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

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?

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

Pertussis burden is hard to measure

WHO Region, Cases in millions

African American Eastern Mediterranean European South East Asian Western Pacific

Total Total cases

12.8 5.3 5.9 3.4 12.5 8.6

48.5

Crowcroft NS et al, Lancet Infect Dis. 2003 Jul;3(7):413-8

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

Whooping cough cases and vaccine coverage England and Wales 1940-2001 Immunisation introduced 200 180 160 140 120 100 80 60 40 20 0 1940 1950 1960 1970 Year 1980 1990 100 90 2000 0 20 10 80 70 60 50 40 30

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

3% 2% 1% 0% 7% 6% 5% 4% 1-4

Proportion of samples with high PT IgG titres England & Wales, 1996

5-9 100-199 200+ 10-14 15-19 20-29

Age Group

30-39 40-59 60+

Quarterly notification rates of whooping cough (all ages and infants aged 0-2 months, per 100 000 population) and pertussis vaccine coverage: England and Wales, 1982-98 800 700 600 500 400 Notification rate (age <3 months) Notification rate (all ages) Vaccine coverage 300 200 100 0 82 83 84 85 86 87 88 Reproduced from

CDR Weekly

volume 9 no23, p201 89 90 Year 91 92 93 94 95 96 97 98 50 40 30 20 10 0 100 90 80 70 60

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

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

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

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

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

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)

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

Source of infection: Who was the first case in the family? First case Parent Proportion confirmed 11/13 Sibling Baby or co-primary 2/10 8/10 Total 21/33

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

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

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

Summary of changes to the pertussis vaccination programme in the UK

Current vaccination schedules UK and Canada Age Infants 18 months Pre-school Teenagers Adults DTaP-IPV (2,4,6 months) DTaP-IPV DTaP-IPV (4-6 years) dTaP Single dose DTaP-IPV (2,3,4 months)

none

DTaP-IPV (3.5-5 years)

none none

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?

Notifications, deaths and vaccine coverage by 2 nd birthday

100,000 90,000 80,000 70,000 60,000 50,000 40,000 30,000 20,000 10,000 0 Accelerated schedule Pre-school booster 100 90 80 70 60 50 40 30 20 10 0 19 70 19 72 19 74 19 76 19 78 19 80 19 82 19 84 19 86 19 88 19 90 19 92 19 94 19 96 19 98 20 00 20 02 20 04 20 06 ** Deaths Notifications coverage by 2nd birthday

**provisional

Notification rate per 100,000 population (England and Wales)

350 300 250 200 150 100 Accelerated schedule Pre-school booster 50 0 19 88 <3m 19 90 3-5m 19 92 19 94 6-11m 19 96 1-4 yrs 19 98 20 00 5-9 yrs 20 02 10-14 yrs 20 04 20 06 15+ yrs

350 300 250 200 150 100 50 0

Pertussis hospital admission rates by age, 1998-2006

Pre school booster 1998 1999 2000 a. <3m 05-09 yrs 2001 b. 3-5m 2002 10-14 yrs 2003 c. 6-11m 15+ 2004 2005 01-04 yrs 2006

Total laboratory confirmed cases by age group and year – all methods

350 300 250 200 150 100 Pre school booster Introduction of testing by serology and PCR 50 0 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 a. < 3 months e. 5-9 years b. 3-5 months f. 10-14 years c. 6-11 months g. 15+ years d. 1-4 years

Incidence of culture confirmed cases of pertussis in all age groups

200 150 100 50 0 19 94 19 95 19 96 19 97 19 98 19 99 20 00 20 01 20 02 20 03 20 04 20 05 20 06 a. < 3 months d. 1-4 years g. 15+ years b. 3-5 months e. 5-9 years c. 6-11 months f. 10-14 years

Laboratory confirmed cases by serology by age and year

200 150 100 50 0 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 a. < 3 months e. 5-9 years b. 3-5 months f. 10-14 years c. 6-11 months g. 15+ years d. 1-4 years

Rates of pertussis in infants <3 months in different systems

350 300 250 200 150 100 50 0 1998 1999 2000 2001 2002 2003 2004 2005 2006 notifications hospital admissions lab confirmed - all methods

Notifications and deaths from pertussis

16,000 14,000 12,000 10,000 8,000 6,000 4,000 2,000 0 19 88 19 89 19 90 19 91 19 92 19 93 19 94 19 95 19 96 19 97 19 98 19 99 20 00 20 01 20 02 20 03 20 04 20 05 20 06 ** 6 5 8 7 4 3 2 1 0

**provisional

Deaths from all sources (not reconciled)

3 2 1 0 7 6 5 4 19 94 19 95 19 96 19 97 19 98 19 99 20 00 20 01 20 02 20 03 20 04 20 05 20 06 * lab deaths HES deaths ONS deaths *provisional data

Immunisation status of laboratory confirmed cases aged ≥6 months

100 90 80 70 60 50 40 30 20 10 0 19 98 19 99 20 00 20 01 20 02 20 03 20 04 20 05 20 06 % of cases known to have had 3+ doses coverage by 1st birthday

Detection of B. pertussis: traditional methods

Culture:

• traditional ‘gold standard’ • poor sensitivity • slow • isolates useful for reference

Pertussis Serotypes

100 90 80 70 60 50 40 1,2 1,3 1,2,3 30 20 10 0 pr e-1 95 8 19 65 19 68 19 71 19 74 -7 5 19 79 19 82 19 85 19 88 19 91 19 94 19 97 20 00 20 03 20 06

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

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

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

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

Oral fluid results May-July 2007

Age group < 1 yr 1-9 10-14 15+ Total Pertussis confirmed / Oral fluid received

4/11 13/48 11/13 19/37 48/109 (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

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)

Pertussis: increasing disease as a result of reducing transmission

Aguas et al Lancet Infect Dis 2006

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

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

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

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