Brian Williams with acknowledgements to Philippe Glaziou · ARTI in South Korea South Korea Halving...

Late night thoughts on tuberculin surveys

Brian Williams with acknowledgements to

Philippe Glaziou

Cairo, October 2009

Karel Styblo: 1985

If the annual risk of TB infection

is 1% the annual incidence of

TB disease is 50/100k/yr.

If the prevalence of TB in

children aged A is P then the

annual risk of TB infection is

ARI = 1-(1-P)1/A

We can use the prevalence in

children to estimate the

incidence in adults

First the good news…

Frequency distribution of induration sizes in Cape Town

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

1955 1965 1975 1985 1995

AR

TI in

So

uth

Ko

rea

South Korea

Halving every

ln(2)/0.08 ≈ 10 years

Rate of decline = 7.8%/yr

0

100

200

300

400

500

600

700

800

900

1960 1965 1970 1975 1980 1985 1990 1995

Pre

va

len

ce

SS

+ T

B/1

00

kSouth Korea

Rate of decline = 8.0%/yr

0

100

200

300

1960 1970 1980 1990

SS

+ T

B in

cid

en

ce

/10

0k

ARTI×50

Civil servants

South Korea

Rate of decline = 8%/yr

Now the bad news…

South Korea Survey of

Incidence among Civil Servants

1998: Baseline

920,000 had chest radiography

1990: Follow up

790,000 available for CXR

2,500 with suspicious X-rays

2000 had sputa taken

300 culture positive

200 smear positive

Styblo’s argument assumptions (before chemotherapy)

Each prevalent SS+ case infects 10 people per year

Disease duration is 2 years

Each incident SS+ case infects 20 other people

ARI = 20××××Incidence

Incidence = ARI/20

Incidence××××100k = (ARI××××100)/100××××100k/20

= (ARI/100)××××50

1% ARI corresponds to and incidence of 50/100k

ARI is independent of age. Average over last ten years

Low prevalence

As the incidence declines, the

prevalence of infection declines and it

gets much harder to measure it.

Changes in distribution patterns of

induration size in Korea

Environmental mycobacteria

Prevalence of environmental

mycobacteria seems to be very high

around the equator and declines at very

high and very low latitudes

Frequency distribution of induration sizes in Somalia.

Red: fitted; black: environmental; green: TB

Dependence on testing day

(Somalia 2006)

Proportion positive when the induration was read on

three of four days after the challenge

Dependence on BCG

(Somalia 2006)

Proportion positive with and without a BCG scar

The way forward?

Tuberculin skin test responses in

houehold contacts of active TB cases979 children, median age 7yr, Istanbul

0

10

20

30

40

50

60

70

80

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31

ELISpot -ve

ELISpot +ve

Source: Bakir et al 2006

Thank you

0 5 10 15 20 25

Induration size (mm.)

Fre

qu

en

cy (

%)

10

8

6

4

2

0

Annual risk of tuberclous infection in the northern zone of India

Chadha, V.K. et al. Bull. WHO (2003)

Styblo assumptions (cont)

• An infected case develops TB with probably 0.1 over his lifetime

• The probability for TB to be smear positive is 0.5

• Therefore, 1 smear positive generates: 10 x 2 x 0.1 x 0.5 = 1 new smear positive case over 1 transmission cycle and TB is stably endemic

Origin of Styblo’s ruleBull IUAT vol 60, 1985

Ratio basedon

Risk of infection(%)

Ratio ofrisk:incidence

Netherlands 1921-38 Mortality 2.7 – 6.0 38

Netherlands 1951-76 Incidence 0.038 – 0.4 37

Developingcountries

1956-61 Prevalence 2.0 – 8.0 40-60

Alaskaeskimos

1948-51 Mortality 25 52

Indialongitudinalstudy

1961-68 Prevalence 1.5 53

Indiapreventiontrial

1969-71 Prevalence 4.1 51

Changes in Styblo ratio in Chennai, S. India

0

50

100

K P E Th Ti TiT All

Blocks in Chingelput district

Inc

ide

nc

e S

+C

+/A

RT

I

1968-71

1973-78

Source: IJTLD 5, 142 (2001)

Assumptions (cont)

• 2 year duration of infectiousness: not necessarily true, duration may decrease with increasing programme performance

• 10 cases infected per year: depends on living conditions, number of household members, etc, and may decline over time

• TB is in a steady state: untrue in most countries

High sensitivity to assumptions on

distributions in Somalia

Inconsistent patterns

(Somalia 2006)

In summary

• Interpretation of data can be problematic

• Diagnostic value of PPD test difficult to predict

• Uncertainty about the relationship between prevalence of infection and incidence

• Uncertainty about time changes in the distribution of determinants of induration size

• Difficult to interpret time-changes in ARI

Diverging time-changes between

SS(+) prevalence and ARI in China

Source: Bulletin of the World Health Organization 2008;86:20–26.

Diverging time-changes between SS(+)

prevalence and ARI in the Philippines

Source: Bulletin of the World Health Organization 2008;86:20–26.

Ethical considerations

• No (or little) benefit to surveyed individuals

• Most often done in children

• Ethical requirements:

– Clearance from ethical committee

– Informed consent from parents

– Informed consent from children

Sampling

Typically multistage with clusters defined as schools or classes within schools→ need to account for sampling design when computing age-specific prevalence of infection→ is the sample self-weighed (each selected child should represent the same number of children)?→ missing values (e.g. Malawi, 21%)

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20 25 30

0

100

200

300

400

500

600

0 5 10 15 20 25 30

Induration (mm.)

Nu

mb

er/

mm

.Can tuberculin surveys measure risk of infection?

Data from Somalia 2006