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