1. Pertussis in the UK: The more you look the more you find Dr Natasha S. Crowcroft Health Protection Agency and the Ontario Ministry of Health and Long Term Care, Central Public Health Laboratory

2. Outline Many countries (Canada The Netherlands, France, Germany, USA) report increases in pertussis Fewer doses of pertussis vaccine are given in UK Why? –How is evidence used to make policy? Any relevance for Ontario?

3. What’s the evidence base? Routine surveillance data –Notifications –Laboratory reports –Hospitalisation data –Death certificates –Serosurveillance –Vaccine coverage –Adverse events Mathematical and economic modelling Special studies –Clinical studies in infants and adults

4. Pertussis burden is hard to measure Crowcroft NS et al, Lancet Infect Dis. 2003 Jul;3(7):413-8

5. Uncertainty is seen in the sensitivity analysis Varied: –proportion of children infected by each age –vaccine efficacy against infection or death –case fatality ratio Cases 24-54 million Deaths 7-755 thousand

6. Whooping cough cases and vaccine coverage England and Wales 1940-2001 Immunisation introduced

7. Under-notification Estimates in epidemic periods: ~ 1 in 10 cases are notified Ratio of hospitalisations to notifications to laboratory reports in infants <3 months –2-3 hospital admissions for every notification –3 notifications for every laboratory report Ratio of hospitalisations to notifications is reversed in older ages Van Buynder et al Epidemiol Infect 1999

11. Paediatricians worried…. Ranganathan S, Tasker R, Booy R, Habibi P, Nadel S, Britto J. Pertussis is increasing in unimmunized infants: is a change in policy needed? Arch Dis Child. 1999 Mar;80(3):297-9

12. Paediatric intensive care study 1998-2000 Infants under 5 months of age admitted to PICU with: – Respiratory failure – Apnoea and/or bradycardia – Acute life threatening episode Excluded: –Persistent pulmonary hypertension of the new- born, meconium aspiration, hyaline membrane disease

13. Burden of pertussis 17% (24/143) had laboratory-confirmed pertussis 23% (33/142) had pertussis including epidemiologically-linked cases 4% (6/142) were culture positive Pertussis was clinically suspected on admission in 28% infants

14. Culture, PCR, serology All culture positive cases were PCR positive Of 12 PCR positive, 7 were negative by serology Of 8 serology positive 3 were negative by PCR Methods of diagnosis are complementary

15. Other features Length of stay on PICU mean 5.7 days Stay in hospital mean 15.6 days Two deaths 11 had co-infection with RSV

16. Infants with pertussis compared to those without pertussis Not more likely to cough More apnoeas (p=0.03) More likely to whoop (p<0.005) Longer duration of cough –15 versus 11 days p=0.003 Higher lymphocyte count (p=0.003)

17. Pertussis vaccination Most cases unvaccinated or partially vaccinated because of their age 91% (30/33) adult contacts of cases vaccinated 97% (29/30) child contacts of cases vaccinated –Same as contacts of non-cases

18. Source of infection: Who was the first case in the family? First caseProportion confirmed Parent11/13 Sibling2/10 Baby or co-primary8/10 Total21/33

19. Pertussis in the community Study in one general practice in UK, 1996- 7 investigated (culture/serology) all presentations of whooping cough or acute tracheitis in >4y Pertussis found in all age groups Highest in 5-14y (45%) and 15-44y (28%) Observed incidence 330/100 000 Notifications <4/100 000 in the same period Miller et al Commun Dis Public Health 2000;3:132-4

20. Overlap Between Deaths in Enhanced pertussis Surveillance System (ES), ONS Mortality Database (ONS), and Hospital Episode Statistics (HES) 1994-9 Total 33 deaths observed –ONS = 18 –ES = 22 –HES = 9 Estimate true number is 46 (95% CI 37-71) or ~ 9 per yr Official statistics detected 18/33 (54%) observed or 18/46 (39%) estimated deaths Crowcroft et al Arch Dis Child 2002;86:336-8

21. Outcome of analysis in 2001 Morbidity from pertussis under-recognised PCR and serology increase ascertainment Adults and children introduce pertussis into families, even fully vaccinated families Health economic analysis of options Outcome: –PCR and serology diagnostics provided by Public Health Laboratory –Pre-school booster in 2001 Crowcroft et al Arch Dis Child. 2003 Sep;88(9):802-6

22. Summary of changes to the pertussis vaccination programme in the UK

23. Current vaccination schedules UK and Canada Age InfantsDTaP-IPV (2,4,6 months) DTaP-IPV (2,3,4 months) 18 monthsDTaP-IPVnone Pre-schoolDTaP-IPV (4-6 years) DTaP-IPV (3.5-5 years) TeenagersdTaPnone AdultsSingle dosenone

24. Questions for the UK in 2007 What was the impact of the pre-school booster introduced in 2001? Are boosters needed for older children and adults? What is the aim of the vaccination programme?

25. Notifications, deaths and vaccine coverage by 2 nd birthday **provisional Accelerated schedule Pre-school booster

26. Notification rate per 100,000 population (England and Wales) Accelerated schedule Pre-school booster

27. Pertussis hospital admission rates by age, 1998-2006 Pre school booster

28. Total laboratory confirmed cases by age group and year – all methods Pre school booster Introduction of testing by serology and PCR

29. Incidence of culture confirmed cases of pertussis in all age groups

30. Laboratory confirmed cases by serology by age and year

31. Rates of pertussis in infants <3 months in different systems

32. Notifications and deaths from pertussis **provisional

33. Deaths from all sources (not reconciled) *provisional data

34. Immunisation status of laboratory confirmed cases aged ≥6 months

35. Detection of B. pertussis: traditional methods Culture: traditional ‘gold standard’ poor sensitivity slow isolates useful for reference

36. Pertussis Serotypes

37. Enhanced methods: PCR Correct samples: nasopharyngeal aspirates or swabs Criteria: – Child age =< 1 year admitted to PICU or paediatric ward with respiratory illness compatible with pertussis

39. Enhanced methods: serology Correct samples: not less than 400ul of serum Criteria: Single serum sample taken >2 weeks after onset for any individuals with prolonged cough without a recent history of vaccination

40. Enhanced methods: Oral fluid assay Correct sample: oral fluid Criteria: to be used following notification (when serum specimen is not available) 80% sensitivity compared to serum assay

41. Oral fluid: Pilot study Aim: to improve evidence base for pertussis vaccination policy decision- making through; –improved case ascertainment, –increased rates of confirmation and –more detailed information on notified cases of pertussis Two areas: Leicestershire and Thames Valley –Some swabs mailed to patients, some used by family doctor

42. Oral fluid results May-July 2007 Age group Pertussis confirmed / Oral fluid received < 1 yr4/11 1-913/48 10-1411/13 15+19/37 Total48/109 (43%)

43. Outcome of pilot study Oral fluid follow-up of notified pertussis cases improves laboratory confirmation rates Yields extra information about cases No excessive burden on the workload of clinicians or public health departments Oral fluid is more convenient to collect than serum Since June 2007, available routinely in England

44. Impact of vaccination on pertussis transmission When coverage was low in the UK, epidemic cycles continued at 3-4 yearly intervals –The inter-epidemic period has not lengthened greatly Reducing transmission of pertussis may reduce boosting of immunity and increase disease severity (Aguas et al Lancet Infect Dis 2006)

45. Pertussis: increasing disease as a result of reducing transmission Aguas et al Lancet Infect Dis 2006

46. Something to worry about… Vaccine efficacy in preventing secondary cases in households estimated at 85% (46-95) (Preziosi & Halloran Vaccine 2003) More severe cases are more infectious If vaccinating 14-15 year olds then immunity will wane over 10 years expect infections around 10 years later –25 years and over Could future parents be more infectious? Need robust models for better predictions

47. Conclusions for UK The current vaccination schedule seems effective But pertussis is a challenge, and cannot be eradicated by current vaccines Different immunisation strategies have direct and indirect (herd immunity) effects –Reducing incidence in one age group can lead to increases in another Need for good surveillance

48. Considerations for Ontario How well is pertussis controlled in Ontario? Current surveillance in Ontario relies on clinical reports, culture and PCR diagnosed cases – what about other diagnostic methods? –Serology –Oral fluid Are other surveillance and disease burden studies needed? –eg data linkage, deaths, modelling

49. Acknowledgments Thanks to Helen Campbell, Norman Fry, Tim Harrison, Elizabeth Miller, Robert George, Nalini Rawal, Karen Wagner, Joanne White, Tony Nardone, Andrew Vyse And to Jean-François Aguilera, Katy Davison, John Edmunds, Nigel Gay, Scott Halperin, Herb Hethcote, Mark LaForce, Richard Pebody, Angie Rose, Gaston de Serres, Francois Simondon