Dr Ifeanyichukwu Okike's presentation at Meningitis Research Foundation's 2013 conference Meningitis & Septicemia in Children & Adults 2013

1. Group B streptococcal infection & neonatal
meningitis
Neonatal meningitis in the
UKDr Ifeanyichukwu O Okike
Paediatric Infectious Diseases Research
Group
St George’s, University of London
MRF Conference, London.

2. OUTLINE
 Burden of bacterial meningitis (BPSU) study*
 GBS meningitis*
 Assessment of healthcare delivery*
*Note. All data are preliminary and
unpublished

3. bacterial meningitis in E+W, 20042011 (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 (118155)
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)p values <0.0001
2.0 (1.7-2.3)
All
The rate in <3month-olds is >70 x that of adults!
Okike IO, Ribeiro S, Ramsay M, Heath PT, Sharland M & Ladhani SN. Paper
submitted

4. Previous neonatal
surveillance
studies in
E+W (≤28 days of age)
Location
Period
/ 1000 LB <2500g
Fatality
(%)
Leeds
19471960
0.5
NW Thames
19691973
0.26
Nottingham
19801989
0.37
25
Oxford
region
19841991
0.25
Sequelae
26
Lancet. 1976;1:701 Arch Dis Child 1991;66:603-7 Arch Dis Child Fetal Neonatal Ed 2001;84:F85-9
E+W
19851987
0.2
2.5
E+W= England &
Wales
25
50%

5. 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
Other Gram negative
bacteria
5%
12%
12%
8%
Arch Dis Child 1991;66:603-7 Arch Dis Child Fetal Neonatal Ed 2001;84:F85-9

6. Initiatives in the last two decades
(UK)
PCV 13
Davidson & Ramsay e ADC
2003
Ladhani et al CID
2012
• National Guidelines
- Feverish illness 2007
(2013)
- Bacterial meningitis 2010
• Neonatal networks
• Regional transport

7. 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

8. Methods
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
3200
Return rate 93%
Orange card:
Other Sources
-National laboratory
surveillance

9. Incidence (/ 1000 live births): by
country
Place 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.

10. Incidence by birth weight &
gestation at birth (/1000LB)
Category
223 (71)
0·31 (0·27-0·35)
1.00
Reference
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
Gestation at
birth (weeks)
≥ 2500g
1500-2499g
Birth weight
(grams)
No of cases (%)
Incidence/ 1000 LB (95% CI) IRR (95% CI)
P value
21 (7)
4·77 (2·95-7·28)
15·51 (9·92- 24·23)
<0.0001
≥ 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

11. Demographics of
cases
Category
Value
Male
202 (55%)
Median age in days
(IQR)
Admitted from home
17 (4-41)*
Preterm (<37 weeks)
27%
63%
*No difference between age at onset by birth weight category

12. Combination of features
Presenting
Percentage of cases
80%
Percentage of cases
features
Fever and irritability
60%
Fever and lethargy
50%
40%
Fever, lethargy and poor feeding
30%
70%
41
33
29
20%
10%
Fever, irritability and poor perfusion
19
0%
All
0-28 d
>28 d
Fever and convulsion
Convulsion and bulging fontanelle
11
7
Convulsion, bulging fontanelle
Presenting
Non-specificneck stiffness features
and
1
Specific

13. Presentation by route of admission &
gestation
Feature
All n
(%)
Home
In patient
OR
(95%CI)
P
value
Term
Preterm
OR
(95% CI)
P
value
Poor feeding
221
(67)
166
(81)
53
(44)
5.4
(3.3-9.0)
0.000
1
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)
0.000
1
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)
0.000
1
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)
0.000
1
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)
0.000
1
33
(14)
41
(46)
0.2
(0.1-0.4)
0.0001

14. (%)
Presenting features
Baumgartner
N=24, USA
2-6 weeks
Riordan
N=42, Merseyside
<3months
Okike et al
N=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

15. Other Gram
pos
24
8
CONS
6
2
S. aureus
5
2
E. faecalis
4
1
S. bovis
4
1
S. pyogenes
2
1
S. salivarius
1
<1
S. viridans
1
<1
Bacillus spp.
1
<1
Other Gram neg
24
8
Pseudomonas
4
1
Klebsiella spp
4
1
Enterobacter
4
1
Serotype or serogroup
H. influenzae
3
1
Unknown Gram
7F 13 (59%), 3 2 (9%), 1 2 (9%) and one each of 9F,
neg bacilli
2
1
Citrobacter
1
<1
35B, 19A, 15B, 12F
M. morganii
1
<1
Pasteurella
1
<1
Men B 21 (91%), one each Prevotella C and Men Y<1
of Men
1
Raoultella
1
<1
1
<1
Hib 1 Salmonella
Ureaplasma
1
<1
Identified bacteria (n=300)
Organism
GBS
Cases
150
%
50
40
13
S. pneumoniae
N. meningitidis
Bacteria
28
23
9
8
LMSPN
11
4
24
8
24
8
E. coli
(n=22)
Other Gram pos
NM
(n=23)
Other Gram neg
Hi (n=3)
SPN= S. pneumoniae, NM= N. meningitidis, LM= Listeria monocytogenes Hi= H. influenzae.

16. Identified bacteria by month of
life (%)
Bacteria
All
1st
month
2nd
month
3rd
month
Group B
strep
E. coli
50
58
47
24
13
15
12
11
S.
9
6
7
pneumoniae
N.
8
2
15
meningitidis of Listeria meningitis after 29 days
No case
29
24

17. Identified bacteria:
100%
by route of admission & gestation at
birth
90%
80%
47%
Percentage of cases
70%
60%
50%
N. meningitidis
40%
Other G negative
E. coli
30%
Other G positive
L. monocytogenes
20%
Non pyogenic streptococci
S. pneumoniae
10%
Group B strep
0%
Home (term)
Home (preterm)
In-patient (term)
Route of admission and maturity at birth
In-patient (preterm)

18. Aetiology of neonatal (0-28 days of
age) current vs historical for England &
Bacteria
1985-87
Wales1996-97
(0.22/1000)
(0.21/1000)
2010-11
(0.21/1000)
GBS
38%
48%
60%
E. coli
25%
18%
14%
S. pneumoniae
6%
6%
6%
L.
monocytogenes
N. meningitidis
7%
5%
3%
4%
4%
2%
Other Gram
12%
8%
8%
neg
Other Gram
5%
12%
7%
pos Arch Dis Child 1991;66:603-7 . Arch Dis Child Fetal Neonatal Ed 2001;84:F85-9

19. Comparison of aetiology with
other international studies
Cases 0-28 days of age
Bacteria
GBS
E. coli
NM
SPN
LM
Other GNB
Other GPC
France 200107
N=439
258 (59%)
123 (28%)
14 (3%)
8 (2%)
7 (2%)
19 (4%)
10 (2%)
UK & ROI 201011
N=195
111 (57%)
29 (15%)
3 (2%)
11 (6%)
10 (5%)
17 (9%)
14 (7%)

20. Comparison of aetiology with other international studie
UK & ROI 2010-11
100%
90%
GBS:
86.1%
Percentage of total cases
USA 2003-07
Cases < 2 months of age
80%
70%
60%
GBS:
78.1%
50%
40%
30%
20%
10%
0%
<2mo

21. Overall Outcome
Overall CFR 25/329 = 7.6% [95% CI: 5.2-11.0]
Death or any serious complication 90/329 = 27% [95% CI: 23-33]
Organism
Total Died (%)
*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
Non-pyogenic
streptococci
9
0 (0)
2 (22)
7
1 (14)
2 (33)
Other Gram positive
11
2 (18)
1 (11)
Other Gram negative
19
5 (26)
4 (29)
*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,

22. Independent risk factors for
death / any serious
complication
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) <0.0001
Coma on admission
10.4 (2.1- 52.0)
Multivariate logistic regression analysis of risk of death or developing a serious
complication.
Features present at the time of admission
0.004

23. Independent risk factors for
death / any serious
complication
Variable
OR (95% CI) p value
Prematurity (<28 weeks)
4.6 (1.8- 11.6)
0.001
Temperature instability on admission
3.0 (1.5- 5.8)
0.001
Convulsions on admission
4.8 (2.4 - 9.4) <0.0001
Coma on admission
19.7 (3.9- 98.7) <0.001
S. pneumoniae
6.6 (2.3- 19.3) <0.0001
Multivariate logistic regression analysis of risk of death or developing a serious

24. Role of LP in making a diagnosis
• LP was done in 315/329 (96%)
• Post antibiotics 197/307 (64%)
- in-patient vs. home admissions: 84% vs. 52%,
p<0.0001
Timing of LP
No bacteria in the CSF (%)
Pre antibiotics
27 (21)
Post antibiotics
103 (79)
[X2, p=0.001]

25. CSF WCC Values: The
challenge
Category (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
Category
17/196 (9%)*
CSF WCC < 10/ mm3
8/94 (9%)**
29-89 d olds

26. Role of blood culture in diagnosis
(n=329)
Overall blood culture negative 134/329
(41%)
Study
Category
Garges (all
B/C negative et alcases)
Wiswell et al
Negative blood culture (%)
EO (0-6d) LO (7-89d) P-value
(38)
43/112 35/9291/217 (42) 0.5
(38)
12/43 (28)
Variable
Visser et al
6/39 (15)
Blood culture positive where no bacteria identified
in CSF
Vergnano et al
9/27 (33)
n/N (%)
75/143 (52)
Wiswell et al Pediatrics. 1995, Vissser at J Pediatr.1980, Garges Pediatrics. 2006, Vergnano ADC- Fetal and Neonatal

27. GBS
meningitis

28. Demographics: Group B strep meningitis
cases
Category
No of cases
2010-2011
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%

29. Presenting features: GBS vs. others
80%
70%
Percentage of total cases
60%
50%
40%
30%
20%
GBS
10%
Other bacteria
0%
Non specific
Presenting features
Specific

30. Comparison of meningitis vs. GBS study in 2000-1
Category
2000-2001 (UK &
ROI)
2010-2011 (UK &
ROI)
Duration
13 months
13 months
Age group
0-89 days
0-89 days
122
0.15 (0.13 - 0.18)
150
0.16 (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)
38 (35-40)
3030 (2110-3460)
39 (37- 40)
3130 (2530-3530)
Total cases
Incidence (/ 1000 LB)
Median gest age (IQR)
Median BW (IQR)

31. 2000 vs. 2010: GBS Case fatality
(%)
Category
2000-2001 2010-2011 p value
All
Term (≥ 37 weeks)
Preterm (<37 weeks)
All EO (0-6 days)
All LO (7-89 days)
Category
Term EO
Preterm EO
Term LO
Preterm LO
12
10
16
15
11
2000-2001
11
23
10
13
5
2
16
2
7
0.04
0.02
1
0.04
0.4
2010-2011 p value
0
0.05
17
1
3
0.2
15
1

32. Outcome

33. Percentage of total cases
Percentage of total number of cases
Timing of onset 2000/1 vs
2010/11
40
35
30
25
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
2000-2001
2010-2011
0-2
20
3
4
5
6
Day of life
2010-11 (n=150)
15
2000-01 (n=122)
10
5
0
1
2
3
4
5
6
7
8
Week of life
9
10 11 12 13

34. 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. 201011), p=0.4
•
blood culture negative cases (%)
23% vs. 19% (2000-1 vs. 2010-11), p=0.4

35. Independent risk factors for
poor outcome in GBS
meningitis
Variable
OR (95% CI) p value
Prematurity (<28 weeks)
9.0 (1.2- 64.8)
0.03
Temperature instability on admission
3.2 (1.1- 9.7)
0.04
Convulsions on admission
3.2 (1.2- 8.6)
0.02
13.1 (2.3- 73.9)
0.003
Coma on admission
Multivariate logistic regression analysis of risk of death or developing a serious
complication.

36. Can we improve our
management?
Objectives
To 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

37. Methodolog
y
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 2013
Ethics Cambs 2 REC: Ref: 10/H0308/64

38. diagnosis
(preliminary data)
Category
Male
Age in days: median (IQR)
Value
18 (59%)
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)

39. 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

40. Summary 1: Burden of
disease
 Incidence
- Has not changed in neonates over last 3 decades
 Risk factors
- Prematurity and low birth weight
 Presentation
- Non specific, fever absent in around half of cases
 Aetiology
- GBS> E. coli> S. pneumoniae.
- No Listeria meningitis in infants >1 month of age
• Outcome
- CFR has not changed over last 2 decades

41. 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

42. 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

43. Acknowledgements
Chief Investigator
Prof Paul T Heath
Dr Nelly Ninis (London)
Dr. Mark Anthony (Oxford)
Dr. Laura Jones (Edinburgh)
Prof Mary Cafferkey (Ireland)
Dr. Katy Sinka (Scotland)
AMR & HCAI
Prof. Alan Johnson
Katherine Henderson
Ruth Blackburn
Dr. Berit Muller-Pebody
Helen Friend
Richard Lynn
MRL Manchester
All Paediatricians
Prof. Ray Borrow
in the UK & the RoI
Support Charities:
Meningitis UK/ Meningitis
Trust
Dr. Claire Cameron
and Group B Strep Support
Dr. Alison Smith-Palmer
St George’s Vaccine Institute
Dr. Eisin McDonald
meningitis@sgul.ac.uk
staff
Dr. Robert Cunney
Others
(HSE Ireland)
Dr Eva Galiza
UK & ROI Paediatricians and PIC contacts
Dr. S Ladhani
(HCD)
Funding