco use during pregnancy, low Apgar score at 5min

8. Medical Costs Annual hospitalizations < 2yo ~ 150,000 Mean length of stay 3.3 days –Mean cost/hospitalization = $3800 –Total direct costs = $543 million per year Pelletier AJ, Mansbach JM, Camargo CA. Direct medical costs of bronchiolitis hospitalizations in the United States. Pediatrics. 2006, 118(6): 2418-23.

9. Clinical Manifestations Constellation of symptoms beginning with cough, coryza in children < 2yo –Progresses over 2-5 days to nasal flaring, wheezing, grunting, retractions Wheezing usually predominates –Fever in 60% –Typically present for medical care at day 3-6 Complications include apnea, dehydration, respiratory failure, rarely bacterial superinfection

10. Differential Diagnosis Infant with acute onset wheezing with URI –Asthma – typically recurrent pattern, more responsive to bronchodilators –Pneumonia –Congestive heart failure –Foreign body aspiration –Wheezing from GERD –Cystic Fibrosis

11. Diagnosis CLINCAL DIAGNOSIS Direct Immunoflouresence tests exists for RSV and other causative viruses. –Sensitivity 80-90% on rapid tests from nasal wash –May be useful if specific antiviral therapy available (influenza), would help avoid antibiotic therapy, or needed to cohort patients in hospital

12. Ancillary Tests Routine CXR, CBC, Viral antigen testing not necessary and often do not affect clinical outcome –Metanalysis of 82 articles by Bordley et al. No studies stated whether knowing causative agent affected clinical outcomes Randomization of children with bronchiolitis to CXR or not results in more Abx to those given CXR, mean recovery time and outcomes were the same Routine use of CBC does not help guide therapy or affect outcomes Bordley, WC, Viswanathan, M, King, VJ, et al. Diagnosis and testing in bronchiolitis: a systematic review. Arch Pediatr Adolesc Med 2004; 158:119.

13. Ancillary Tests CXR indicated –focal exam –cardiac murmur –not responding to therapy

14. Determining Disease Severity Severe disease – signs/symptoms associated with poor feeding, respiratory distress characterized by tachypnea, nasal flaring, and hypoxemia –Substantial variability in severity assessment scoring, even in research settings –Have higher likelihood of requiring IVF, supplemental oxygen, and intubation –Risk factors: oxygen sats < 95%, age < 3months, RR > 70, atelectasis on CXR RR > 70, atelectasis on CXR Limited, conflicting evidence relating these to outcomes

15. Disease Course Respiratory status typically improves in 2-5 days Wheezing can persist for up to 4-5 weeks Telephone survey of 486 discharged patients –60% difficulty feeding, sleeping on day of d/c –20% persistent symptoms on day 5 after d/c –Coughing and wheezing persisted in 30% 4-6 days after d/c Robbins, JM, Kotagal, UR, Kini, NM, et al. At-home recovery following hospitalization for bronchiolitis. Ambul Pediatr 2006; 6:8.

16. Disease Complications Most common apnea, respiratory failure, secondary bacterial infection –16% of all RSV bronchiolitis admissions need ICU care –25% if concurrent history of underlying CHD, BPD, immunosupression

17. Risk of Apnea In study of 691 hospitalized infants 2.7% (n=19) infants developed apnea –18 of 19 had at least one high risk criteria Full term < 30 days of age Preterm birth <37 wks and < 48 wks postconception Report of apnea at home Willwerth B, Harper MB, Greenes DS. Clincal Decision Rule to identify infants with bronchiolitis at low risk for apnea. Pediatric Res 2001; 49:83A.

18. Respiratory failure Occurs in 14% of infants < 1yo If mechanical ventilation and RSV: –high rates of secondary bacterial pneumonias, 40% by tracheal aspirates and cultures (50% community acquired and 50% nosocomial) --- recommend empiric Abx Willson, DF, Landrigan, CP, Horn, SD, Smout, RJ. Complications in infants hospitalized for bronchiolitis or respiratory syncytial virus pneumonia. J Pediatr 2003; 143:S142.

19. Concurrent bacterial infection In prospective trial of 1248 patients with temp > 38.0, 38.0, < 60 days old N = 269 of patients (22%) were RSV + Therefore – especially for UTI rate of serious bacterial infection are appreciable Treat fever as normally would for age, +/- LP Levine, DA, Platt, SL, Dayan, PS, et al. Risk of serious bacterial infection in young febrile infants with respiratory syncytial virus infections. Pediatrics 2004; 113:1728. RSV + RSV - P value Overall SBI 7%12.5%<0.05 UTI5.4%10.1%<0.05 Bacteremia1.1%2.3%NS Meningitis-0.9%NS

20. Initial Management Primarily supportive Adequate hydration, nasal saline drops and bulb suctioning –Little evidence to support deep nasal suctioning in the ER or inpatient setting –Supplemental oxygen?

21. What saturation is significant? Shaw K et al. demonstrated that sats <95% may predict disease severity, n= 213 Prospective study of 689 patients, prolonged hypoxia <90% was risk factor for: –Prolonged hospitalization > 5day: OR 1.3 (1.2-1.5) –ICU admission: OR 3.7 (1.9-6.9) –Ventilation: OR 3.9 (1.6-9.5) Shaw K et al. Outpatient assessment of infants with bronchiolitis. Am J Dis Child, 145: 151-155, 1991. Wang EE. Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) prospective study of risk factors and outcomes in patients hospitalized with respiratory syncytial viral lower respiratory tract infection. Jounral Pediatrics, 126: 212-0, 1995.

22. Supplemental Oxygen Some evidence from clinical studies that intermittent or chronic hypoxia 90-94% may have long term cognitive effects If PCO2 >55 even if normal saturations may require mechanical ventilation Bass, JL, Gozal, D. Oxygen therapy for bronchiolitis. Pediatrics 2007; 119:611. Bass, JL, Corwin M, Gozal D, et al.The effectof chronic or intermittent hypoxia on cognition in childhood: a review of the evidence. Pediatrics 2004; 114:805.

23. Supplemental Oxygen Oxygen as needed for Pox < 90% by AAP guidelines –OxyHgb dissociation curve: “in absence of resp distress and feeding difficulties gain little benefit from increasing PaO2 with supplemental oxygen above 90%” –Fever, acidosis raise threshold as larger ↓ in PaO2 for same ↓ sats Bass, JL, Gozal, D. Oxygen therapy for bronchiolitis. Pediatrics 2007; 119:611. Bass, JL, Corwin M, Gozal D, et al.The effect of chronic or intermittent hypoxia on cognition in childhood: a review of the evidence. Pediatrics 2004; 114:805.

24. Pharmacologic Options BronchodilatorsEpinephrineGlucocorticoidsAntivirals Advanced Therapies –Heliox, Surfactant, 3% saline nebs, synagis

25. Nebulized Bronchodilators Difficult to determine which pts predisposed to airway hyper reactivity vs isolated bronchiolitis Cochrane review of 8 RCT of 394 children –At most 1 in 4 children treated have transient improvement –No effect on overall course of illness or avoidance of hospitalization AAP recommends trial and evaluation before and after treatment to assess response –Weigh cost benefit, but reasonable to treat responders Zorc, JJ. Bronchiolitis trial and tribulation. Acad Emerg Med 2008; 15:375. Diagnosis and management of bronchiolitis. Pediatrics 2006; 118:1774. Gadomski, AM, Bhasale, AL. Bronchodilators for bronchiolitis. Cochrane Database Syst Rev 2006; 3:CD001266.

26. Pharmacologic Options BronchodilatorsEpinephrineGlucocorticoidsAntivirals Advanced Therapies –Heliox, Surfactant, 3% saline nebs, synagis

27. Nebulized Epinephrine Demonstrated slightly better clinical effect than albuterol in side by side RCT –Cochrane review: “Some evidence to suggest that epinephrine may be favorable to albuterol and placebo in outpatient setting” –Does not affect hospitalization rates or ER length of stay –AAP guidelines state “epinephrine may be the preferred bronchodilator for trial in the ER and hospitalized patients” –No data on home use, safety Hartling, L, Wiebe, N, Russell, K, et al. Epinephrine for bronchiolitis. Cochrane Database Syst Rev 2004; :CD003123. Diagnosis and management of bronchiolitis. Pediatrics 2006; 118:1774.

28. Pharmacologic Options BronchodilatorsEpinephrineGlucocorticoidsAntivirals Advanced Therapies –Heliox, Surfactant, 3% saline nebs, synagis

29. Glucocorticoids Cochrane review of 1200 patients in 13 trials showed no significant difference in length of stay, admission rates, or readmission rate No data to suggest efficacy in first episode of wheezing May be of benefit in patients with CLDz or previous episodes of wheezing (at risk for asthma) Corneli, HM, Zorc, JJ, Majahan, P, et al. A multicenter, randomized, controlled trial of dexamethasone for bronchiolitis. N Engl J Med 2007; 357:331. Patel, H, Platt, R, Lozano, J, Wang, E. Glucocorticoids for acute viral bronchiolitis in infants and young children. Cochrane Database Syst Rev 2004; 3:CD004878.

30. Pharmacologic Options BronchodilatorsEpinephrineGlucocorticoidsAntivirals Advanced Therapies –Heliox, Surfactant, 3% saline nebs, synagis

31. Antivirals Ribavirin inhibits replication of RNA and DNA viruses, nucleoside analog –11 RCT’s: 7 show modest benefit in oxygenation, length of stay, 4 show no benefit –No utility in otherwise healthy children –Minimal benefit in children with immunosupression or signif cardiopulmonary disease Cost for therapy ~ $1000/day up to 7 days Mutagenic, gonadotoxic, potentially tumor producing so a significant risk for healthcare workers in aerosolized form

32. Pharmacologic Options BronchodilatorsEpinephrineGlucocorticoidsAntivirals Advanced Therapies –Heliox, Surfactant, 3% saline nebs, synagis

33. Advanced Therapies Heliox: mixed results in several RCT’s, but does decrease duration of ICU stay (5.4 to 3.5 days) RSV-specific IVIG (synagis): no benefit in acute phase Surfactant: may shorten duration of ventilation & ICU stay Hypertonic saline: in hospitalized patients NS vs 3% saline nebs q2hr x 3, decreased length of stay in 3% group (2.6 vs 3.5 days) (n=96) –Facilitates removal of inspissated mucus through osmotic hydration, disrupts mucus strand cross-linking, & reduces edema Tibby, SM, Hatherill, M, Wright, SM, et al. Exogenous surfactant supplementation in infants with respiratory syncytial virus bronchiolitis. Am J Respir Crit Care Med 2000; 162:1251. Luchetti, M, Casiraghi, G, Valsecchi, R, et al. Porcine-derived surfactant treatment of severe bronchiolitis. Acta Anaesthesiol Scand 1998; 42:805. Vos, GD, Rijtema, MN, Blanco, CE. Treatment of respiratory failure due to respiratory syncytial virus pneumonia with natural surfactant. Pediatr Pulmonol 1996; 22:412. Mandelberg, A, Tal, G, Witzling, M, et al. Nebulized 3% hypertonic saline solution treatment in hospitalized infants with viral bronchiolitis. Chest 2003; 123:481. Sarrell, EM, Tal, G, Witzling, M, et al. Nebulized 3% hypertonic saline solution treatment in ambulatory children with viral bronchiolitis decreases symptoms. Chest 2002; 122:2015. Kuzik, BA, Al-Qadhi, SA, Kent, S, et al. Nebulized hypertonic saline in the treatment of viral bronchiolitis in infants. J Pediatr 2007; 151:266. Calogero, C, Sly, PD. Acute viral bronchiolitis: to treat or not to treat-that is the question. J Pediatr 2007; 151:235.

34. Decision to Hospitalize Severe disease –Toxic appearance, poor feeding, lethargy, dehydration –Moderate to severe respiratory distress Nasal flaring, retractions, RR>70, dyspnea, cyanosis –Apnea in ER or report at home –Hypoxemia 45 AAP guideline do not recommend supplemental oxygen unless < 90% but give no guidelines on hospitalization threshold –Poor home environment As indicated by multiple ER/MD visits –Significant underlying medical condition (CLDz, CHDz) –Age < 30 days, especially if prematurity

35. Discharge Criteria No established guidelines Consensus opinion at Cincinnati Children’s Hospital –RR < 70 –Caretaker can perform effective bulb suctioning –Stable without supplemental oxygen, >90% –No need for IVF –Resources adequate at home –PCP notified, identified and able to followup

36. Cincinnati Guidelines

38. Education Expected clinical course: –Median 12 days illness –20% symptomatic at 3 wks –10% symptomatic at 4 weeks Proper technique to suction nose

39. Prevention Strategies Synagis –monoclonal Ab against RSV F glycoprotein –Given monthly IM from Nov for 5 months Infants < 24 months with CLDz, prematurity or required diuretics, home oxygen in 6 months prior to start of season Infants < 32 weeks gestation Children < 2yo with clinically significant CHDz –Reduction in hospitalization 39-79% in large RCT’s –Most cost studies do not show cost effectiveness

40. Other interesting studies Influence of pulseox and RR on admission rate A randomized trial of home oxygen therapy from the emergency department for acute bronchiolitis Determining Severity of Bronchiolitis in PED: A Clinical Decision Rule

41. Bronchiolitis management preferences and the influence of pulse oximetry and respiratory rate on the decision to admit, Mallory MD et al. - AAP section of EM survey n = 519 PEM physicians - AAP section of EM survey n = 519 PEM physicians - Identical clinical vignettes given with variation in SpO2 and RR, not dehydrated, non toxic, 6 month old, temp 101 - Would you admit patient? -Pulseox stronger predictor of admission than RR (not signif in RR) - Perhaps increased hospitalization rates in last 20 years reflects over- reliance on pulseox data Mallory, MD, Shay, DK, Garrett, J, Bordley, WC. Bronchiolitis management preferences and the influence of pulse oximetry and respiratory rate on the decision to admit. Pediatrics 2003; 111:e45. Sp02 = 94% Sp02 = 92% RR = 50 RR = 65 RR = 50 RR = 65 43%58%83%85%

42. A randomized trial of home oxygen therapy from the emergency department for acute bronchiolitis, Bajaj L et al. Children 2-24 mo with bronchiolitis and hypoxia <=87% oxygen sat after 8 hrs obs in the ER –Randomized to home oxygen or admission –N = 53 to home, N = 39 to admission –Only 1 discharged patient returned (cyanotic spell at 36hrs post discharge) –Low complication rate cannot determine safety, but satisfaction was high Pediatrics. 2006 Mar;117(3):633-40

43. Platform Presentation PAS 2008 Determining Severity of Bronchiolitis in PED: A Clinical Decision Rule 8 sites in Canada over 3 years Inclusion: bronchiolitis and < 1 yo Excluded if previous wheezing or albuterol use –Predictors: Age, sex, environmental factors, respiratory distress index, PMHx and others (22 variables) –Severe bronchiolitis = intubation, apnea, death, ICU admission Results: –1554 enrolled, mean age 22 wks, 80% white, 4% previously intubated, –27% febrile, mean resp index 8.2, sats <92% in 9% –31% admitted, 2.3% with severe bronchiolitis –18 to ICU from PED, 5 to ICU from floor Severe bronchiolitis more likely if HR>180, RR>80, Sats 180, RR>80, Sats<88% –Sens to detect severe bronchiolitis 100%, Spec 81%

44. Summary Bronchiolitis has a high disease burden Self limited disease with few effective management options –Reasonable to trial albuterol or epinephrine and continue if responds Treatment algorithms and admission criteria often dictated by consensus opinion Large ongoing studies needed to further define risk factors for progression –Oxygen sats, RR, Age