Multiple Modalities to Explore
Typhoid among Children:
implication in vaccination policy
Samir K Saha
Child Health Research Foundation
&
Dhaka Shishu Hospital
• ~150 million people
BANGLADESH
–7th most populous
country in the world
• Population density
~2,000 persons/square
kilometer
–Highest among any
country
• Global mean 42 persons/
km2
• Per capita income - US$
840
®
Dhaka Trade Mark
Prior Antibiotic – Community and Hospital
Before coming to hospital
32%
At hospital, prior to specimen collection
20%
Overall cases without prior antibiotic
48%
•
•
•
•
Surveillance for Invasive Bacterial
Infections – Multiple Modalities
Multicentre laboratory based
surveillance in Dhaka city
Multicentre hospital based
surveillance – Urban and Rural
Population based surveillance in a
rural community
Population based surveillance in an
urban slum
3
Multicentre Laboratory Based
Surveillance in Dhaka City (1994 – 2011)
Out patient based
diagnostic centers
DHAKA CITY
PDC
– Expensive private
facilities
– Cases referred by senior
pricey practitioners
– Higher SES
4
Multicentre Laboratory Based
Surveillance in Dhaka City (1994 – 2011)
Total Blood Culture = 74,210
Positive Cases = 6,678 (9%)
PDC
Salmonella Typhi = 4,111 (62%)
5
Hospital Based Surveillance Network of 4 Hospitals (1,055 beds)
Rural
Hospital
• 60 Km from
Dhaka
• 80 Paediatric
Beds
Chittagong
Dhaka Shishu Hospital
600 Paediatric Beds
WHO Sentinel Site
SSF,
Dhaka
•300 Km from
Dhaka
•200 Paediatric
beds
• Dhaka
• 175
Paediatric
Beds
KWMCH
60km
SSF
DSH
Dhaka
300km
COMSH
Multicentre Hospital Based Surveillance for
invasive bacterial diseases
Screen babies of
2-59 months
IF MEET INCLUSION
EXCLUSION CRITERIA
ELIGIBLE
Consent taken
BLOOD COLLECTION
ENROLLED
CULTURE
Multicentre Hospital Based Surveillance for
Invasive Bacterial Diseases – 3 urban hospitals
Number of blood
cultures (18,652)
495
500
– 495 S. typhi
400
– 64% of all isolates
Predominance of S. typhi
300
– True for other hospitals
All admitted cases
200
100
– More severe cases than
community patients in lab
based surveillance
89
68
53
28
21
0
Pneumococcus Haemophilus
E. coli
Klebsiella
S. Typhi
Paratyphi
14
Other
Salmonella
Multicentre Hospital Based Surveillance for
Invasive Bacterial Diseases – Rural hospital
35
30
30
25
23
20
15
10
5
0
10
4
3
2
• Total blood
culture – 4,203
• Relatively low
rate of isolation
– 42% of all
isolate
– Relatively low
prevalence
Mirzapur, Rural Bangladesh
POPULATION BASED FIELD SITE
Integrated Rural Field Site
• Mirzapur
Rural
Hospital
– 63 kilometers north of Dhaka
city
– Population: 400,000
• Health facilities:
Chittagong
Dhaka Shishu Hospital
SSF, Dhaka
– Kumudini
beds)
Hospital
(750
• ~120 pediatric patients at
OPD daily
• >500 patients a day
• Pediatric ward of 80 beds
– Upazilla Health Complex (31
beds)
Distribution of Blood Culture in Rural
Bangladesh
30
25
Frequency of Isolates
24
20
15
10
5
0
9
4
2
2
1
1
Variables
No.
Population
144,000
Total enrolled
11,439
Episodes with
temp ≥100.40F
3,978
Blood Culture
done
3,724
Age-specific Incidence of typhoid
fever <5 children in rural Bangladesh
Age
groups
(months)
0 – 11
Culture
confirmed
cases
Typhoid
incidence/
per 100,000
person-years
0 (0)
0
12 – 23
3 (12.5)
94
24 – 35
6 (25)
145
36 – 47
13 (54.2)
304
48 – 59
2 (8.3)
64
24 (100)
151
Total
Population Based Surveillance in
Urban Slum
14
Population Based Surveillance in Urban Slum
Active surveillance
all age group
•Fever ≥380C – blood culture
Total blood culture – 888
Total positive – 65 (7%)
S. typhi – 49 (75%)
•Predominant cause of
bacteraemic fever
Incidence
•<5 years – 19
episodes/1000 person-years
•≥5 years – 4 episodes/1000
person-years
Brooks et al 2005
15
The specter of anti-microbial
resistance
DO WE KNOW THE DYNAMICS?
Treatment of Typhoid Fever
• 1st line of Antibiotic
– Amoxycillin
– Chloramphenicol
– Cotrimoxazole
– Slow epidemic of multidrug resistant S. Typhi in
the subcontinent
• Concern for the public health
practitioners
• Confusion between clinicians
and microbiologists
60
50
40
• Problem since 1990s
62%
30
• 2nd line of antibiotic
20
10
– Ceftriaxone - Expensive
– Ciprofloxacin – Widely Used
0
MDR (1992-93)
Saha et al. 1995
17
Trend of Drug Resistance ‘94-’11
(N=5,937 )
• Progressive
71
Hospital
70 increase in
Community
60 relative
56
50 resistance to
40
40 ciprofloxacin
33
% of Multidrug resistant strains
80
30
20
10
0
30
26 in clinical
– Delay
response
16
13 11
7
– Treatment
failure
95 96 97 98
–94Recurrences
100
in Nalidixic
Acidresistance
Resistance
•Increase
Decrease
in drug
72
63
62
• Remarkable
difference
59
57
56
between hospital and
48
46
community
isolates!!!
44
44
41
90
80
70
60
50
29 40 29
22
30
14
20
33
14
38
41
– Ideal sub-continental
35 practice
34
in treating typhoid
25
34
• Community Vs Hospital
– Origin of data
18
23
22
10
0
99 0098 01
03 020403 05
06 060707 08
9 10
10 1111
99 02
00 01
04 05
08 09
Saha et al Antimicrobial Agents Chemother1990, Saha et al Antimicrobial Agents Chemother1995
Emergence of Highly Cipro-Resistant S.
Typhi: Molecular Basis of Resistance
• Highly ciprofloxacin
resistant S. Typhi
– MIC 512 µg/ml
– Double mutation at
point 83 and 87 of
gyrase genome
– Contrast to “No
mutation” in
sensitive strains
Control, No
treatment
Double
mutations
No
mutation
Saha et al. J. Clin Microbiol 2006
Financial Implications of Drug
Resistance
• High prevalence of
MDR and NalidR
• Increasing trend
isolation at hospital
– Hospitalization lead to
10 times increase in
direct cost ($22-29 Vs
$172-286)
• Mean income of
typhoid cases - $73
– Indirect cost – absence
from the business, food
for attendants, missing
schools, etc.
250
200
150
100
50
0
01 02 03 04 05 06 07 08 09 10 11
20
Improved Living Conditions – sanitation, hygiene,
piped water and so on
WHAT COULD BE THE POSSIBLE IMPACT
ON TYPHOID?
Comparative Prevalence of Typhoid
in Urban and Rural Bangladesh
Urban Rural
Among blood cultures Hospital 2.7%
Among blood cultures - Community 5.4
0.80%
0.64%
Among isolates - Hospital 64%
41%
Among isolates - Community 75%
56%
Incidence/100,000 1,900
151
45
40
35
30
25
20
15
10
5
0
51
61
74
81
91
01
15
Immunization against Typhoid
PERSPECTIVE FOR BANGLADESH
AND BEYOND
Typhoid: Dogma of Recent Past
The disease is not prevalent among Preschool
Children
Even if it is there, the disease episodes are
benign
Age Group Distribution of Typhoid
Cases (N= 5,937)
16
14
14
14
• Maximum number of
cases in 2nd year of
life
• Not in agreement
with the common
belief of age
distribution
13
12
12
%
10
8
6
4
2
8
6
6
7
4
4
3
2
1
1
1
1
1
1
0
1st 2nd 3rd 4th 5th 6th 7th 8th 9th 10th 11th 12th 13th 14th 15th 16th 17th 18th
Age in Year
Age Group Distribution (N= 5,937) –
impact on typhoid vaccination policy
120
Conjugate
Original
Adapted
vaccine
recommendation
recommendation
can give
for vaccination
for
vaccination
98%
coverage
100
Percentage
80
60
Existing
Conjugate
vaccine
vaccine
not
immunogenic
needed for this
in
23%group
of cases
78
59
49
37
40
23
20
0
92
100
0.8
0-6m
7
0-12m
0-24m
0-36m
0-48m
Age
0-60m
0-9y
0-19y
All age
Typhoid in Early Age
IS IT REALLY SEVERE IN YOUNGER
AGE GROUP?
Magnitude of S. Typhi bacteraemia
No. of Bacteria per ml of blood
35
30
25
31
23
• Previous concept:
Less severe in
young infants?
22
– High magnitude of
bacteremia
– Facility based
study
20
15
15
16
11
10
7
5
0
1-12m 13-24m 25-36m 37-48m
Saha et al PIDJ, 2000
5-9y
• Care seeking
behavior
• Access to health
– We dealt with
sicker children
• Severity in young
children is no less
10-19y =>20y
Age Distribution of Typhoid Cases in
Hospital and Community
-30
Isolates in hospital-10
-20
0Isolates in community
10
1st
2nd
3rd
4th
5th
6th
7th
8th
9th
11th
12th
13th
14th
15th
16th
17th
18th
20
Duration of Hospital
by age
Duration
ofStayHospital
Stay by Age Group
18
13
12
12
9
12
10
10
7
6
14
14
10
6
16
16
6
7
5
6
5
4
2
1
3
2
15 14 13 12 11 10 9
8
7
6
5
< 2 year
<2 years
4
3
2
0
1 0
3
2
21
1
10
8
8
5
10
2
2
2
1
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
2-5 year
2-5 years
• Similar duration of hospital stay irrespective of age
group
So we can not just escape the children
THESE ARE NOT THE POPULATION
WE ARE LOOKING FOR
What needs to be done to prevent Typhoid
IMPROVED SANITATION AND
IMMUNIZATION
Highest Price Tag for Child Survival
WATER AND SANITATION
Impact of Immunization is Straight
Forward
• Bangladesh has Few
Things to be Proud
22
15
Neonatal Tetanus Deaths
13
7
2
3 4 3 3
1 0
– Our Immunization
Program
– a success story e.g. near
disappearance of
Tetanus, Diphtheria,
Polio, Hib, etc.
• In the process of
introducing Pneumo
vaccine
Issues with Typhoid Vaccines –
Polysaccharide vs Protein
Conjugated Vaccine
When conjugation technology is
available for last 3 decades
Why the Uncertainty about Conjugate
Vaccine for Typhoid?
Industries are not
interested
No dedicated group
to translate the
typhoid research to
public policy. As
there is no donor!!
Disproportionately
affects the people
of developing
countries
Minimal
commercial value
Possibility of
market failure
Are we too much focused to our own agenda?
HOPE TO GET BACK THE PERIPHERAL
VISION SOON
Expectations from this Meeting
• Bangladesh will be part of Global Health Work
of UoT focusing on
– Infectious Diseases
– Translation of Science to Public Policy
Donor Driven Research
WE DIDN’T INTEND TO DO ANY
RESEARCH ON TYPHOID SPECIFICALLY
Key Issues for this Talk
•
•
•
•
•
Child Health
Infectious Diseases
Typhoid
Surveillance
Vaccines
Illogical
of Child
Technologies
LimitedDistribution
Resources Vs
Death
80
60
S. Typhi cases per year in Ontario,
2002-2007
72
70
50
72
55
60
40
20
0
2002 2003 2004 2005 2006 2007
Why the typhoid issue at Toronto?
DIDN’T WE ERADICATE TYPHOID
YEARS AGO?
Morris et al 2009
Typhoid Travels Across the World
1,503 Typhoid cases in UK, 2006-09
1200
1000
998
Central
& South
America
, 1%
800
600
423
400
200
28
0
England
London Tower Hamlets Newham
439
400
439
413
2008
2007
347
300
200
100
0
2010
2009
Africa,
1%
Oceania,
1%
Unspecifi
ed,4%
54
Typhoid cases in USA
500
227 Typhoid Cases in Japan,
2005-08
SEA,
21%
Japan
16%
South
Asia
56%
Typhoid – A Global Disease
IT CAN NOT BE FOOLED BY SAYING - THESE
ARE NOT THE POPULATIONS YOU ARE
LOOKING FOR!
Typhoid Through the Centuries
Developing Countries
Municipal Water Treatment / Sanitation ?
Urbanization
Developed Countries
50%
60%
75%
Enteric Fever Cases
Municipal Water Treatment / Sanitation
Urbanization
50%
60%
75%
Industrialization
1800
1850
Isolation of
S. typhi
organisim
(1880)
1900
Widal
Diagnostic
(1896)
1950
Typhoid
immunization
available
Development of
Chloramphenicol
heat-inactivated
(1948+)
phenol-preserved
whole-cell typhoid vaccine
150 years
Acetoneinactivated
whole-cell
typhoid
vaccine
(1960s
Ty21a
(live oral)
Purified
Vi PS
2000
?
Quinolones and
3rd gen.
cephalosporins
?? Vi conjugate??
?? Single-dose
live oral ??
2050
2100
How Big a Problem Is This and Where?
• Estimates 17-21.6
million cases
• 216,000 to 600,000
deaths
– Comparable to many
other diseases!
• Where?
Typhoid Remains Neglected
• None at WHO
• No GAVI Initiative,
• Recent initiative from BMGF – DOMI (Diseases
of the most impoverished) programme
• More Recently “Coalition Against Typhoid”
DOMI TYPHOID PROGRAM
Population-based studies
700
600
500
400
300
200
100
0
2-4Y
573
413
5-15Y
494
340
180
149
24
29
CHINA, INDIA, INDONESIA, PAKISTAN, VIETNAM
Tunnel Versioned!
I HOPE THESE INITIATIVES COULD
BE WITH BROADER PERSPECTIVES
Bangladesh Team
TAKEN THEIR VISION OUT OF THE
TUNNEL TO UNDERSTAND TYPHOID