Dr Manish Sadarangani's presentation at Meningitis Research Foundation's 2014 Meningitis Symposium http://www.meningitis.org/symposium2014

1. UK-ChiMES
UK Childhood Meningitis & Encephalitis Study
Dr Manish Sadarangani
Clinical Lecturer in Paediatric ID/Immunology, University of Oxford
11th June, 2014
Chief Investigators: Andrew Pollard & Tom Solomon
Co-Investigators (Meningitis): Simon Nadel, Paul Heath,
Dominic Kelly, Manish Sadarangani

2. ENCEPH-UK
Programme
Studies of
encephalitis in
children and
adults
UK
Childhood
Meningitis
Study Group
Studies of
meningitis in
children
Origins of UK-ChiMES

3. ENCEPH-UK
Programme
Studies of
encephalitis in
children and
adults
UK
Childhood
Meningitis
Study Group
Studies of
meningitis in
children
Origins of UK-ChiMES
UK-
ChiMES

4. Overview
• Background to the study
• Outline of UK-ChiMES
• Results
– Pilot Study
– Preliminary UK-ChiMES data

5. Current issues in meningitis
1. What causes meningitis in children?
2. How can we identify bacterial meningitis early?
3. Where should we target adjunctive therapy?
4. What are the outcomes of meningitis?

6. 1. What causes meningitis?

7. Bacterial meningitis decreasing
Haemophilus influenzae
type b (Hib)
Martin et al. Lancet Inf Dis 2014

8. Bacterial meningitis decreasing
Neisseria meningitidis
Martin et al. Lancet Inf Dis 2014

9. Bacterial meningitis decreasing
Streptococcus pneumoniae
Martin et al. Lancet Inf Dis 2014

10. But not all...
Group B Streptococcus
Lamagni et al. Clin Inf Dis 2013

11. Viral meningitis?
0
100
200
300
400
500
600
700
800
900
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Numberofhospitaladmissions
Year
Hospital Episode Statistics (England), Health & Social Care Information Centre. www.hscic.gov.uk

12. Meningitis in the 21st Century
Country Population Years Total % bacterial Ref
USA 1m – 19y
2001-
2004
3295 3.7%
Nigrovic et al.
JAMA, 2007
France 1m-16y
2000-
2004
155 5.8%
Dubos et al.
Arch Dis Child, 2006
Belgium 1m-15y
1999-
2003
277 10.5%
Pierart et al.
Rev Med Liege, 2006
Belgium 1m-18y
1996-
2008
174 14.9%
Tuerlinckx et al.
Acta Clin Belg, 2012

13. 2. How can we identify bacterial
meningitis early?

14. Identifying bacterial meningitis
• Bacterial meningitis compared to
– Viral meningitis
– Other infections
Why?
• Early, targeted use of adjunctive treatment
– Steroids
– Other therapies?

15. Bacterial vs Viral Meningitis
• Retrospective study, 1997-2005, n=92, Belgium
• Bacterial
– Higher CSF WBC, neutrophils, protein
– Lower CSF glucose
– Higher CRP, WBC
SYMPTOM Bacterial Viral p-value
Fever 90% 82% 0.026
Convulsions 19% 3% 0.01
Petechial rash 62% 7% <0.0001
Headache 10% 78% <0.0001
Neck stiffness 62% 88% 0.006
Nausea 48% 79% 0.005
Vomiting 52% 71% 0.009
De Cauwer et al. Eur J Emerg Med 2007

16. Bacterial vs Aseptic Meningitis
• Prospective study, 1985-1998, n=172, USA
NA = not applicable; NS = not significant
0-12 months
SYMPTOM
>12 months
Bacterial Aseptic p-value Bacterial Aseptic p-value
44% 12% 0.0007 Bulging fontanelle NA
52% 5% <0.0001 Neck stiffness 93% 73% 0.0436
36% 7% 0.0003 Positive Kernig 68% 28% 0.0009
68% 16% <0.0001 Positive Brudzinski NS
40% 12% 0.0025 Toxic/moribund 57% 4% <0.0001
80% 46% 0.0037 Lethargic/comatose 93% 41% <0.0001
NS Shock 18% 0 0.003
Walsh-Kelly et al. Annals Emerg Med 1992

17. Bacterial Meningitis Score
• Predicting children with meningitis at low risk of
a bacterial cause
– No seizure before presentation
– Blood neutrophil count <10 x 109/l
– Negative CSF Gram stain
– CSF neutrophil count <1000 per μl
– CSF protein <80 g/l
• NPV of 97-100% in children >2 months
Nigrovic et al. Pediatrics 2002; Nigrovic et al. JAMA 2007

18. 3. Where should we target adjunctive
therapy?

19. Steroids in meningitis
Bacterial meningitis and meningococcal septicaemia in children. NICE, 2010

20. Steroids in meningitis
Bacterial meningitis and meningococcal septicaemia in children. NICE, 2010

21. Steroids in meningitis
Bacterial meningitis and meningococcal septicaemia in children. NICE, 2010

22. Steroids in meningitis
Bacterial meningitis and meningococcal septicaemia in children. NICE, 2010

23. Steroids in meningitis
Bacterial meningitis and meningococcal septicaemia in children. NICE, 2010

24. 4. What are the outcomes of meningitis?

25. Outcomes of Meningitis
• Bacterial meningitis
– Death: case-fatality rate 5-10%
– Sensorineural hearing loss, visual impairment
– Epilepsy
– Motor and cognitive impairment
– Learning and behavioural problems
• Viral meningitis (7 studies, all except one had <35 cases)
– Full recovery? Transient complications?
– Delayed language & cognitive development?

26. UK-ChiMES
UK Childhood Meningitis & Encephalitis Study

27. Aims of UK-ChiMES
• Determine aetiology of meningitis & encephalitis
• Develop a predictor tool for HSV encephalitis
• Describe clinical & laboratory features of encephalitis & meningitis
• Develop a highly specific clinical decision rule for bacterial meningitis
• Predictors of other causes of encephalitis & predictors of outcome
• Evaluate the “Bacterial Meningitis Score” (BMS)
• Assess outcomes following meningitis & encephalitis
• Pathogenesis studies of encephalitis & meningitis
• Host genetic response to meningitis and encephalitis
• Audit current management of meningitis vs NICE guidance
• Assess QoL in suspected encephalitis and meningitis
• Health economic analysis relating to encephalitis

28. Aims of UK-ChiMES
1. What causes meningitis in children?
2. How can we identify bacterial meningitis early?
3. Where should we target adjunctive therapy?
4. What are the outcomes of meningitis?

29. ‘omics
O’Connor and Pollard. Clin Inf Dis 2013; Ramilo et al. Blood 2007

30. Study population
• Prospective cohort
• 34 sites
• 3,000 children
• Participant involvement 18 months
• Recruitment timeline 3 years
– December 2012 – December 2015

31. Study locations
Oxford
St. Mary’s, London
St. George’s, London
Bart’s and The London
Evelina, London
Great Ormond Street
North Middlesex
Southampton
Bristol
Cardiff
Swansea
Sheffield
Arrowe Park
Milton Keynes
Bradford
Huddersfield
Royal Oldham
Liverpool
Birmingham Heartlands
Birmingham Childrens
Sandwell & West B’ham
Royal Manchester
North Manchester
Royal Preston
Leeds
Mid-Yorkshire Hospitals
Newcastle
Middlesbrough
Glasgow
Edinburgh
Reading
Royal Cornwall
Stoke Mandeville
Wexham Park

32. Inclusion critera
1. <16 years old
2. Admitted to hospital
3. Suspected meningitis or encephalitis
OR lumbar puncture performed as part of
evaluation for infection

33. Exclusion criteria
1. Confirmed non-infectious or non-inflammatory
central nervous system (CNS) disorder
2. Pre-existing indwelling ventricular devices
(e.g. External ventricular drain, VP shunt)

34. Study Assessments
Clinical information
Laboratory data
CSF
(Spinal fluid)
Blood
Stool
Respiratory sample
Saliva
Serum RNA DNA
Determine cause
of meningitis
Clinical Information
Questionnaires
Hospital discharge
3, 6, 12, 18 months
Outcomes
Clinical decision rule
For bacterial meningitis
Pathogenesis
studies
Host genetic
response
Identifying bacterial
meningitis early
Therapeutic
targets?

35. Pilot Study
• Prospective
• 3 sites
– Oxford
– St Mary’s, London
– St George’s, London
• 388 children
• 12 months
– June 2011 to June 2012

36. Summary
• Meningitis is changing
• Bacterial meningitis is difficult to identify
• No cause found in 50% of aseptic meningitis
– We need better diagnostics
UK-ChiMES will provide a scientific basis
to determine priorities for health care,
research and education regarding
childhood meningitis & encephalitis

37. • Children and their families
• Research teams throughout the UK
Thank you

38. Thank you