Progress in typhoid epidemiology

John A. Crump, MB ChB, MD, DTM&H

McKinlay Professor of Global Health

10th International Conference on Typhoid

and Other Invasive Salmonelloses

4 April 2017

Overview

• Mode of transmission and sources

– Evidence and importance

• Burden of disease

– Current estimates and trends

– Extrapolation, uncertainty, and data gaps

– Severe disease and death

– Occurrence by age

Modes of transmission

Direct transmission

Direct contact

Droplet spread

Indirect transmission

Airborne

Vectorborne

Vehicleborne

= ‘Person-to-person transmission’

Direct contact between persons without intermediaries

Chain of infection

Portal of

exitPortal of entry

Susceptible

hostReservoir

Mode of

transmission

Other

What is the source and

predominant mode(s) of

transmission?

What is the

relative

contribution of

acute shedders

versus chronic

carriers?

Source

Mode of transmission in aggregate

• Mogasale systematic review and meta-analysis association between unimproved water and typhoid fever

– Persons with unimproved water have 2.4 times odds of typhoid fever compared with those with improved water

– Aggregating empiric studies is informative

• WHO Foodborne Diseases Epidemiology Reference Group Source Attribution Task Force, structured expert elicitation using Cooke's Classical Method

– Water: 0.33-0.57

– Food: 0.08-0.49

– Other: 0.11-0.47

Mogasale V, et al. Lancet Glob Health 2014; 2: e570-80

Hald T, et al. PLoS One 2015; 11: e0145839

Mode of transmission locally

• Foodborne

– Restaurant-associated outbreaks linked to chronic carriage in food handler in countries where typhoid is rare e.g., Colorado, United States

• Waterborne

– Municipal water supplies e.g., Kathmandu, Nepal

• Waterborne and foodborne

– Consuming surface water and produce grown in pit latrine seepage e.g., Central Division, Fiji

Hancock-Allen J, et al. MMWR Morb Mortal Wkly Rep 2017; 66: 295-8

Karkey A, et al. PLoS Neglect Trop Dis 2016; 10: e0004346

Prasad N, et al. 10th International Conference on Typhoid and Other Invasive Salmonellses, 2017

Jenkins A,, et al. 10th International Conference on Typhoid and Other Invasive Salmonellses, 2017

Role of infection class on transmission

• Fecal shedding classes following onset of acute illness

– Acute shedding: <3 months

– Convalescent carriers: 3-12 months

– Chronic carriers: >12 months

• Things that we ‘know’

– At low force of infection a larger proportion of acute typhoid is in age groups more susceptible to becoming chronic carriers

– As acute typhoid infections approach zero the role of chronic carriers as the reservoir approaches 100%

– Much to learn

History of published estimates of typhoid burden

Year

Metrics 1980 1996 2000 2010 2010 2010 2010 2013 2015 2015

Origin WHO WHO US CDC IVI JHU WHO IHME IHME IHME Yale

Coverage Global,

except

China

Global Global LMIC,

unadjusted

Global Global Global,

including

paratyphoid

Global Global LMIC

Illnesses

(millions)

12.5 16.0 21.7 20.6 26.9 20.1 - 11.0 12.5 17.8

DALYs

(thousands)

- - - - - 10,292 12,239 11,128 10,576 -

Deaths - 600,000 216,510 223,000 - 144,890 190,200 160,700 148,800 -

Global population, 1980-2015

0

1

2

3

4

5

6

7

8

1980 1985 1990 1995 2000 2005 2010 2015

Year

Po

pu

lati

on

(b

illio

ns)

Global population and typhoid illness estimates

1980-2015

0

5

10

15

20

25

0

1

2

3

4

5

6

7

8

1980 1985 1990 1995 2000 2005 2010 2015

Year

Po

pu

lati

on

(b

illio

ns)

Typ

ho

id i

lln

esses (

millio

ns)

Excluded China

Global population and typhoid illness estimates

1980-2015

0

5

10

15

20

25

30

35

40

0

1

2

3

4

5

6

7

8

1980 1985 1990 1995 2000 2005 2010 2015

Year

Po

pu

lati

on

(b

illio

ns)

Typ

ho

id i

lln

esses (

millio

ns)

Global population and typhoid illness estimates

1995-2015

0

5

10

15

20

25

0

1

2

3

4

5

6

7

8

1995 2000 2005 2010 2015

Year

Po

pu

lati

on

(b

illio

ns)

Typ

ho

id i

lln

ess

es

(m

illi

on

s)

Typhoid incidence and deaths

1995-2015

0

200,000

400,000

600,000

800,000

0

50

100

150

200

250

300

350

400

1995 2000 2005 2010 2015

Year

Typ

ho

id i

ncid

en

ce/

100,0

00/

year

Typ

ho

id d

eath

s p

er

year

Extrapolation, uncertainty, and data gaps

• Improvements in methods for extrapolation

• Estimating uncertainty

• Data gaps

– Areas and age groups needing incidence data

– More and better data on disability and death

– The ‘hidden’ problem in Oceania

Antillon M, et al. PLoS Neglect Trop Dis 2017; 11: e0005376

Change in improved drinking water coverage

by region, 1990 to 2015

UNICEF and WHO. 2015

Sub-Saharan Africa

Oceania

Typhoid fever in infants and young children aged <2 years

0

200

400

600

0 6 12 18 24

Age (months)

Inc

ide

nc

e p

er

10

0,0

00/y

ea

r Volume

inadequacyContamination

Under-ascertainment

by blood culture

UnderuseMaternal

antibody

Breast

feeding

Protection, disease,

and lack of exposure

Mild

disease

Force of infection

William Budd, b. 14 Sep 1811, d. 9 Jan 1880

Role of infection class in transmission

• Things that we would like to know more about

– Proportion stool cultures positive in acute disease

vs. chronic carriage

– Concentration of Salmonella Typhi in feces in acute

disease vs. chronic carriage

Thomson S. J Hyg 1954; 52: 67-70

Merselis JG, et al. Am J Trop Med Hyg 1964; 13: 425-9

Distribution of typhoid fever by age group at

various incidence levels, 2000

Crump JA, et al. Bull World Health Organ 2004; 82: 346-53

Typhoid fever DALYs and deaths by age

Global Burden of Disease 2015

0

200

400

600

800

1000

EN

LN

PN

1-4

5-9

10-1

4

15-1

9

20-2

4

25-2

9

30-3

4

35-3

9

40-4

4

45-4

9

50-5

4

55-5

9

60-6

4

65-6

9

70-7

4

75-7

9

80+

Age (years)

DA

LY

s p

er

10

0,0

00

Disability Adjusted Life Years

0

2

4

6

8

10

EN

LN

PN

1-4

5-9

10-1

4

15-1

9

20-2

4

25-2

9

30-3

4

35-3

9

40-4

4

45-4

9

50-5

4

55-5

9

60-6

4

65-6

9

70-7

4

75-7

9

80+

Dea

ths

pe

r 1

00

,000

Age (years)

Deaths

http://vizhub.healthdata.org/gbd-compare/

Social inequity

• High-income countries

– Declined following increased access to safe water and

food in urban areas

– Disease of travelers, beneficiaries of typhoid vaccines

• Low- and middle-income countries

– Poor sanitation, unsafe water and food

– Crowding

– Limited access to vaccines

Acute disease and chronic carriage as reservoir

0

20

40

60

80

100

None Low Medium High Very high

Typhoid incidence level

Pro

po

rtio

n o

f in

fecti

on

s w

ith

ch

ron

ic c

arr

ier

as r

ese

rvo

ir

Deaths by cause and age, Hamburg, Germany, 1872-1900

Sedgwick WT, et al. J Infect Dis 1910; 7: 490-564 1872 1900

1872 1900

Typhoid fever deaths

Infant deaths

Elbe River water

filtered

Improved drinking water coverage, global, 2015

UNICEF and WHO. 2015

Data inequity

• High-income countries

– Laboratory confirmation

– Notifiable disease with high reporting

– Robust data

• Low- and middle-income countries

– Dependence on clinical diagnosis

– Weak surveillance with low reporting

– Poor quality routine data

– Special studies

Moving targets for vaccine

• Person, place, and time

– Vaccination of ‘high risk groups and populations’ based on ‘local epidemiologic situation’

– Who should be vaccinated and where?

• Age

– ‘Immunization of school-age and/or preschool-age children’

– Typhoid conjugate vaccines can protect below 2 years of age

– At what age should we vaccinate to prevent the most disease?

Global distribution of typhoid fever, 2000 vs. 2010

Crump JA, et al. Bull World Health Organ 2004; 82: 346-53 Mogasale V, et al. Lancet Glob Health 2014; 2: e570-80

Salmonella enterica bloodstream infections, Queen

Elizabeth Central Hospital, Blantyre, Malawi, 1998-2014

Feasey NA, et al. Clin Infect Dis 2015; 61 (suppl 4): S363-71

Conclusions

• Current typhoid fever estimates are remarkably consistent, improving with

– New data

– Better extrapolation and modeling

• Data are weakest in areas with most disease

– Complications and death

• Typhoid fever incidence varies in person, place, and time

– Targeting vaccine is challenging

– Need to understand more about disease in infants and young children

Role of infection class in transmission

• Fecal shedding classes following onset of acute illness

– Acute shedding: <3 months

– Convalescent carriers: 3-12 months

– Chronic carriers: >12 months

• Things that we ‘know’

– At low force of infection a larger proportion of acute

typhoid is in age groups more susceptible to becoming

chronic carriers

– As acute typhoid infections approach zero the role of

chronic carriers as the reservoir approaches 100%

Role of infection class in transmission

• Things that we would like to know more about

– Proportion stool cultures positive higher in acute

disease vs. chronic carriage?

– Concentration of Salmonella Typhi in feces higher in

acute disease vs. chronic carriage?

• Chronic carriers (when positive): 106-1010 CFU/g (Merselis)

• <102-107 (Thomson)

Thomson S. J Hyg 1954; 52: 67-70

Merselis JG, et al. Am J Trop Med Hyg 1964; 13: 425-9