UK ChiMES (Childhood Meningitis and Encephalitis study) update

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

ENCEPH-UK Programme

Studies of encephalitis in children and

adults

UK Childhood Meningitis

Study Group

Studies of meningitis in

children

Origins of UK-ChiMES

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

Overview

• Background to the study

• Outline of UK-ChiMES

• Results

– Pilot Study

– Preliminary UK-ChiMES data

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?

1. What causes meningitis?

Bacterial meningitis decreasing

Haemophilus influenzae type b (Hib)

Martin et al. Lancet Inf Dis 2014


Neisseria meningitidis



Streptococcus pneumoniae


But not all...

Group B Streptococcus

Lamagni et al. Clin Inf Dis 2013

Viral meningitis?

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100

200

300

400

500

600

700

800

900

2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

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Year Hospital Episode Statistics (England), Health & Social Care Information Centre. www.hscic.gov.uk

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

Identifying bacterial meningitis

• Bacterial meningitis compared to

– Viral meningitis

– Other infections

Why?

• Early, targeted use of adjunctive treatment

– Steroids

– Other therapies?

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

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

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

Steroids in meningitis

Bacterial meningitis and meningococcal septicaemia in children. NICE, 2010

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?

UK-ChiMES UK Childhood Meningitis & Encephalitis Study

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

Aims of UK-ChiMES

1. What causes meningitis in children?




‘omics

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

Study population

• Prospective cohort

• 34 sites

• 3,000 children

• Participant involvement 18 months

• Recruitment timeline 3 years

– December 2012 – December 2015

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

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

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)

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?

Pilot Study

• Prospective

• 3 sites

– Oxford

– St Mary’s, London

– St George’s, London

• 388 children

• 12 months

– June 2011 to June 2012

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

• Children and their families

• Research teams throughout the UK

Thank you

Thank you

UK ChiMES (Childhood Meningitis and Encephalitis study) update

Health & Medicine

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