multiple modalities to explore typhoid among children ......multiple modalities to explore typhoid...
TRANSCRIPT
Multiple Modalities to Explore Typhoid among Children:
implication in vaccination policy
Samir K Saha Child Health Research Foundation
& Dhaka Shishu Hospital
• ~150 million people –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%
BANGLADESH
3
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
4
PDC
Multicentre Laboratory Based Surveillance in Dhaka City (1994 – 2011)
DHAKA CITY
Out patient based diagnostic centers – Expensive private
facilities – Cases referred by senior
pricey practitioners – Higher SES
5
PDC
Multicentre Laboratory Based Surveillance in Dhaka City (1994 – 2011)
Total Blood Culture = 74,210
Positive Cases = 6,678 (9%)
Salmonella Typhi = 4,111 (62%)
Hospital Based Surveillance - Network of 4 Hospitals (1,055 beds)
Rural Hospital
• 60 Km from Dhaka
• 80 Paediatric Beds
Chittagong
•300 Km from Dhaka
•200 Paediatric beds
SSF, Dhaka
• Dhaka • 175
Paediatric Beds
Dhaka Shishu Hospital 600 Paediatric Beds
WHO Sentinel Site
Dhaka SSF
KWMCH
COMSH
60km
300km
DSH
Multicentre Hospital Based Surveillance for invasive bacterial diseases
IF MEET INCLUSION EXCLUSION CRITERIA
Screen babies of 2-59 months
Consent taken
BLOOD COLLECTION
ELIGIBLE
CULTURE
ENROLLED
Multicentre Hospital Based Surveillance for Invasive Bacterial Diseases – 3 urban hospitals
68
21
53
89
495
28 14
0
100
200
300
400
500
Pneumococcus Haemophilus E. coli Klebsiella S. Typhi Paratyphi Other Salmonella
Number of blood cultures (18,652) – 495 S. typhi – 64% of all isolates
Predominance of S. typhi – True for other hospitals
All admitted cases – More severe cases than
community patients in lab based surveillance
23
10
4 3
30
2
0
5
10
15
20
25
30
35
Multicentre Hospital Based Surveillance for Invasive Bacterial Diseases – Rural hospital
• Total blood culture – 4,203
• Relatively low rate of isolation – 42% of all
isolate – Relatively low
prevalence
POPULATION BASED FIELD SITE Mirzapur, Rural Bangladesh
Integrated Rural Field Site
Rural Hospital
Chittagong
SSF, Dhaka
Dhaka Shishu Hospital
• Mirzapur – 63 kilometers north of Dhaka
city – Population: 400,000
• Health facilities: – Kumudini Hospital (750
beds) • ~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
24
9
4 2 2 1 1
0
5
10
15
20
25
30 Frequency of Isolates Variables No.
Population 144,000
Total enrolled 11,439
Episodes with temp ≥100.40F
3,978
Blood Culture done 3,724
Age groups
(months)
Culture confirmed
cases
Typhoid incidence/ per 100,000
person-years
0 – 11 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
Total 24 (100) 151
Age-specific Incidence of typhoid fever <5 children in rural Bangladesh
Population Based Surveillance in Urban Slum
14
15 Brooks et al 2005
Population Based Surveillance in Urban Slum
Incidence •<5 years – 19 episodes/1000 person-years •≥5 years – 4 episodes/1000 person-years
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
DO WE KNOW THE DYNAMICS?
The specter of anti-microbial resistance
17
Treatment of Typhoid Fever • 1st line of Antibiotic
– Amoxycillin – Chloramphenicol – Cotrimoxazole
• Problem since 1990s – Slow epidemic of multi-
drug resistant S. Typhi in the subcontinent
• 2nd line of antibiotic – Ceftriaxone - Expensive – Ciprofloxacin – Widely Used 0
10
20
30
40
50
60
MDR (1992-93) Saha et al. 1995
• Concern for the public health practitioners
• Confusion between clinicians and microbiologists 62%
Trend of Drug Resistance ‘94-’11 (N=5,937 )
71
56
33 30
40
26
16 13
0
10
20
30
40
50
60
70
80
94 95 96 97
% o
f M
ultid
rug
resi
stan
t st
rain
s Hospital
Community
11
29 29 33
72
62 57
63
56
38 34
41
18 22
7
14 14
22
34
41 44
48
59
46
35
44
25 23
98 99 00 01 02 03 04 05 06 07 08 9 10 11
• Decrease in drug resistance • Remarkable difference
between hospital and community isolates!!! – Ideal sub-continental practice
in treating typhoid • Community Vs Hospital
– Origin of data
Saha et al Antimicrobial Agents Chemother1990, Saha et al Antimicrobial Agents Chemother1995
• Progressive increase in relative resistance to ciprofloxacin – Delay in clinical
response – Treatment
failure – Recurrences
0
10
20
30
40
50
60
70
80
90
100
98 99 00 01 02 03 04 05 06 07 08 09 10 11
Increase in Nalidixic Acid Resistance
Emergence of Highly Cipro-Resistant S. Typhi: Molecular Basis of Resistance
Saha et al. J. Clin Microbiol 2006 No mutation
Double mutations
Control, No treatment
• 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
20
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. 0
50
100
150
200
250
01 02 03 04 05 06 07 08 09 10 11
WHAT COULD BE THE POSSIBLE IMPACT ON TYPHOID?
Improved Living Conditions – sanitation, hygiene, piped water and so on
Comparative Prevalence of Typhoid in Urban and Rural Bangladesh
0 5
10 15 20 25 30 35 40 45
51 61 74 81 91 01 15
Urban Rural
Among blood cultures Hospital 2.7% 0.80%
Among blood cultures - Community 5.4 0.64%
Among isolates - Hospital 64% 41%
Among isolates - Community 75% 56%
Incidence/100,000 1,900 151
PERSPECTIVE FOR BANGLADESH AND BEYOND
Immunization against Typhoid
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)
6
14 14 13
12
8
6 7
4 4 3
2 1 1 1 1 1 1
0
2
4
6
8
10
12
14
16
1st 2nd 3rd 4th 5th 6th 7th 8th 9th 10th 11th 12th 13th 14th 15th 16th 17th 18th
%
Age in Year
• Maximum number of cases in 2nd year of life
• Not in agreement with the common belief of age distribution
Age Group Distribution (N= 5,937) – impact on typhoid vaccination policy
0.8 7
23
37
49 59
78
92 100
0
20
40
60
80
100
120
0-6m 0-12m 0-24m 0-36m 0-48m 0-60m 0-9y 0-19y All age
Perc
enta
ge
Age
Original recommendation
for vaccination
Adapted recommendation
for vaccination
Existing vaccine not immunogenic in
23% of cases
Conjugate vaccine needed for this
group
Conjugate vaccine can give
98% coverage
IS IT REALLY SEVERE IN YOUNGER AGE GROUP?
Typhoid in Early Age
Magnitude of S. Typhi bacteraemia
31
23 22
15 16
11
7
0
5
10
15
20
25
30
35
1-12m 13-24m 25-36m 37-48m 5-9y 10-19y =>20y
No.
of B
acte
ria p
er m
l of b
lood
• Previous concept:
Less severe in young infants? – High magnitude of
bacteremia – Facility based
study • Care seeking
behavior • Access to health
– We dealt with sicker children
• Severity in young children is no less
Saha et al PIDJ, 2000
-30 -20 -10 0 10 20
1st 2nd 3rd 4th 5th 6th 7th 8th 9th
11th 12th 13th 14th 15th 16th 17th 18th
Isolates in hospital Isolates in community
Age Distribution of Typhoid Cases in Hospital and Community
Duration of Hospital Stay by age
1 1
2
6
5
6
10
6
12
9
12
13
7
5
2
1
15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0
< 2 year
0
3
2
5
7
10
16
14
10 10
3
8
2 2 2
1
0
2
4
6
8
10
12
14
16
18
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
2-5 year
Duration of Hospital Stay by Age Group
• Similar duration of hospital stay irrespective of age group
2-5 years <2 years
THESE ARE NOT THE POPULATION WE ARE LOOKING FOR
So we can not just escape the children
IMPROVED SANITATION AND IMMUNIZATION
What needs to be done to prevent Typhoid
WATER AND SANITATION Highest Price Tag for Child Survival
Impact of Immunization is Straight Forward
• Bangladesh has Few Things to be Proud – Our Immunization
Program – a success story e.g. near
disappearance of Tetanus, Diphtheria, Polio, Hib, etc.
• In the process of introducing Pneumo vaccine
22
15 13
2
7
3 4 3 3 1 0
Neonatal Tetanus Deaths
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?
Disproportionately affects the people of developing countries
No dedicated group to translate the typhoid research to public policy. As there is no donor!!
Industries are not interested Minimal commercial value Possibility of market failure
HOPE TO GET BACK THE PERIPHERAL VISION SOON
Are we too much focused to our own agenda?
Expectations from this Meeting
• Bangladesh will be part of Global Health Work of UoT focusing on – Infectious Diseases – Translation of Science to Public Policy
WE DIDN’T INTEND TO DO ANY RESEARCH ON TYPHOID SPECIFICALLY
Donor Driven Research
Key Issues for this Talk
• Child Health • Infectious Diseases • Typhoid • Surveillance • Vaccines
Limited Resources Vs Child Death Illogical Distribution of Technologies
DIDN’T WE ERADICATE TYPHOID YEARS AGO?
Why the typhoid issue at Toronto?
70
50
72
55
72 60
0
20
40
60
80
2002 2003 2004 2005 2006 2007
S. Typhi cases per year in Ontario, 2002-2007
Morris et al 2009
Typhoid Travels Across the World
998
423
28 54 0
200 400 600 800
1000 1200
England London Tower Hamlets Newham
1,503 Typhoid cases in UK, 2006-09
Japan 16%
South Asia 56%
SEA, 21%
Central & South America
, 1%
Africa, 1%
Oceania,1%
Unspecified,4%
227 Typhoid Cases in Japan, 2005-08
439
347
439 413
0
100
200
300
400
500
2010 2009 2008 2007
Typhoid cases in USA
IT CAN NOT BE FOOLED BY SAYING - THESE ARE NOT THE POPULATIONS YOU ARE LOOKING FOR!
Typhoid – A Global Disease
Typhoid Through the Centuries
Industrialization
Urbanization 50% 60% 75%
Enteric Fever Cases
Municipal Water Treatment / Sanitation ?
Urbanization 50% 60% 75%
Developing Countries
Developed Countries
1800 1900 2000 2100 1850 1950 2050
Widal Diagnostic
(1896)
Development of heat-inactivated
phenol-preserved whole-cell typhoid vaccine
Typhoid immunization
available
Chloramphenicol (1948+)
Acetone- inactivated whole-cell
typhoid vaccine (1960s
Ty21a (live oral)
Purified Vi PS
Quinolones and 3rd gen.
cephalosporins
150 years
?? Vi conjugate?? ?? Single-dose
live oral ??
?
Municipal Water Treatment / Sanitation
Isolation of S. typhi
organisim (1880)
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
CHINA, INDIA, INDONESIA, PAKISTAN, VIETNAM 573
340
149
413
494
180
24 29 0
100
200
300
400
500
600
700 2-4Y 5-15Y
I HOPE THESE INITIATIVES COULD BE WITH BROADER PERSPECTIVES
Tunnel Versioned!
TAKEN THEIR VISION OUT OF THE TUNNEL TO UNDERSTAND TYPHOID
Bangladesh Team