1. RSV update 2011-2012 Chuck Hui MD FRCPC Pediatric Infectious Diseases Medical Director, RSV Prophylaxis clinic CHEO MOHLTC Ontario RSV Prophylaxis program advisory group member

2. Conflict of Interest Declaration Local investigator on two investigator driven, Abbott funded trial Member of the Canadian Pediatric Society Infectious Diseases Immunization Committee, the Committee to Advise on Tropical Medicine and Travel, and the Ministry of Health and Long Term Care of Ontario RSV Advisory Group

3. Objectives Address the AAP and CPS guidelines Identify the underlying assumptions and reasoning for the guidelines Contrast the guidelines with the MOHLTC 2011-2012 guideline To review the process for enrolling patients into the provincial RSV Prophylaxis for High-Risk Infants Program for the 2011-12 season To highlight changes to the enrolment form, enrolment process, drug ordering process and dosing schedule

4. What is RSV? RNA paramyxovirus –2 strains – A and B Often circulate concurrently Humans are only source Almost all children infected at least once by 2 yrs of age Re-infection is common Presents as a common URI in older children and adults

5. Epidemiology Annual season in Canada –November to April Viral shedding 3-8 days –May be longer in young and immunosuppressed Incubation period 2-8 days Supportive care, no good treatment

6. Burden of RSV in Young Children Population based study in children < 5yrs ER (2000-2004); Pediatric offices (2002-2004) 5067 enrolled; 919(18%) RSV infections; RSVH overall (11%) RSV associated with:18% ER visits 15% office visits Average RSVH: 17/1000 <6 months of age 3/1000 < 5 years of age Hall CB et al. NEJM 2009;360:588-598

7. Burden of RSV in Young Children Majority of children had no underlying medical illness Only risk factors identified: < 2 years of age, history of prematurity Under 5 yrs of age RSV results in:  1 of 38 visits to the ER  1 of 13 visits to a primary care (FD) office Hall CB et al. NEJM 2009;360:588-598

8. Global Burden Global burden of disease related to RSV in children younger than 5 years Systematic review 1995-2009 –33.8 million new episodes of RSV-associated ALRI occurred worldwide in children younger than 5 years –3.4 million episodes representing severe RSV-associated ALRI necessitating hospital admission –66 000–199 000 children younger than 5 years died from RSV associated ALRI in 2005 99% of these deaths occurring in developing countries Lancet. 2010 May 1; 375(9725)

9. Treatment Does not work… –Bronchodilators –Steroids –Hypertonic saline –Physiotherapy –Montelukast –Antibiotics Cochrane Database Systematic Review. 2006 Cochrane Database of Systematic Reviews. 2004 Cochrane Database Systematic Reviews 2007 NEJM 357;4, July 26, 2007 NEJM 360;20 May 14, 2009 British Medical Journal 1966;1:83–5

10. Prevention - Palivizumab Efficacy IMPACT Pediatrics 1998

11. When we don’t have anything else, we have a bunch of grumpy old ‘experts’ sitting around a table…

12. American Academy of Pediatrics (AAP) Background Statements 1998, 2003, 2009 Significant geographic variability in the US Third party payers AAP recommendations are meant only for American Pediatricians

13. American Academy of Pediatrics (AAP) 2009 Congenital Heart Disease (CHD) and Chronic Lung Disease (CLD) Unchanged Dosing maximal number of 5 doses for all geographic locations for infants with hemodynamically significant CHD, CLD, or birth before 32 weeks' 0 days' gestation maximal number of 3 doses for infants with a gestational age of 32 weeks 0 days to 34 weeks 6 days without hemodynamically significant CHD or CLD

14. American Academy of Pediatrics (AAP) 2009 32 0 to 34 6 Risk factors: –infant attends child care; or –1 or more siblings or other children younger than 5 years live permanently in the child's household Infants with a gestational age of 32 weeks 0 days through 34 weeks 6 days born within 3 months before the start of RSV season or at any time throughout the RSV season will qualify for prophylaxis under the new recommendations if they have at least 1 of these 2 risk factors. Previous recommendations required 2 of 5 risk factors Infants born from 32 weeks' 0 days' through 34 weeks' 6 days' gestation who qualify for prophylaxis under the new recommendations should receive prophylaxis only until they reach 90 days of age or a maximum of 3 doses (whichever comes first). This is a change from the previous recommendation for 5 months of prophylaxis

15. Risk factors for RSV hospitalization worldwide Exposure Age at start of RSV season Siblings Crowding at home Day care attendance Day care attendance of siblings Discharge between October and December Social Factors Breast feeding Physiologic Factors Low birth weight Male sex Family history of wheezing CLD Neurologic problems Birth order >2 nd Eur J Clin Microbiol Infect Dis (2008) 27:891–899

17. Variables in the final Logistic Regression Model (Risk Scoring Tool- PICNIC Study) Variable Score SGA (GA <10%)[ Yes/No ]12 Gender (Male/Female)11 Birth Month (Nov,Dec,Jan)25 Subject or Siblings in Day Care [ Yes/No ]17 Family History without eczema [ Yes/No ]12 >5 individuals in the home counting the subject [ Yes/No ]13 Two or more smokers in the house [Yes/No ]10 Total100

18. Only 3 doses? McCormick J, Pediatr Pulmonol. 2002;34:262-266.

20. Canadian Paediatric Society (CPS) Background Previous position statements 1999, 2003, 2009 Updated 2011 GRADE evidence based assessment Cost-effectiveness assessment

21. Canadian Paediatric Society (CPS) 2011 Congenital Heart Disease (CHD) and Chronic Lung Disease (CLD) Criteria – unchanged Recommendation –receive up to five doses of palivizumab (strong recommendation/high-quality evidence) Remarks - Decisions regarding the use of palivizumab in this and all other high-risk groups need to take competing local priorities for funding into account, which may allow for use of palivizumab in only selected infants in this cohort Values and preferences - This recommendation places a high value on preventing hospitalizations in these vulnerable infants despite the high cost of palivizumab

22. Canadian Paediatric Society (CPS) 2011 Infants in remote communities who would require air transportation for hospitalization: Recommendation #1 –Consideration should be given to administering up to five doses of palivizumab for all infants born before 36 weeks’ GA and younger than six months of age at the beginning of the RSV season (strong recommendation/high-quality evidence). Remarks. It is not clear whether this recommendation should apply only to Inuit infants, to all Aboriginal infants or to all infants in remote communities. The incidence of RSV hospitalization in a remote community in previous years should be taken into account when making this decision. A practical issue is that the onset and duration of RSV season is unpredictable in the Far North. Occasionally, more than a year goes by between RSV seasons (Michael Young, personal communication). To save money, one would delay administering palivizumab until there is confirmed RSV activity in a remote community. The attendant risk is that significant spread may have already occurred. Values and preferences. This recommendation places high value on preventing RSV hospitalizations because of the high cost of such admissions.

23. Canadian Paediatric Society (CPS) 2011 Recommendation #2 –Consideration may be given to administering up to five doses of palivizumab to term Inuit infants younger than six months of age in communities with documented persistent high rates of RSV hospitalizations (weak recommendation/no evidence) Remarks. There is no direct evidence of the efficacy of palivizumab in term Inuit infants, but observational studies in preterm Inuit infants and in term infants with other risk factors suggest that there would be efficacy. There are insufficient data regarding the morbidity from RSV to recommend use in term infants in other Northern populations

24. Canadian Paediatric Society (CPS) 2011 32 weeks 0 days to 35 weeks 6 days’ GA: Recommendation #1 –A panel of experts should be convened in each province or territory (weak recommendation/no evidence) to establish a policy for these infants Remarks - The upper limit of GA may need to be determined by available funding Recommendation #2 –The panel may want to use the American Academy of Paediatrics (AAP) criteria, or the Canadian risk-scoring tool, to select infants eligible for palivizumab prophylaxis (weak recommendation/no evidence) Remarks. It seems likely that applying the AAP criteria would result in more infants being prophylaxed, but for a shorter time. It is impossible to predict the relative impact on hospitalizations

25. Canadian Paediatric Society (CPS) 2011 Recommendation #3 –Irrespective of the criteria chosen, giving the last dose at three months’ chronological age should be considered in this GA cohort (weak recommendation/no evidence) Remarks. This recommendation is an attempt to balance cost and benefit, and is designed to protect infants at greatest risk of hospitalization

26. Canadian Paediatric Society (CPS) 2011 Immunodeficiencies, Down syndrome, cystic fibrosis, upper airway obstruction or a chronic pulmonary disease other than CLD: Recommendation –Palivizumab is not routinely recommended. However, it may be considered for children younger than 24 months of age (because they may not yet have encountered their first RSV infection) who are likely to be exposed to RSV and are on home oxygen, have had a prolonged hospitalization for severe pulmonary disease, or are severely immunocompromised (weak recommendation/no evidence) Remarks. This recommendation should be expanded to include more children with pulmonary disease if evidence becomes available that avoidance or delay of the initial RSV hospitalization impacts long-term pulmonary function How should palivizumab be administered? Recommendation –Each jurisdiction should optimize processes to implement these recommendations in the most cost- effective manner. Well-organized palivizumab clinics decrease drug wastage (strong recommendation/no evidence)

27. OK, tell me what I need to know!!!!!!

28. MOHLTC Ontario 2011-2012 Background Administered through the Exceptional Access Program (EAP) MOH RSV Advisory Group RSV Adjudicators

29. MOHLTC Ontario 2011-2012 Background Administered through the Exceptional Access Program (EAP) MOH RSV Advisory Group RSV Adjudicators NO CHANGE!

30. MOHLTC Ontario 2011-2012 Prematurity ≤ 32 completed weeks gestation and aged ≤ 6 months at the start of, or during, the local RSV season; or 33 – 35 completed weeks gestation and aged ≤ 6 months at the start of, or during the local RSV season, who DO NOT live in isolated communities AND have a Risk Assessment Tool Score of 49 to 100; or 33 – 35 completed weeks gestation and aged ≤ 6 months at the start of, or during the local RSV season, and who LIVE IN isolated communities where paediatric hospital care is not readily accessible and ambulance transportation for hospital admission is required;

31. MOHLTC Ontario 2011-2012 CHD/BPD/Down Syndrome < 24 months of age with Down Syndrome / Trisomy 21; or < 24 months of age with BPD/CLD and who required oxygen and/or medical therapy within the 6 months preceding the RSV season; or < 24 months of age with hemodynamically significant (HS) cyanotic or acyanotic congenital heart disease (CHD); requiring corrective surgery or is on cardiac medication for hemodynamic significant disease

32. MOHLTC Ontario 2011-2012 Special Requests Assessed on an individual basis Requires letter from requesting physician and an ID + Respirologist signature Potential diagnoses: –Upper airway anomalies, severe immunodeficiencies, neuromuscular diseases, etc.

34. START: Ontario RSV Medical Advisory Group has recommended November 14 th, 2011 as season start END: April 1 st, 2012 or when season is declared ended locally, whichever comes first Season is considered on-going when there are 2 or more local RSV hospitalizations / week for two consecutive weeks SEASON START / END

35. Out of season process From May 1 st – November 1 st, 2011 NICUs identify patients that qualify for prophylaxis in a log book and send the referrals to CHEO RSV Coordinator monthly Enrolment forms / appointment arrangements completed by CHEO RSV Coordinator

36. During season (November – March) NICUs enroll their own patients with Abbott First dose of Synagis  is administered prior to discharge from NICU Follow up appointments may be made by NICUs by directly contacting CHEO’s Ambulatory Care Call Center (613-737-2222) NICUs fax / email Abbott reference no. and patient info to CHEO RSV Coordinator

37. Summary of Changes: 2011-12 1.Enrolment process 2.Enrolment forms 3.Drug ordering process 4.Dosing schedule

38. ENROLMENT PROCESS All enrolments will now be processed and reference numbers provided by Abbott The ministry’s coordinator will review all those with BPD/CHD criteria and the special requests Enrolment forms are faxed directly to the Synagis  Coordinator at Abbott Canada (1-800-513-7337)

39. ENROLMENT Turn around time is usually one business day (prematurity criteria) For enrolments under the BPD / CLD and CHD criteria and Special Requests, turn around time is three business days

40. ENROLMENT FORMS Since the form is now going to Abbott Canada and not MOHLTC, NO personal health identifiers (name, address, OHIP no.) are to be provided Fields for the child’s full name and OHIP no. have been removed from the enrolment forms Really simplified – one form for all Risk Assessment Tool is now part of the enrolment form on page 2

46. DRUG ORDERING PROCESS Shipment orders directed to Synagis  Coordinator at Abbott (fax: 1-800-513-7337) For NICUs who will give the first dose in November, it can be ordered using enrolment form (Section 7) All subsequent doses should be ordered on Synagis  order form Shipments occur within 24 hours, except for orders placed on Fridays, weekends and stat holidays

48. The ministry requests that all providers be mindful of costs such that drug wastage is minimized When an entire vial is not required for a patient, residual product may be used for a second patient if administered within 6 hours from the time of reconstitution under controlled and aseptic conditions $752.26 $1,504.51

49. DOSING SCHEDULE (as per Ontario’s RSV Medical Advisory Group DoseWeek #Month 10Mid-November 23December 37January 411February 515March

50. ENROLMENT FORMS (on line) http://www.health.gov.on.ca/english/providers/progr am/drugs/funded_drug/fund_respiratory.aspx

52. CHEO RSV Clinic Fridays (primarily) in clinic C1 on the main floor of CHEO First clinic: November 18, 2011 Team for the 2011-12 season: Josée Chiasson, RPN Chantal Horth, RC Carolyn Lawrence, RN Joanne Matton, PSC / Alyssa Long, PSC Barbara Murchison, RC Allyson Shephard, RN Chuck Hui, MD (Medical Director) Lisa Nesbitt (Clinical Manager)

53. CONTACT US By email: rsvclinic@cheo.on.carsvclinic@cheo.on.ca By telephone: 613-737-7600 Ext 2406 (Coordinator) By fax: 613-738-4329