The double burden of diabetes

mellitus and tuberculosis:

interactions and challenges for care
__________________________
Anthony D Harries
The Union, Paris, France
London School of Hygiene and Tropical Medicine

Structure of the Presentation

Background Epidemiology
Collaborative Framework for Care
Challenges for Care
Conclusion

Non-communicable and
communicable disease
Diabetes Mellitus (DM)
Disease of antiquity
Three main types: Type 1
Type 2
Gestational DM

Diagnosis: Blood glucose

Treatment: diet, drugs,
insulin for life

Tuberculosis (TB)
Disease of antiquity
Three main types: Site of disease
Bacterially confirmed
Drug sensitive / resistant

Diagnosis: Smear for AFB

Treatment: 6 months of
drugs

Global Burden of DM and TB

Diabetes Mellitus: 2012

Tuberculosis: 2012

371 million people

living with DM

12.0 million people

living with TB

10 million new cases

per annum

8.6 million new cases in

the year

4.8 million people died

of DM during the year

1.3 million people died

of TB during the year

[IDF Diabetes Atlas 2012]

[WHO- Global TB Control 2013]

Global Distribution of DM and TB

Diabetes Mellitus: 2012

Tuberculosis: 2012

South East Asia 19%

South East Asia 40%

Western Pacific

36%

Western Pacific 19%

Africa

4%

Africa

27%

80% in LIC and MIC

95% in LIC and MIC

[IDF Diabetes Atlas 2012]

[WHO- Global TB Control 2013]

India and China [2012]

India

China

63 million DM

92 million DM

2.2 million TB per

annum

1.0 million TB per

annum

Not diagnosed or notified

Diabetes Mellitus 2012

Tuberculosis 2012

371 M with DM

8.6 M with TB

187 M (50%)
undiagnosed

3.0 M (35%) not

notified to NTPs

IDF Diabetes Atlas 2012

WHO Global Report 2013

The global increase in DM

2012

371 million with DM

2030

552 million with DM

[Diabetes Atlas: International Diabetes Federation, 2012]

THE TUBERCLE BACILLUS

TUBERCULOSIS
M.tuberculosis bacteria

~ 2.0 billion people carry this

bacteria in their bodies

Life-time risk of active TB = 5-15%

Risk of active TB increased in

Extremes of age (infants and elderly)

HIV/AIDS
Other causes of immune suppression (steroids)
Silicosis
Malnutrition
Smoke from domestic stoves or cigarettes
Alcohol and substance abuse

Diabetes mellitus

Recognised in Roman times

that DM increases risk of TB

Diabetes Mellitus increases the

risk of TB by a factor of 2 - 3
Stevenson et al, Chronic Illness 2007
Jeon and Murray, PLoS Medicine 2008
Dooley and Chaisson, Lancet Infectious Diseases, 2009
Ruslami et al, Tropical Medicine & International Health, 2010
Goldhaber-Fiebert et al, International Journal Epidemiology 2011

Some evidence that poor DM control increases TB risk (HbA1c >7% = RR 2.56)
[USA,UK, Canada, Mexico, Russia, India, Taiwan, South Korea, Indonesia]

Is this biologically plausible?

YES: Animal models diabetic mice have
impaired cell mediated immunity and have
higher M.TB loads than normal mice

Patients with DM have impaired immunity

and poor lung defences against M.TB

WHO estimates for 2012

PAF of DM for adult TB

No. adults with TB and DM

World

8.3%

1,042,000

South-East Asia

7.6%

423,000

Western Pacific

9.1%

238,000

Africa

5.0%

194,000

Europe

8.5%

94,000

Eastern Mediterranean

9.4%

51,000

The Americas

9.6%

41,000

PAF = population attributable fraction

Lonnroth, Lancet Diabetes Endocrinol 2014

WHO estimates for 2012

PAF of DM for adult TB

No. adults with TB and DM

India

8.6%

302,000

China

9.6%

156,000

South Africa

8.3%

70,000

Indonesia

5.6%

48,000

Pakistan

6.8%

43,000

Bangladesh

5.5%

36,000

Philippines

6.0%

29,000

PAF = population attributable fraction

Lonnroth, Lancet Diabetes Endocrinol 2014

Collaborative Framework for Care

Expert Meeting convened in
November 2009
(WHO, Union, WDF, IDF, Academia,
Ministries of Health)

Rationale for a Framework

Evidence of interaction between DM and TB

Need for guidance on collaborative activities
Evidence weak to support specific guidance
Thus, Provisional Framework
Launched in 2011

To be reviewed and revised by 2015

Collaborative
Framework for Care
and Control of TB
and Diabetes
Launched in August 2011

The recommendations

Document available at: http://www.who.int/tb/publications/2011/en/index.html

Three challenges for care

1. Bi-directional screening

Screening TB patients for Diabetes (DM)

[DM may not be recognised clinically]
Screening DM patients for active TB
[TB may present differently]
Jeon CY et al, TMIH 2010; 15: 1300-1314

Bi-Directional Screening
of TB and Diabetes
Mellitus

China and India

World Diabetes Foundation Support

National Stakeholders Meeting
Training for implementers

Implementation of screening
Review of activities and data
National Stakeholders Meeting

Screen TB patients for DM

Is there is a known diagnosis of DM?

No known diagnosis - screen first with RBG

If RBG 6.1 mmol/l, screen with FBG

If FBG 7.0 mmol/l, then diagnose DM and refer to DM care

Screening TB patients for DM in India

Indicator

TOTAL

Number of patients with TB registered and enrolled

Number (%) with known diagnosis of DM

8269
682 (8)

Number needing to be screened with RBG

7587

Number (%) actually screened with RBG

7467 (98)

Number with RBG >110 mg/dl and needing to be screened with FBG
Number (%) screened with FBG
Number (%) with FBG 126 mg/dl (newly diagnosed with DM)

2838
2703 (95)
402 (5)

Number (%) with known and newly diagnosed DM

1084 (13)

Number (%) with known / newly diagnosed DM referred to DM care

1033 (95)

India TB-DM study group TMIH 2013: 18: 636-45

Screening TB
patients for DM in
India
directive from India TB
Programme to screen TB
patients for DM and link
them to diabetes care
directive from India NCD
programme to use
glucometers to screen TB
patients for DM

Back of the TB Treatment card used in India

Simple parameters added for routine

recording in quarterly TB reports
Number of TB patients registered
Number of TB patients screened for DM
Number of TB patients diagnosed with DM

Screen DM patients for TB

Screen once a quarter when DM patients come to clinic

Ask: Has TB been diagnosed during the quarter

If no, screen for positive symptoms of TB

Refer those with positive symptoms for TB diagnosis and care

Screening of DM Patients for TB in India

DM patients
Number seen in the quarter
Number diagnosed with TB in the quarter from elsewhere
Screened for TB symptoms in the DM clinic in the quarter

Q2-2012
12237
74
6393 (52%)

Positive TB symptom screen

135 (2%)

Referred for TB investigations

128 (95%)

Diagnosed with a new episode of TB

11

Total number with new TB and TB from elsewhere

85

Known to have started or to be on anti-TB Treatment

80

TB cases per 100,000 DM patients seen per quarter

695

India DM-TB study group TMIH 2013; 18: 646-654

Challenges in screening DM
patients for TB
Diabetes doctors not interested extra work
No structured recording systems in DM clinics
No cohort analysis or public health approach

Ways forward: i) programme integration

TB
Clinic

Diabetes Clinic

Peripheral clinic needs

integrated DM / TB facilities

ii) better screening tools

TUBERCULOSIS
Sputum smear microscopy

Xpert MTB/RIF

DIABETES MELLITUS
Fasting blood glucose

Glycated haemoglobin

iii) cohort analysis for DM for case

burden and treatment outcomes

2. DM and TB treatment outcomes

Previous studies in TB patients show that
DM is associated with: possible delay in sputum culture conversion
increased risk of death
increased risk of recurrent TB

BUT many limitations to these studies

Baker MA et al, BMC Medicine 2011; 9: 81

Risk of remaining sputum culture positive after 2-3 months of

treatment for DM patients with TB versus non-DM patients with TB
DM positive
sputum culture
2-3 months/
Total DM

8 studies:
RR 0.8 3.2

Non-DM positive
sputum culture
2-3 months/
Total Non-DM

Study

Country

RR (95% CI)

Kitahara (1994)

Japan

11/71 (15.5%)

33/449 (7.3%)

2.11 (1.12, 3.98)

Hara (1995)

Japan

32/93 (34.4%)

43/301 (14.3%)

2.41 (1.62, 3.57)

Wada (2000)

Japan

14/90 (15.6%)

16/334 (4.8%)

3.25 (1.65, 6.40)

Alisjahbana (2007) Indonesia

7/41 (17.1%)

68/372 (18.3%)

0.93 (0.46, 1.90)

Banu Rekha (2007) India

8/69 (11.6%)

10/68 (14.7%)

0.79 (0.33, 1.88)

Blanco (2007)

Canary Islands,Spain 4/13 (30.8%)

13/85 (15.3%)

2.01 (0.77, 5.24)

Guler (2007)*

Turkey

32/44 (72.7%)

88/262 (33.6%)

2.17 (1.69, 2.78)

Dooley (2009)

USA

9/30 (30%)

50/163 (30.7%)

0.98 (0.54, 1.77)

Heterogeneity I-squared = 62% (17, 82)

Weights are from random effects analysis

.3

Risk of death for DM patients with TB compared to

non-DM patients with TB
DM Deaths/
Total DM
Study

Country

Kitahara (1994)

Japan

Non-DM Deaths/
Total Non-DM

23 studies:
Pooled RR 1.85 [1.5-2.4]

RR (95% CI)

3/71 (4.2%)

14/449 (3.1%)

1.36 (0.40, 4.60)

Ambrosetti (1995 Report) Italy

3/32 (9.4%)

29/746 3.9%)

2.41 (0.78, 7.50)

Ambrosetti (1996 Report) Italy

4/50 (8.0%)

19/773 (2.5%)

3.25 (1.15, 9.20)

Ambrosetti (1997 Report) Italy

1/40 (2.5%)

43/667 (6.4%)

0.39 (0.05, 2.74)

Centis (1998 Report)

Italy

5/56 (8.9%)

49/1044 (4.7%)

1.90 (0.79, 4.59)

Bashar (2001)

USA

7/50 (14%)

1/105 (0.95%)

14.70 (1.86, 116.27)

Centis (1999 Report)

Italy

2/40 (5%)

26/852 (3.1%)

1.64 (0.40, 6.66)

Fielder (2002)

USA

13/22 (59.1%)

29/152 (19.1%)

3.10 (1.92, 4.99)

Oursler (2002)

USA

8/18 (44.4%)

14/108 (13.0%)

3.43 (1.68, 6.98)

Mboussa (2003)

Congo

8/32 (25%)

8/100 (8%)

3.13 (1.28, 7.65)

Ponce d Leon (2004)

Mexico

34/172 (19.8%)

61/409 (14.9%)

1.33 (0.91, 1.94)

Kourbatova (2006)

Russia

5/20 (25%)

87/440 19.8%)

1.26 (0.58, 2.76)

Mathew (2006)

Russia

8/44 (18.2%)

175/1872 (9.3%)

1.94 (1.02, 3.70)

Pina (2006)

Spain

8/73 11.0%)

97/1438 (6.7%)

1.62 (0.82, 3.21)

Singla (2006)

Saudi Arabia 1/134 (0.7%)

3/383 (0.8%)

0.95 (0.10, 9.08)

Alisjahbana (2007)

Indonesia

2/94 (2.1%)

0/540 (0%)

28.47 (1.38, 588.46)

Vasankari (2007)

Finland

22/92 (23. 9%)

86/537 (16.0%)

1.49 (0.99, 2.26)

Fisher-Hoch (2008)

USA

46/391 (11.8%)

112/1022 (11%)

1.07 (0.78, 1.48)

Hasibi (2008)

Iran

3/6 (50.0%)

6/44 (13.6%)

3.67 (1.23, 10.93)

Chiang (2009)

Taiwan

52/241 (21.6%)

137/886 (15.5%)

1.40 (1.05, 1.86)

Dooley (2009)

USA

6/42 (14.3%)

20/255 (7.8%)

1.82 (0.78, 4.27)

Maalej (2009)

Tunisia

2/57 (3.5%)

0/82 (0%)

7.16 (0.35, 146.29)

Wang (2009)

Taiwan

13/74 (17.6%)

11/143 (7.7%)

2.28 (1.08, 4.85)

Summary
Heterogeneity I-squared = 44% (9, 66)
Weights are from random effects analysis

1.85 (1.50, 2.28)

.3

1 1.85

Risk of TB relapse for DM patients with TB

compared to non-DM patients with TB

Study

Country

Population
with DM
Relapse/
Total

Population
without DM
Relapse/
Total

Wada, 2000

Japan

7/61 (11%)

4/284 (1%)

8.15 (2.46, 26.97)

Mboussa, 2003 Congo

6/17 (35%)

9/77 (12%)

3.02 (1.24, 7.35)

Singla, 2006

Saudi Arabia 2/130 (2%)

3/367 (1%)

1.88 (0.32, 11.14)

Maalej, 2009

Tunisia

4/55 (7%)

1/82 (1%)

5.96 (0.68, 51.95)

Zhang, 2009

China

33/165 (20%)

9/170 (5%)

3.78 (1.87, 7.65)

5 Studies:
Pooled RR 3.89 [2.4 6.2]

RR (95% CI)

Summary

3.89 (2.43, 6.23)

Heterogeneity I-squared = 0% (0,79)

Weights are from random effects analysis
.3

3.89

15

60

Why an increased risk of adverse outcomes?

Drug-drug interactions between oral
hypoglycaemic drugs and rifampicin
(decreased RF concentrations and poor glycaemic control)

DM is a risk factor for liver toxicity with TB drugs

Immune-suppressive effects of DM
Possible exposure to TB in DM clinics

But many questions.

DM control and TB treatment outcomes

6-months anti-TB treatment adequate?
Timing of death in DM-TB patients
Reasons for death
Strategies to prevent death
Recurrent TB reactivation or re-infection?
Integration of DM and TB care

3. Preventing TB in DM
Two observational studies in 1958 and
1969 showing that isoniazid prophylaxis in
DM patients reduces risk of TB
Knowledge gaps:
Very poorly conducted studies and therefore
evidence base still weak
Pfaffenberg et al, 1958 [Germany]
Lesnichii et al, 1969 [Russia]

Summary:
DM-TB is similar to HIV-TB
HIV-TB
Increased TB cases
More difficult to
diagnose TB cases
Increased death
Increased recurrent TB
Increased failure

DM-TB
Increased TB cases
More difficult to
diagnose TB cases
Increased death
Increased recurrent TB
Increased failure

Harries AD et al, Int J Tuberc Lung Dis 2011; 15: 1436 - 1444

Need to tackle the upstream issues

HIV prevention/control
Behaviour
Condoms
Male circumcision
Early use of ART
ART as HIV prevention

DM prevention/control:
Healthy diets
Exercise
Obesity
Early detection of
impaired glucose
tolerance

Summary:
Diabetes and Tuberculosis
Rapidly growing pandemic of diabetes
This could threaten tuberculosis control by:increasing the number of cases
increasing case fatality
increasing the risk of failure or relapse

Global framework for collaborative activities

exists but we need country-level action