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Paediatric Meningitis in the Conjugate Vaccine Era and Development of a Novel Clinical Decision Model to Predict Bacterial Aetiology in 3,002 Children with Suspected Meningitis

42 Pages Posted: 17 Jul 2023

See all articles by Natalie Martin

Natalie Martin

University of Otago Christchurch - Department of Paediatrics

Sylviane Defres

University of Liverpool - Institute of Infection, Veterinary and Ecological Sciences

Louise Willis

University of Oxford - Department of Paediatrics

Rebecca Beckley

University of Oxford - Department of Paediatrics

Annabel Coxon

University of Oxford - Department of Paediatrics

Seilesh Kadambari

Great Ormond Street Hospital for Children NHS Foundation Trust

Ly-Mee Yu

University of Oxford - Nuffield Department of Primary Care Health Sciences

Xinxue Liu

University of Oxford - Centre for Vaccinology and Tropical Medicine

Ushma Galal

University of Oxford - Nuffield Department of Primary Care Health Sciences

Kerry Conlin

University of Oxford - Department of Paediatrics

Michael J. Griffiths

University of London - Institute of Infection and Immunity

Rachel Kneen

Alder Hey Children's NHS Foundation Trust - Department of Neurology

Simon Nadel

St Mary’s Hospital

Paul T. Heath

University of London - Institute of Infection and Immunity

Dominic F. Kelly

University of Oxford - Department of Paediatrics

Tom Solomon

University of Liverpool - Institute of Infection, Veterinary and Ecological Sciences

Manish Sadarangani

BC Children's Hospital Research Institute - Vaccine Evaluation Center

Andrew J. Pollard

University of Oxford - Oxford Vaccine Group

UK-ChiMes Study Group

Independent

ENCEPH UK Study Group

Independent

More...

Abstract

Background: Implementation of bacterial conjugate vaccines have resulted in dramatic reductions in bacterial meningitis globally. The aetiology of childhood meningitis in the conjugate vaccine era is not well-defined, and differentiating bacterial meningitis from other similar childhood illnesses is a major challenge. The aims of this study were to assess aetiology and clinical characteristics in childhood meningitis, and develop clinical decision rules to distinguish bacterial meningitis from other similar clinical syndromes.

Methods: Children aged <16 years hospitalised with suspected meningitis/encephalitis were included. Meningitis was defined as identification of bacteria/viruses from CSF and/or a CSF WBC>5/μL. Aetiology and clinical and laboratory features were analysed. Two new clinical decision rules were developed to distinguish bacterial meningitis from aseptic or suspected meningitis.

Findings: 3,002 children (median age 2·4 months, IQR: 1·0-12·7) were prospectively recruited at 31 UK hospitals. Overall 1,101/3,002 (36·7%) had meningitis, including 203 with a bacterial aetiology, 423 viral and 280 with no pathogen identified. Enterovirus was the most common pathogen in those aged < six months and 10-16 years, with N. meningitidis and/or S. pneumoniae commonest at age six months–nine years. The Bacterial Meningitis Score had a negative predictive value of 95·3%. We developed two clinical decision rules, that could be used either before (sensitivity 82%, specificity 71%) or after LP (sensitivity 84%, specificity 93%), to determine risk of bacterial meningitis.

Interpretation: Bacterial meningitis comprised only 6% of children presenting to hospital with suspected meningitis/encephalitis. Our clinical decision rules provide important novel approaches to identify the children with bacterial meningitis.

Funding: This independent research was supported by the UK Meningitis Research Foundation, Pfizer, and the National Institute for Health Research Programme Grants for Applied Research Programme (Understanding and improving the outcome of viral encephalitis, RP-PG-0108- 10048). MS is supported via salary awards from the BC Children’s Hospital Foundation and Michael Smith Health Research BC. TS is supported by the National Institute for Health and Care Research (NIHR) Health Protection Research Unit in Emerging and Zoonotic Infections (Grant Nos. IS-HPU- 1112-10117 and NIHR200907).

Declaration of Interest: MS has been an investigator on projects funded by GlaxoSmithKline, Merck, Moderna, Pfizer, Sanofi-Pasteur, Seqirus, Symvivo and VBI Vaccines. All funds have been paid to his institute, and he has not received any personal payments. AJP was a member of the World Health Organization’s Strategic Advisory Group of Experts on Immunization until January 2022 and remains chair of the UK Department of Health and Social Care's Joint Committee on Vaccination and Immunisation (JCVI). AJP also reports providing advice to Shionogi on COVID-19, and funding from the National Institute for Health Research (NIHR), AstraZeneca, the Bill & Melinda Gates Foundation, Wellcome, the Medical Research Council, and the Coalition for Epidemic Preparedness Innovations (CEPI). Oxford University has entered into a partnership with AstraZeneca for the development of COVID-19 vaccines. TS is Director of The Pandemic Institute, which has received funding from Innova, CSL Seqirus, Aviva and DAM Health; was an advisor to the GSK Ebola Vaccine programme and the Siemens Diagnostic Programme; Co-Chaired the WHO Neuro-COVID task force and sat on the UK Government’s Advisory Committee on Dangerous Pathogens, and the Medicines and Healthcare Products Regulatory Agency (MHRA) Expert Working Group on Covid-19 vaccines. PH has been an investigator on projects funded by GlaxoSmithKline, Merck, Moderna, Pfizer, Sanofi- Pasteur, Novavax, Valneva, Minervax and AZ. All funds have been paid to his institute, and he has not received any personal payments. He is a member of the UK JCVI. All other authors have no COI to disclose.

Ethical Approval: The study was approved by NRES Committee East Midlands - Nottingham 1 (Ref: 11/EM/0442).

Keywords: meningitis, encephalitis, paediatrics, vaccines, Neisseria meningitidis, Streptococcus pneumoniae, group B Streptococcus, clinical decision rule, enterovirus, lumbar puncture

Suggested Citation

Martin, Natalie and Defres, Sylviane and Willis, Louise and Beckley, Rebecca and Coxon, Annabel and Kadambari, Seilesh and Yu, Ly-Mee and Liu, Xinxue and Galal, Ushma and Conlin, Kerry and Griffiths, Michael J. and Kneen, Rachel and Nadel, Simon and Heath, Paul T. and Kelly, Dominic F. and Solomon, Tom and Sadarangani, Manish and Pollard, Andrew J. and Group, UK-ChiMes Study and Group, ENCEPH UK Study, Paediatric Meningitis in the Conjugate Vaccine Era and Development of a Novel Clinical Decision Model to Predict Bacterial Aetiology in 3,002 Children with Suspected Meningitis. Available at SSRN: https://ssrn.com/abstract=4506566 or http://dx.doi.org/10.2139/ssrn.4506566

Natalie Martin

University of Otago Christchurch - Department of Paediatrics ( email )

Sylviane Defres

University of Liverpool - Institute of Infection, Veterinary and Ecological Sciences ( email )

United Kingdom

Louise Willis

University of Oxford - Department of Paediatrics ( email )

Rebecca Beckley

University of Oxford - Department of Paediatrics ( email )

Annabel Coxon

University of Oxford - Department of Paediatrics ( email )

Seilesh Kadambari

Great Ormond Street Hospital for Children NHS Foundation Trust ( email )

London
United Kingdom

Ly-Mee Yu

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Xinxue Liu

University of Oxford - Centre for Vaccinology and Tropical Medicine ( email )

Oxford
United Kingdom

Ushma Galal

University of Oxford - Nuffield Department of Primary Care Health Sciences ( email )

Oxford
United Kingdom

Kerry Conlin

University of Oxford - Department of Paediatrics ( email )

Michael J. Griffiths

University of London - Institute of Infection and Immunity

Rachel Kneen

Alder Hey Children's NHS Foundation Trust - Department of Neurology ( email )

Simon Nadel

St Mary’s Hospital ( email )

Paul T. Heath

University of London - Institute of Infection and Immunity ( email )

London
United Kingdom

Dominic F. Kelly

University of Oxford - Department of Paediatrics ( email )

Tom Solomon

University of Liverpool - Institute of Infection, Veterinary and Ecological Sciences ( email )

Manish Sadarangani (Contact Author)

BC Children's Hospital Research Institute - Vaccine Evaluation Center ( email )

Canada

Andrew J. Pollard

University of Oxford - Oxford Vaccine Group ( email )

UK-ChiMes Study Group

Independent

ENCEPH UK Study Group

Independent

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