Invasive Meningococcal Disease in England & Wales

Shamez Ladhani, Pauline Kaye and Mary Ramsay

Immunisation DepartmentPublic Health England ColindaleE-mail: shamez.ladhani@phe.gov.uk

... on the basis of the available evidence, routine infant or toddler immunisation using Bexsero is highly unlikely

to be cost-effective ...

... if the vaccine had no impact on ...carriage .... adolescent immunisation is also unlikely to be cost-

effective....

Invasive Meningococcal DiseaseEngland & Wales, 1998/99 to 2012/13

1998/1999

1999/2000

2000/2001

2001/2002

2002/2003

2003/2004

2004/2005

2005/2006

2006/2007

2007/2008

2008/2009

2009/2010

2010/2011

2011/2012

2012/2013

0

500

1000

1500

2000

2500

3000Ungrouped

Other

Y

W

C

B

Epidemiological Year

Lab

ora

tory

-co

nfi

rmed

Cas

es

Meningococcal Cases by Age & YearEngland and Wales, 2006/07-2012/13

<1 1-4 5-9 10-14 15-19 20-24 25-44 45-64 >=650

50

100

150

200

250

300

350

400

450

2006/2007

2007/2008

2008/2009

2009/2010

2010/2011

2011/2012

2012/2013

Age Group (years)

Nu

mb

er o

f ca

ses

≥

Where do these figures come from?

IMD Surveillance in England & Wales

• PHE Meningococcal Reference Unit (MRU): • National service for species confirmation and capsular

grouping of invasive Neisseria meningitidis isolates• ~ “Real-time” PCR-testing of clinical samples for molecular

diagnosis of IMD• Routinely requests clinical isolates for PCR-positive cases• Molecular characterisation of a proportion of isolates annually • Clinical & diagnostic support for IMD clusters & outbreaks• Laboratory support for meningococcal vaccine trials

IMD Surveillance in England & Wales

• PHE Colindale• Enhanced national surveillance of IMD• Monitor MenC vaccination programme – impact,

effectiveness, replacement disease, population immunity• Follow-up of clinical cases (when needed)• Public health advice and national guidance for management

of cases and contacts, including outbreaks• Modelling, carriage studies, vaccine trials, health economic

analyses and other relevant studies to inform national immunisation policy

Alternative Data Sources: LabBase2

Labase2• Voluntary electronic reporting of laboratory-confirmed

clinically significant pathogens by NHS hospital microbiology departments in England & Wales

• Proportion of laboratories reporting to LabBase2 has been increasing over the past decade

• Currently ~ 83% of cases reported through LabBase2• BUT:

- Only laboratory-confirmed cases- No clinical data- Variable quality and timing of reporting by laboratories

PCR Diagnosis for IMD

• 5,471 lab-confirmed cases by PHE MRU during 2006/07-10/11 (5 years)

• Average annual incidence: 1.8/100,000

• Incidence in infants: 38.6/100,000

• 1,034 lab-confirmed cases in 2010/11

• Only 14 cases in LabBase2 were not reported to PHE MRU

0

200

400

600

800

1000

1200

1400 B C W135 Y Other

Epidemiological year

Nu

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er

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s

Contribution of PCR-testing to IMD diagnosis England & Wales, 1998/99-2012/13

1998/1999

1999/2000

2000/2001

2001/2002

2002/2003

2003/2004

2004/2005

2005/2006

2006/2007

2007/2008

2008/2009

2009/2010

2010/2011

2011/2012

2012/2013

0

500

1000

1500

2000

2500

3000

PCR ONLY

CULTURE ONLY

CULTURE AND PCR

Epidemiological Year

Num

ber o

f Cas

es

• 25,379 specimens to MRU for PCR testing: 1,492 patients (6.8%) tested positive

• Of 1,924 IMD cases: 1099 (57%) were confirmed by PCR only 432 (23%) by culture only 393 (20%) by both tests

• Multiple PCR Specimens:

Of 2827 patients with multiple PCR-samples submitted, only one patient had a discordant result between two EDTA samples submitted on the same day.

• PCR sensitivity against cultures:

Comparing PCR-negative/culture-positive samples taken on the same day (n=5) to cases confirmed by both methods (n=393), the sensitivity of PCR was 99%

• Comparison with LabBase2:

Only 47/509 (10%) isolates not submitted to PHE MRU

But 36/47 (77%) had already been tested PCR-positiveHeinsbroek et al. Journal of Infection (2013); 67: 385-90

Added Value of PCR-testing to IMD Surveillance (England, 2009 and 2010)

Changing epidemiology of MenY disease(England & Wales, 2006-2013)

2006/2007 2007/2008 2008/2009 2009/2010 2010/2011 2011/2012 2012/20130

5

10

15

20

25

30

35

40A <1 B 1-4 C 5-9 D 10-14 E 15-19 F 20-24 G 25-44 H 45-64 I >=65

Epidemiological Year

Num

ber

of M

enY

cas

es

Recent increase in MenW cases(England & Wales, 2006-2013)

2006/2007 2007/2008 2008/2009 2009/2010 2010/2011 2011/2012 2012/2013

Other 18 20 15 15 15 10 17

2a 1 2 NaN 5 11 20 33

5

15

25

35

45

55

18 2015 15 15

10

17

12

511 20

33

Epidemiologocal Year

Num

ber

of M

enW

cas

es

Are we truly capturing all invasive meningococcal

cases?

Estimating the total burden of IMD in England using multiple national data sources

MRU DATABASEINDIVIDUAL HOSPITAL ADMISSIONS

ELECTRONIC LAB REPORTS

DEATH NOTIFICATIONS

• HES• Hospital Episode Statistics for all hospital admissions in

England only• Data format requires complex analysis, especially if linking

with other data sources• Diagnosis based on ICD-10 codes at discharge• BUT

- Only includes hospitalised cases- Coding may be non-specific (e.g. meningitis, pneumonia)- No laboratory-confirmation (clinically diagnosed cases vs.

petechial rash treated with 7 days of IV antibiotics)

National Data Sources: HES

National Data Sources: ONS Deaths

• Death Registrations• ICD10 codes and cause of death available electronically for

all death registrations in England • May identify non-hospitalised cases at post-mortem (although

usually still need laboratory-confirmation)• Allows assessment of timing and cause of death for

laboratory-confirmed IMD cases• BUT:

- Least specific data source for pathogen-specific disease- Pathogen may not be known at the time of registration- Pathogen may not be reported even if known (“meningitis”)

ICD10 Codes for Bacterial Meningitis & IMD

ICD10 codes: A39* and G00* expanded

433 cases: coded as IMD in HES, but not linked to MRU

Completeness of case ascertainment (England & Wales, 2007-2011)

787 cases: MRU Positive & coded as IMD in HES

293 cases: MRU-positive, infection-related ICD10 code in HES for most (~87.5%) cases

22 cases: coded in ONS as IMD but not linked to MRU or HES

IMD Cases0

200

400

600

800

1000

1200

1400

1600

787

293

22

265

168

433

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 300

100

200

300

400HES cases that were PCR-negative

Interval (days) between admission and testing

Nu

mb

er

of

Ca

se

s

Completeness of case ascertainment (England & Wales, 2007-2011)

IMD Cases0

200

400

600

800

1000

1200

1400

1600

787

293

22

265

168

433265 cases: Coded as IMD in HES but MRU-negative

168 cases: coded as IMD in HES but no lab-confirmation

Age distribution of HES cases that were MRU-confirmed, MRU-negative & unmatched

Conclusions

Current surveillance of IMD in England and Wales relies on PHE MRU• National Reference Centre for clinical isolates and PCR-testing

• Standardised methodology – consistent over time

• Allows molecular surveillance of meningococci causing IMD

PHE monitors completeness of case ascertainment at regular intervals using multiple alternative national datasets

• Currently surveillance captures >90% of laboratory-confirmed cases

• Redundancy in free PCR-testing service ensures high case ascertainment

PHE working to develop standardised methodology for routinely linking multiple national datasets to enhance IMD surveillance

• Particular emphasis on cases without laboratory confirmation

Pathogens causing Bacterial Meningitis (LabBase2, England & Wales, 2004-2011)

2004 2005 2006 2007 2008 2009 2010 20110

0.4

0.8

1.2

1.6

2

Children (<15 years)

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Year

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-0.0999999999999997

3.05311331771918E-16

0.1

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Adults (≥15 years)

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Acknowledgements

MenB Cases

< 1 1-4 5-9 10-14 15-19 20-24 25-44

45-64 ≥ 65 NK Total

2006/07 274 314 83 28 102 44 53 56 30 3 987

2007/08 274 357 78 32 117 42 74 72 31 5 1082

2008/09 284 335 70 39 111 46 51 82 30 4 1052

2009/10 210 236 53 36 77 41 50 51 27 5 786

Total 1042 1242 284 135 407 173 228 261 118 17 3907

Disease in <2 year-olds

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 230

5

10

15

20

25

30

35

40

Ungrouped

Other groups

ACWY

B

Age (months)

Nu

mb

er

of

rep

ort

s

Disease in <24 year-olds

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 240

50

100

150

200

250

300

Ungrouped

Other groups

ACWY

B

Age (years)

Nu

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ort

s