UK ChiMES (Childhood Meningitis and Encephalitis study) update

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

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UK ChiMES (Childhood Meningitis and Encephalitis study) update

  1. 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. 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. 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. 4. Overview • Background to the study • Outline of UK-ChiMES • Results – Pilot Study – Preliminary UK-ChiMES data
  5. 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. 6. 1. What causes meningitis?
  7. 7. Bacterial meningitis decreasing Haemophilus influenzae type b (Hib) Martin et al. Lancet Inf Dis 2014
  8. 8. Bacterial meningitis decreasing Neisseria meningitidis Martin et al. Lancet Inf Dis 2014
  9. 9. Bacterial meningitis decreasing Streptococcus pneumoniae Martin et al. Lancet Inf Dis 2014
  10. 10. But not all... Group B Streptococcus Lamagni et al. Clin Inf Dis 2013
  11. 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. 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. 13. 2. How can we identify bacterial meningitis early?
  14. 14. Identifying bacterial meningitis • Bacterial meningitis compared to – Viral meningitis – Other infections Why? • Early, targeted use of adjunctive treatment – Steroids – Other therapies?
  15. 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. 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. 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. 18. 3. Where should we target adjunctive therapy?
  19. 19. Steroids in meningitis Bacterial meningitis and meningococcal septicaemia in children. NICE, 2010
  20. 20. Steroids in meningitis Bacterial meningitis and meningococcal septicaemia in children. NICE, 2010
  21. 21. Steroids in meningitis Bacterial meningitis and meningococcal septicaemia in children. NICE, 2010
  22. 22. Steroids in meningitis Bacterial meningitis and meningococcal septicaemia in children. NICE, 2010
  23. 23. Steroids in meningitis Bacterial meningitis and meningococcal septicaemia in children. NICE, 2010
  24. 24. 4. What are the outcomes of meningitis?
  25. 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. 26. UK-ChiMES UK Childhood Meningitis & Encephalitis Study
  27. 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. 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. 29. ‘omics O’Connor and Pollard. Clin Inf Dis 2013; Ramilo et al. Blood 2007
  30. 30. Study population • Prospective cohort • 34 sites • 3,000 children • Participant involvement 18 months • Recruitment timeline 3 years – December 2012 – December 2015
  31. 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. 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. 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. 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. 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. 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. 37. • Children and their families • Research teams throughout the UK Thank you
  38. 38. Thank you

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