Childhood bacterial and aseptic meningitis:findings from the UK-ChiMES study and beyond

Dr Natalie Martin 2018

OutlineThe UK-Childhood Meningitis and Encephalitis cohort Study

• What causes meningitis in children nowadays?

• How can we distinguish the few children with bacterial meningitis on presentation to hospital?

• Can we improve early diagnosis of enteroviral meningitis?

• What are the outcomes following childhood viral and bacterial meningitis?

• Future New Zealand studies

Acknowledgements• University of Oxford St Cross Partnered Scholarship in Paediatrics• UK Meningitis Research Foundation• NZ Graham Aitken Nuffield Postgraduate Travelling Scholarship• NZ RACP Research Development Scholarship

St Cross College

Team

The Oxford Vaccine Group

Some ChiMES investigators

ChiMES Oxford team

(St George’s London, St Mary’s London, Liverpool Brain

Infections Group)

Louise Willis –research nurse

Manish Sadarangani -lecturer

Annabel Coxon-administration

me – clinical research fellow

Rebecca Beckley-project manager

Emma Harper-administration

Kelly Fitzgerald-study monitor

John Radcliffe Hospital

Definitions

• Meningitis: Pathogen in CSF OR raised CSF WBC count OR both

• Aseptic meningitis: Non-bacterial meningitis

What do we already know?

• Most are aseptic (bacterial 4-18%, few studies Europe+USA)→ often no cause found (≈40-76%)→ enteroviruses cause most when a pathogen isolated (54-88%)

• Viral meningitis usually self limiting, but most children admitted + receive intravenous antibiotics

• Clinical features bacterial vs aseptic/viral→ few studies, limited sample size→ Bacterial Meningitis Score for low risk bacterial (not previously validated UK)

• Viral meningitis outcomes poorly defined→ recent systematic review submitted Hudson, Broad, Martin NG et al

References: PHE, Okike 2014, Campbell 2009, Heath 2002, Nigrovic 2007, 2012, 2013 Dubos 2006, Pierart 2006, Tuerlinckx 2012, Sadarangani 2015, DeOry 2013, Lee 2006, Waespe 2010, Sadarangani 2015, Kadambari 2014, Huizing 2011, Lyons 2012, King 2007, Dewan 2010, Ramers 2000, Yun 2012, Graham 2005

What causes meningitis in children in the UK?

• retrospective epidemiology from hospital admissions data• prospective aetiology from UK-ChiMES study

MenCvaccine

12 mthbooster

Martin NG et al. Lancet Inf Dis 2014

Pneumococcal Meningitis

Meningococcal Infections

PCV7 PCV13

H. InfluenzaeMeningitis

Hibvaccine

Hib catch up 12 mnthbooster

MenCvaccine

12 mthbooster

Hospital admission rates for viral meningitis in children

Arrow 1 shows the time of widespread introduction of MMR. Arrow 2 is the time of known outbreaks of Echovirus 13 and 30 in 2000 and 2001

Martin NG et al. Lancet Inf Dis 2016

<15 years <1 year

What about New Zealand?Pneumococcal Meningitis Hospitalisations per 100 000 children <15 years

Meningococcal Disease Hospitalisations per 100 000 children <15 years

•Walls T,..,Martin NG et al. PIDJ 2018

What about New Zealand?

•Walls T,..,Martin NG et al. PIDJ 2018, in press

Children <15 years

Children <15 years

UK-ChiMES study• Prospective, multicentre, UK-wide study• 32 UK hospital sites• Children <16 years, admitted to hospital

with suspected meningitis or encephalitis, or LP for septic screen

• Extensive clinical data - patient records + interview with parents

• Scavenged+ additional research samples

• Outcomes - telephone interviews + postal questionnaires (18 months)

• Recruitment 3003 Dec 2012-June 2016

Study Assessments

Clinical informationLaboratory data

CSF(Spinal fluid) BloodStool

Respiratory sampleSaliva

Serum RNA DNADetermine causeof meningitisClinical Information

QuestionnairesHospital discharge3, 6, 12, 18 months

Outcomes

Clinical decision rulefor bacterial meningitis

Pathogenesisstudies Host genetic

response

Distinguish bacterialvs viral meningitis

Therapeutictargets?

Aetiology in children with meningitis

Definite bacterial, n=172 Probable bacterial, n=21

Definite viral, n=378 Probable viral, n=14

Other, n=27 Unknown aseptic, n=280

n=892 (32%)

Aetiology in meningitisCause of illness <3 months 3-23 months 2-15 years Overall

TOTAL 1561 709 484 2754NON-MENINGITIS 980 471 229 1680 (61.0%)

Encephalitis, Possible meningitis 48 49 85 182 (6.6%)TOTAL MENINGITIS 533 (34%) 189 (27%) 170 (35%) 892 (32.4%)

Bacterial

S. pneumoniae 10 25 18 53N. meningitidis 6 31 14 51

GBS 29 2 0 31E. coli 21 1 0 22

Other bacteria 3 8 4 15TOTAL 69 (13%) 67 (35%) 36 (21%) 172 (19.3%)

Viral

Enteroviruses 253 41 11 305Parechoviruses 46 2 1 49Other viruses 6 6 12 24

TOTAL 305 (57%) 49 (26%) 24 (14%) 378 (42.3%)Other – other known cause, probable

viral/ bacterial, 19 18 25 62 (7.0%)

Meningitis – unknown 140 (26%) 55 (29%) 85 (50%) 280 (31.3%)GBS = Group B Streptococcus

UK-ChiMES, Martin NG DPhil thesis

Aetiology for children and infants with a non-meningitis illness, n=1680

Urinary tract infection, n=271 Suspected sepsis, n=256

Non-specific viral illness, n=233 Febrile seizure, n=99Febrile illness or fever unknown origin, n=78 Seizure other, n=69URTI, n=67 Bacteraemia, n=62Bronchiolitis, n=60 Pneumonia, n=53Chronic condition presenting with acute illness, n=49 Gastroenteritis, including viral or bacterial, n=45

Viral illnes with positive PCR, n=39 enteroviral infection, n=25Other, n=197 Unknown, n=77

Investigations, Antibiotics and Hospital Days in Childhood Meningitis

• Increase in proportion of meningitis no identified aetiology with age

• 92-100% confirmed viral meningitis received IV or IM antibiotics

• Many children pre-treated with antibiotics prior to LP • 38% bacterial, 21% enteroviral, 16% parechoviral, 36% unknown aseptic meningitis

• No aetiology identified in greater proportion of pre-treated children• pre-treated 37.1% versus not pre-treated 28.8%, p=0.016

• Meningitis no aetiology→ 26% no CSF EV-PCR, most no bacterial PCRs

• Longer LOS in meningitis no aetiology vs confirmed viral• aseptic unknown LOS=6 days vs EV + parechoviral meningitis LOS=3 days, p=<0.001

How can we distinguish between viral and bacterial meningitis early?

• viral meningitis → avoid unnecessary hospital days + antibiotics • bacterial meningitis → target treatment

• Clinical decision models• Better and more rapid diagnostics

Bacterial Meningitis Score

• No predictor = very low risk• 1 or more = not low risk• High sensitivity (99.3%), low specificity (62.1%) Nigrovic 2012• UK-ChiMES: sensitivity 100%, LOWER specificity 22%

• >28 days - <16 years, no missing data, not pretreated, n=237

Nigrovic 2002

Development of a new clinical decision model

• Univariate analysis, 37 clinical + laboratory features• Bacterial versus aseptic meningitis • Children >28 days, raised CSF WBC, not pre-treated

• Significant at univariate analysis:• history of fever, respiratory symptoms and signs, vomiting, neck stiffness,

history of altered consciousness, GSC <15, GCS <14, temperature, bulging fontanelle (infants)

• blood WBC, neutrophils, lymphocytes, CRP• CSF corrected WBC count, neutrophils, lymphocytes, protein, CSF:plasma

glucose ratio, Gram film positive

• Nine variables identified <10% missing data and P<0.25 à logistic regression

A new clinical decision model

A new clinical decision model

Can we improve diagnostics in enteroviral meningitis?

Defining enteroviral meningitis

• EV RT-PCR respiratory, stool, serum samples in children with suspected viral meningitis from ChiMES study • RNA extractions: QIAamp Viral RNA Mini kit, EV RT-PCR: Enterovirus R-gene® kit

• Compare clinical + laboratory features, timelines of illness, tests • EV CSF+ with pleocytosis• EV CSF+ no pleocytosis• EV+ at another site, with CSF pleocytosis• EV+ at another site, no CSF pleocytosis• EV- at all sites

• In UK-ChiMES, pleocytosis absent in 40% (118/293) of CSF EV+

Defining enteroviral meningitis

• 100% EV meningitis stool EV+ when available (26/26)

• Stool samples positive many days after symptom onset

• 35% (6/17) meningitis with unknown aetiology stool EV+ • Significantly later LP compared with CSF EV+ group• Consider observing off antibiotics?

• Few children had positive respiratory samples

• Many invalid serum samples

Day of EV-PCR following onset of symptoms

Notes: Filled circle indicates positive result, empty circle indicates negative result, x indicates invalid result. Results of Enterovirus R-gene® kit for stool and respiratory samples test, results of testing at hospital site laboratories for CSF samples.

EV Meningitis with CSF Pleocytosis EV Meningitis without CSF Pleocytosis

What are the outcomes following viral (and bacterial) meningitis?

Outcomes

<2 years 2-4 yrs 5-16 years

Quality of life

ITQoL(parent)

PedsQL -4.0(parent)

PedsQL-4.0(child & parent)

Neuro-psychology

Infant characteristic questionnaire

Preschoolbehaviourchecklist

SDQ (child & parent 11-15y

parent only 5-10y)

Healtheconomic

SF10 (parent)

SF10(parent)

EQ-5D-5L(parent)

EQ-5D-5L(parent +/- child)

• Clinical information, short term outcomes: discharge, 3 months• Questionnaires: discharge, 6, 12, 18 months

Outcomes 3 months post-discharge

Infant-Toddler Quality of Life Results <2 years

• Domains: overall health, physical abilities, growth + development, mood, discomfort, behaviour, health perception, parent emotional + time impacts

• Compared meningitis of different aetiologies, and non-meningitis controls at each time-point

• QOL scores across several domains lower in bacterial meningitis

• At discharge parent emotion impact scores lower in both bacterial and aseptic meningitis of several aetiologies

• In enteroviral meningitis, lower QOL scores compared with control group in limited domains until 18 months post-discharge

ITQOL Results

Future New Zealand Studies

• Neurodevelopmental outcomes in preschool children after EV meningitis

• To assess neurodevelopmental outcomes following enteroviral + parechoviral meningitis in preschool children Canterbury using the Bayley Scale for Infant Development III tool

• The NZ Childhood Meningitis and Encephalitis Study: aetiology, outcomes, validation of a clinical decision rule in childhood bacterial + viral meningitis

• To define the epidemiology of bacterial+aseptic meningitis and encephalitis in NZ children

• To assess outcomes at age 4 years nationally, following meningitis or encephalitis using the Strength and Disabilities Questionnaire obtained during the B4 School Check

• To validate in Canterbury a clinical decision model to identify children with a high probability of bacterial meningitis at hospital presentation

Conclusion• The causes of meningitis are changing

• vaccines, improved diagnostics→ identify current epidemiology→ a novel single test for all causes→ improve understanding of EV meningitis/ infection

• Bacterial and viral meningitis difficult to distinguish early in illness

• preventing unnecessary hospitalisation/ antibiotics, targeting treatment → combining clinical decision rules with more rapid diagnostics→ further rule bacterial meningitis versus all suspected meningitis

• Outcomes after viral meningitis unknown• viral: inform follow-up guidelines and research, for example EV vaccines• bacterial: cost effectiveness studies for vaccine implementation, no

meningococcal vaccine in our NZ schedule→ detailed follow-up until 18 months

Publications arising from studiesPublications:

• Martin NG, Iro MA, Sadarangani M, Goldacre R, Pollard AJ, Goldacre MJ. Hospital admission rates for viral meningitis in children in England over five decades: a population-based observational study. The Lancet Infectious Diseases. Published online 2016 Aug.

• Martin NG, Sadarangani M, Pollard AJ, Goldacre MJ. Hospital admission rates for meningitis and septicaemia caused by Haemophilus influenzae, Neisseria meningitidis and Streptococcus pneumoniae in children in England over five decades: a population-based observational study. The Lancet Infectious Diseases 2014 May;14(5):397-405.

• Martin NG, Snape MD. A multicomponent serogroup B meningococcal vaccine is available for use in Europe: what do we know, and what are we yet to learn? Expert Review of Vaccines 2013 Aug;12(8):837-58.

• Ellul MA, Griffiths MJ, Iyer A, Avula S, Defres S, Baborie A, Vincent A, Martin NG, Sadarangani M, Pollard AJ, Solomon T, Kneen. R.Anti-N-Methyl-D-Aspartate Receptor Encephalitis In A Young Child With Histological Evidence On Brain Biopsy Of Coexistent Herpes Simplex Virus Type 1 Infection. Pediatr Infect Dis J. 2016 Mar;35(3):347-9.

• Sadarangani M, Willis L, Kadambari S, Gormley S, Young Z, Beckley R, Gantlett K, Orf K, Blakey S, Martin NG, Kelly DF, Heath PT, NadelS, Pollard AJ. Childhood meningitis in the conjugate vaccine era: prospective cohort study. Archives of Disease in Childhood, 2015 Mar;100(3):292-4.

Conference Abstracts:

• Martin NG, Sadarangani M, Willis L, Beckley R, Coxon A, Galal U, Defres S, Griffiths MJ, Kadambari S, Kneen R, Kelly DF, Heath PT, Nadel S, Solomon T, Pollard AJ. Development of a new clinical decision rule to distinguish childhood bacterial and aseptic meningitis –findings from the UK childhood meningitis and encephalitis prospective cohort study (UK-ChiMES). Accepted to the Hot Topics in Infection and Immunity in Children course, Oxford, 2018.

• Martin NG, Sadarangani M, Willis L, Pollard AJ et al. Health related quality of life and outcomes following childhood viral and bacterial meningitis – findings from the UK childhood meningitis and encephalitis prospective cohort study (UK-ChiMES). ESPID Conference (European Society for Paediatric Infectious Diseases), 2017.

• Martin NG1,2, Sadarangani M1, Willis L1, Beckley R1, Coxon A1, Defres S 3, Griffiths M3,4, Harper E1, Fitzgerald K1, Kneen R3,4, Kelly DF1, Heath PT5, Nadel S6, Solomon T3, Pollard AJ 1 and the UK-ChiMES study investigators. Comparison of clinical and laboratory features in childhood bacterial and aseptic meningitis – findings from the UK Childhood Meningitis and Encephalitis prospective cohort Study (UK-ChiMES)

• Martin NG1,2, Sadarangani M1, Willis L1, Beckley R1, Coxon A1, Kadambari S4, Kelly DF1, Heath PT4, Nadel S5, Solomon T3, Pollard AJ1

Detection of enterovirus by real-time PCR of stool, serum, and respiratory samples in children with suspected or confirmed viral meningitis – findings from UK-CHiMES.

Acknowledgements

Oxford Vaccine GroupAndrew PollardDominic KellyManish SadaranganiLouise WillisRebecca BeckleyAnnabel CoxonSharon WestcarEmma HarperKelly FitzgeraldThe SOCCR team nurses

Nuffield Department of Population HealthMichael GoldacreRaphael Goldacre