Neonatal meningitis in the UK

Neonatal meningitis in the UKDr Ifeanyichukwu O

OkikePaediatric Infectious Diseases Research GroupSt George’s, University of LondonMRF Conference, London.05 November 2013.

Group B streptococcal infection & neonatal meningitis

OUTLINE

Burden of bacterial meningitis (BPSU) study*

GBS meningitis*

Assessment of healthcare delivery*

*Note. All data are preliminary and unpublished

Okike IO, Ribeiro S, Ramsay M, Heath PT, Sharland M & Ladhani SN. Paper submitted

The rate in <3month-olds is >70 x that of adults!

All p values <0.0001

Laboratory-confirmed cases of bacterial meningitis in E+W, 2004-2011 (PHE, LabBase2)

Age group

% of total population

No of cases (%)

Incidence (95% CI)(/ 100,000 population)

Incidence Rate Ratio

<3months

0.3 978 (16) 72.19 (67.74-76.86)

136 (118-155)

3-11 months

0.9 755 (12) 18.58 (17.27-19.95)

35 (30-40)

1-4 years

4.7 522 (8) 2.54 (2.33-2.77) 4.8 (4.1-5.5)

5-14 years 11.6 270 (4) 0.53 (0.47-0.60) Reference

15-44 years

41.0 1538 (25) 0.86 (0.82-0.91) 1.6 (1.4-1.8)

45-64 years

25.3 1331 (22) 1.21 (1.14-1.27) 2.3 (2.0-2.6)

≥65 years

16.2 752 (12) 1.07 (0.99-1.15) 2.0 (1.7-2.3)

Location Period / 1000 LB

<2500g

Fatality (%)

Sequelae

Leeds 1947-1960

0.5

NW Thames

1969-1973

0.26

Nottingham

1980-1989

0.37 25

Oxford region

1984-1991

0.25 26

E+W 1985-1987

0.2 2.5 25 50%

E+W 1996-1997

0.2 1.7 10 51%

Lancet. 1976;1:701 Arch Dis Child 1991;66:603-7 Arch Dis Child Fetal Neonatal Ed 2001;84:F85-9

Previous neonatal surveillance studies in E+W (≤28 days of age)

E+W= England & Wales

Isolated bacteria (%)Isolated bacteria 1985-87

(E+W) 1996-97 (E+W)

GBS 38% 48%

E. coli 25% 18%

S. pneumoniae 6% 6%

Listeria 7% 5%

N. meningitidis 4% 4%

Other Gram positive bacteria

5% 12%

Other Gram negative bacteria

12% 8%

Arch Dis Child 1991;66:603-7 Arch Dis Child Fetal Neonatal Ed 2001;84:F85-9

Initiatives in the last two decades (UK) PCV 13

• National Guidelines- Feverish illness 2007

(2013)- Bacterial meningitis

2010• Neonatal networks• Regional transport

networks

Ladhani et al CID 2012

Davidson & Ramsay e ADC 2003

Burden of disease study : objectives To define:

• The minimum incidence in the UK and Ireland

• The clinical presentation

• The bacterial pathogens and resistance pattern

• The case fatality and short-term complication rates

Methods

Other Sources-National laboratory surveillance-Meningitis support charities

3200

Orange card: Return rate 93%

Any case where a clinician has made a clinical diagnosis of bacterial meningitis in babies <90 days of age between 1 Jul 2010 & 31 Jul 2011

Incidence (/ 1000 live births): by countryPlace of birth 13-month adjusted LB

2010 *Cases (%) Incidence (95%

CI)

UK & RoI 954189 364 (100) 0·38 (0·34-0·42)

England 744258 298 (82) 0·40 (0·36-0·45)

Wales 38948 15 (4) 0·41 (0·25-0·67)

England & Wales 783206 313 (86) 0·40 (0·36-0·45)

Scotland 63690 19 (5) 0·30 (0·19-0·46)

Northern Ireland 27425 7 (2) 0·26 (0·12-0·53)

Republic of Ireland

79868 25 (7) 0·31 (0·20-0·46)

* Confirmed: 298 (82%) = Isolation of a significant bacterial pathogen from CSF OR isolation of a significant bacterial pathogen from blood culture AND CSF pleocytosis (≥20 cells / mm3 for babies 0-28 days of age and ≥10cells/ mm3 for babies 29-90 days of age).* Probable: 66 (18%) = Clinical signs of meningitis (fever or hypothermia or temperature instability) PLUS 1 or more neurological findings (e.g. coma, seizures, neck stiffness, apnoea, bulging fontanel) AND CSF pleocytosis AND appropriate IV antibiotics are given for > 7 days BUT where no significant pathogen is isolated from blood or CSF.

Incidence by birth weight & gestation at birth (/1000LB)

Category No of cases (%)

Incidence/ 1000 LB (95% CI)

IRR (95% CI) P value

Birth weight (grams)

≥ 2500g 223 (71) 0·31 (0·27-0·35) 1.00 Reference

1500-2499g

43 (14) 0·95 (0·68-1·27) 3·09 (2·22- 4·28) <0.0001

1000-1499g 26 (8) 5·18 (3·38-7·58) 16·83 (11·22- 25·23)

<0.0001

<1000g 21 (7) 4·77 (2·95-7·28) 15·51 (9·92- 24·23)

<0.0001

Gestation at birth (weeks)

≥ 37 201 (70) 0·29 (0·25-0·34) 1.00 Reference

<37 81 (28) 1·36 (1·08-1·70) 4·62 (3·58- 5·99)

<0.0001

32-36 39 (14) 0·99 (0·70-1·35) 3·36 (2·39- 4·74) <0.0001

<32 42 (15) 2·09 (1·51-2·82) 7·11 (5·10- 9·91) <0.0001

Demographics of casesCategory Value

Male 202 (55%)

Median age in days (IQR)

17 (4-41)*

Admitted from home

63%

Preterm (<37 weeks)

27%

*No difference between age at onset by birth weight category

Poor f

eedin

g

Irrita

bility

Leth

argy

Fever

Poor p

erfu

sion

Respir

ator

y dis

tress

Vomitin

g

Apnoe

a

Temp

insta

bility

Jaun

dice

Convu

lsion

Bulging

font

anell

e

Comat

ose

Neck

stiff

ness

0%

10%

20%

30%

40%

50%

60%

70%

80%

All0-28 d>28 d

Presenting features

Pe

rce

nta

ge

of

ca

se

s

Non-specific Specific

Presenting features

Combination of features Percentage of cases

Fever and irritability 41

Fever and lethargy 33

Fever, lethargy and poor feeding

29

Fever, irritability and poor perfusion

19

Fever and convulsion 11

Convulsion and bulging fontanelle

7

Convulsion, bulging fontanelle and neck

stiffness

1

Feature All n (%)

Home

In patient

OR (95%CI)

P valu

e

Term Preterm

OR (95% CI)

P valu

e

Poor feeding

221 (67)

166 (81)

53 (44)

5.4 (3.3-9.0)

0.0001

176(75)

42(47)

3.3 (2.0-5.6)

0.0001

Irritability 208(63)

157 (77)

50 (42)

4.6 (2.8-7.5)

0.0001

174(74)

32(36)

5.1 (3.0-8.6)

0.0001

Abnormal Temp

216 (66)

157 (77)

59 (49)

3.5 (2.1-5.7)

0.0001

160 (69)

49(55)

1.8 (1.1-3.0)

0.0001

Fever 176 (54)

142 (69)

33 (28)

5.9 (3.6-9.7)

0.0001

142(60)

30(33)

3.0 (1.8-5.0)

0.0001

Temp instability

65 (20)

31 (15)

34 (28)

0.4 (0.3-0.8)

0.004

38(16)

27(30)

0.4 (0.3-0.8)

0.004

Apnoea 74 (22)

33 (16)

40(33)

0.4 (0.2-0.7)

0.0001

33 (14)

41(46)

0.2 (0.1-0.4)

0.0001

Presentation by route of admission & gestation

Clinical features compared (%)

Presenting features

BaumgartnerN=24, USA2-6 weeks

RiordanN=42, Merseyside<3months

Okike et alN=329, UK &RoI<3months

Neck stiffness

17 13 3

Seizures 17 35 24

Full fontanelle

13 45 20

Fever 79 70 53

Poor feeding 50 76 67

Lethargic 25 33 63

Irritable 79 70 63

Baumgartner Am J Dis Child 1983 Riordan Postgrad Med Journal 1995

Identified bacteria (n=300)

OrganismCases %

GBS 150 50

E. coli 40 13S. pneumoniae 28 9N. meningitidis 23 8

LM 11 4Other Gram pos 24 8Other Gram neg 24 8

Other Gram pos 24 8 CONS 6 2S. aureus 5 2E. faecalis 4 1S. bovis 4 1S. pyogenes 2 1S. salivarius 1 <1S. viridans 1 <1Bacillus spp. 1 <1Other Gram neg 24 8Pseudomonas 4 1Klebsiella spp 4 1Enterobacter 4 1H. influenzae 3 1Unknown Gram neg bacilli 2 1Citrobacter 1 <1M. morganii 1 <1Pasteurella 1 <1Prevotella 1 <1Raoultella 1 <1Salmonella 1 <1Ureaplasma 1 <1 SPN= S. pneumoniae, NM= N. meningitidis, LM= Listeria monocytogenes

Hi= H. influenzae.

Bacteria

Serotype or serogroup

SPN (n=22)

7F 13 (59%), 3 2 (9%), 1 2 (9%) and one each of 9F, 35B, 19A, 15B, 12F

NM (n=23)

Men B 21 (91%), one each of Men C and Men Y

Hi (n=3) Hib 1

Bacteria All 1st mont

h

2nd mont

h

3rd mont

hGroup B

strep50 58 47 24

E. coli 13 15 12 11

S. pneumoni

ae

9 6 7 29

N. meningitid

is

8 2 15 24

L. monocyto

genes

4 5 0 0

Identified bacteria by month of life (%)

No case of Listeria meningitis after 29 days of age

Identified bacteria:by route of admission & gestation at birth

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Home (term) Home (preterm) In-patient (term) In-patient (preterm)

Perc

enta

ge o

f cas

es

Route of admission and maturity at birth

N. meningitidis

Other G negative

E. coli

Other G positive

L. monocytogenes

Non pyogenic streptococci

S. pneumoniae

Group B strep

47%

Bacteria 1985-87 (0.22/1000

)

1996-97 (0.21/1000

)

2010-11 (0.21/1000)

GBS 38% 48% 60%

E. coli 25% 18% 14%

S. pneumoniae

6% 6% 6%

L. monocytogenes

7% 5% 3%

N. meningitidis

4% 4% 2%

Other Gram neg

12% 8% 8%

Other Gram pos

5% 12% 7%

Aetiology of neonatal (0-28 days of age) current vs historical

for England & Wales

Arch Dis Child 1991;66:603-7 . Arch Dis Child Fetal Neonatal Ed 2001;84:F85-9

Comparison of aetiology with

other international studies

Bacteria France 2001-07N=439

UK & ROI 2010-11N=195

GBS 258 (59%) 111 (57%)

E. coli 123 (28%) 29 (15%)

NM 14 (3%) 3 (2%)

SPN 8 (2%) 11 (6%)

LM 7 (2%) 10 (5%)

Other GNB 19 (4%) 17 (9%)

Other GPC 10 (2%) 14 (7%)

Cases 0-28 days of age

Comparison of aetiology with other international studies

GBS:86.1%

<2mo0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Perc

en

tag

e o

f to

tal cases

GBS:78.1%

USA 2003-07UK & ROI 2010-11Cases < 2 months of age

Organism TotalDied (%)

*Complication in survivors (%)

None detected 65 2 (3) 5 (8)

Group B strep 135 7 (5) 28 (22)

E. coli 35 3 (9) 7 (22)

S. pneumoniae 26 5 (19) 11 (52)

N. meningitidis 20 0 (0) 5 (25)

L. monocytogenes 9 0 (0) 2 (22)Non-pyogenic streptococci 7 1 (14) 2 (33)Other Gram positive 11 2 (18) 1 (11)Other Gram negative 19 5 (26) 4 (29)

Overall OutcomeOverall CFR 25/329 = 7.6% [95% CI: 5.2-11.0]

Death or any serious complication 90/329 = 27% [95% CI: 23-33]

*seizures 26 (9%), motor disorder/abnormal neurology 24 (8%), hydrocephalus 15 (5%), abnormal hearing 8 (3%), severe skin/musculoskeletal defect 5 (2%), other 2 (1%) [drainage cerebral abscess 1, diabetes insipidus 1].

Variable OR (95%

CI)

p

value

Prematurity (<28 weeks) 4.8 (1.7-

13.1)

0.003

Temperature instability on

admission

2.1 (1.1-

4.2)

0.03

Convulsions on admission 4.5 (2.3 -

8.8)

<0.00

01

Coma on admission 10.4 (2.1-

52.0)

0.004

Independent risk factors for death / any serious complication

Features present at the time of admission

Multivariate logistic regression analysis of risk of death or developing a serious complication.

Variable OR (95%

CI)

p

value


11.6)

0.001


admission

3.0 (1.5-

5.8)

0.001

Convulsions on admission 4.8 (2.4 -

9.4)

<0.00

01


98.7)

<0.00

1

S. pneumoniae 6.6 (2.3-

19.3)

<0.00

01

Independent risk factors for death / any serious complication


Role of LP in making a diagnosis

[X2, p=0.001]

Timing of LP No bacteria in the CSF (%)

Pre antibiotics 27 (21)

Post antibiotics 103 (79)

• LP was done in 315/329 (96%)• Post antibiotics 197/307 (64%)- in-patient vs. home admissions: 84% vs. 52%, p<0.0001

CSF WCC Values: The challengeCategory (all cases) Value

Median CSF WCC 335/ mm3 (IQR: 70-1540)

CSF WCC >100/ mm3 198 (68%)

CSF WCC >1000/ mm3 95 (33%)

CSF WCC <20/ mm3 (AND bacteria identified)

30/329 (10%)

Category 0-28 d olds

CSF WCC < 20/ mm3

17/196 (9%)*

Category 29-89 d olds

CSF WCC < 10/ mm3

8/94 (9%)**

Overall blood culture negative 134/329 (41%)

Role of blood culture in diagnosis (n=329)

Category EO (0-6d)

LO (7-89d)

P-value

B/C negative (all cases) 43/112 (38)

91/217 (42)

0.5

Variable n/N (%)

Blood culture positive where no bacteria identified in CSF

75/143 (52)

Study Negative blood culture (%)

Garges et al 35/92 (38)

Wiswell et al 12/43 (28)

Visser et al 6/39 (15)

Vergnano et al 9/27 (33)

Wiswell et al Pediatrics. 1995, Vissser at J Pediatr.1980, Garges Pediatrics. 2006, Vergnano ADC- Fetal and Neonatal Ed 2009

GBS meningitis

Category 2010-2011

No of cases 150

Male 77 (51%)

Median age in days (IQR) 14 (2-30)

Early onset (EO, <7 days) 51 (35%)

Median gestation at birth in weeks (IQR)

39 (37-40)

Preterm (<37 weeks): All EO

31 (24%)12%

Demographics: Group B strep meningitis cases

Presenting features: GBS vs. others

Poor feeding

Lethargy

Irrita

bility

Respira

tory distress

Fever

Poor perfu

sion

Temperature insta

bility

Apnoea

Vomiting

Convulsion

Bulging fontanelle

Comatose

Neck sti

ffness0%

10%

20%

30%

40%

50%

60%

70%

80%

GBSOther bacteria

Presenting features

Perc

enta

ge o

f tot

al c

ases

Non specific Specific

Category 2000-2001 (UK & ROI)

2010-2011 (UK & ROI)

Duration 13 months 13 months

Age group 0-89 days 0-89 days

Total casesIncidence (/ 1000 LB)

1220.15 (0.13 -

0.18)

1500.16 (0.13 - 0.19)

Early onset 40 (33%) 51 (38%)

Late onset 82 (67%) 84 (62%)

Median age (days) 11 (2-29) 14 (2-30)

Median gest age (IQR)Median BW (IQR)

38 (35-40)3030 (2110-3460)

39 (37- 40)3130 (2530-3530)

Comparison of meningitis vs. GBS study in 2000-1

Category 2000-20012010-2011

p value

Term EO 11 0 0.05Preterm EO 23 17 1Term LO 10 3 0.2Preterm LO 13 15 1

Category2000-2001

2010-2011

p value

All 12 5 0.04Term (≥ 37 weeks) 10 2 0.02Preterm (<37 weeks) 16 16 1All EO (0-6 days) 15 2 0.04All LO (7-89 days) 11 7 0.4

2000 vs. 2010: GBS Case fatality (%)

Outcome

Timing of onset 2000/1 vs 2010/11

1 2 3 4 5 6 7 8 9 10 11 12 130

5

10

15

20

25

30

35

40

2010-11 (n=150)2000-01 (n=122)

Week of life

Perc

enta

ge o

f tot

al n

umbe

r of c

ases

0-2 3 4 5 60%

10%20%30%40%50%60%70%80%90%

2000-20012010-2011

Day of life

Perc

enta

ge o

f tot

al ca

ses

1st

week

Risk factors / clinical practice

No change 2000-1 vs. 2010-11:

• % with known risk factors for EO GBS: -i.e. prematurity, ROM >18hrs, known GBS carrier 40% vs. 33% (2000-1 vs. 2010-11), p=0.5

• C/S delivery 28% vs. 20% (2000-1 vs. 2010-11), p=0.4

• blood culture negative cases (%) 23% vs. 19% (2000-1 vs. 2010-11), p=0.4

Variable OR (95%

CI)

p

value


64.8)

0.03


admission

3.2 (1.1-

9.7)

0.04

Convulsions on admission 3.2 (1.2-

8.6)

0.02


73.9)

0.003

Independent risk factors for poor outcome in GBS meningitis


Can we improve our management?

ObjectivesTo define

• Clinical presentation & early symptoms/signs

(from parents’ perspective)

• The current management

AND

To identify opportunities for improving outcome through detailed analysis of early case management

Methodology

Participant Identification centres (PICS)95 NHS Trusts in England, 7 health boards in Wales

Parental Pack (Study information, Consent form, parental questionnaire for onset to progression)

Hospital review of case management (Research fellow visits hospital to review case

management)

Expert panel review of case management(PID, Neonatologist, General Paediatrician, trainee)

Sept 2010 to July 2013Ethics Cambs 2 REC: Ref: 10/H0308/64

Cases already on NNU at diagnosis (preliminary data)

Category Value

Male 18 (59%)

Age in days: median (IQR) 1 (0-7)

Prematurity (<37 weeks) 15 (50%)

Birth risk factors 17 (42%)

Maternal risk factors 10 (32%)

Onset to 1st dose of antibiotics in hours: median (IQR)

2.6 (1.3-8.5)

First dose of antibiotics to LP in hours: median (IQR)

39.4 (9.8-80.9)

Inappropriate empiric antibiotics* 19 (61%)*Based on NICE bacterial meningitis (2010) and NICE EO infection 2012 (empiric antibiotics)

Cases admitted from home (preliminary data)

Category Value

Male 34 (52%)

Age in days: median (IQR) 16 (11-34)

Prematurity (<37 weeks), n=66 8 (12%)

Inappropriate pre hospital management, n=52 20 (38%)

Onset to 1st help in hours: median (1QR), n=50 4.8 (2-10)

Triage in hospital to 1st dose of antibiotics in hours : median (IQR), n-51

1.7 (1.0-3.3)

Inappropriate empiric antibiotics* 30 (54%)

Discharged at age < 2 years, n=56 23 (41%)**

* Empiric antibiotic recommendation as per NICE bacterial meningitis guideline**14 (25%) were discharged after <12 months follow up

Summary 1: Burden of disease

Incidence- Has not changed in neonates over last 3

decadesRisk factors- Prematurity and low birth weight Presentation- Non specific, fever absent in around half of casesAetiology- GBS> E. coli> S. pneumoniae.- No Listeria meningitis in infants >1 month

of age• Outcome- CFR has not changed over last 2 decades

Summary 2: GBS meningitis

Incidence of GBS meningitis has not changed over last decade

Presenting features are not different to those of other bacteria

1/3 are EO cases; 1/3 of EO cases have risk factors

CFR has significantly declined over last decade in term infants

Summary 3: Current management

• Management- Meningitis can occur with normal initial CSF WCC

values- Timing of LP has a significant impact on bacterial

identification

There are important gaps in current management!

- Inappropriate pre hospital management in 1/3 of home admissions

- Median time from triage to antibiotics is long EFNS/ neutropaenic sepsis guideline: antibiotics within 1hour- Inappropriate empiric antibiotics in over half

The quality of clinical practice needs to be improved

AMR & HCAIProf. Alan JohnsonKatherine HendersonRuth BlackburnDr. Berit Muller-Pebody

MRL ManchesterProf. Ray Borrow

Dr. Claire Cameron Dr. Alison Smith-Palmer Dr. Eisin McDonald

Chief InvestigatorProf Paul T Heath

Dr Nelly Ninis (London) Dr. Mark Anthony (Oxford)Dr. Laura Jones (Edinburgh) Prof Mary Cafferkey (Ireland)Dr. Katy Sinka (Scotland)

Dr. Robert Cunney (HSE Ireland)

Helen Friend Richard LynnAll Paediatriciansin the UK & the RoI

Support Charities: Meningitis UK/ Meningitis Trustand Group B Strep SupportSt George’s Vaccine

Institute staffOthersDr Eva GalizaDr. S LadhaniHenry Gowen & Dr G Borgulya

UK & ROI Paediatricians and PIC contacts (HCD)

Acknowledgement

s

[email protected]

Neonatal meningitis in the UK

Health & Medicine

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