Diabetes Mellitus and Tuberculosis:

current status and implications for tuberculosis control __________________________

Anthony D Harries The Union Paris, France

Global Burden of DM and TB

Diabetes Mellitus: 2008
250 million people living with DM 6 million new cases each year 3.5 million people died of DM during the year
[World Diabetes Foundation 2009]

Tuberculosis: 2009
14.0 million people living with TB 9.4 million new cases each year 1.7 million people died of TB during the year
[WHO- Global TB Control 2010]

Global Distribution of DM and TB

Diabetes Mellitus: 2008
South East Asia 20% Western Pacific 23% Africa 5%

Tuberculosis: 2009
South East Asia 35% Western Pacific 20% Africa 30%

70% in LIC and MIC

[World Diabetes Foundation 2009]

95% in LIC and MIC

[WHO- Global TB Control 2010]

The global increase in DM

2010 285 million with DM

2030

440 million with DM

[Diabetes Atlas: International Diabetes federation, 2009]

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

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

Diabetes mellitus

Recognised in Roman times that DM increases risk of TB

Jeon CY, Murray MB. Diabetes Mellitus increases the risk of active tuberculosis: a systematic review of 13 observational studies. PLoS Medicine 2008; 5: e152

Search of PubMed and EMBASE databases: studies reporting age-adjusted quantitative estimate of association between DM and active TB

13 observational studies [3 cohort; 8 case-control; 2 other]

RESULTS
1,786,212 participants with 17,698 TB cases

DM associated with increased risk of TB [Cohort studies = RR 3.1, 95% CI 2.3 4.3]
[Case control studies = OR 1.2 7.8]
Higher risks in young people and communities with high background TB incidence

Other global studies on DM increasing the risk of TB

Stevenson et al (Chronic Illn, 2007):
Medline search for studies after 1995 Increased RR or OR of 1.5 7.8 Risk higher in younger people

India
[Stevenson et al BMC Public Health 2007]
Epidemiological model constructed based on 21M adults with DM and 900,000 new TB cases in 2000 DM accounted for: 15% PTB (7% - 23%) : 20% smear+ve PTB (8% - 42%) Urban areas more affected than rural areas
Diabetes mellitus makes substantial contribution to burden of new TB in India

Diabetes Mellitus increases the risk of TB by a factor of 2 - 3

Dooley and Chaisson, Lancet Infectious Diseases, 2009

Ruslami et al, Tropical Medicine & International Health, 2010 Goldhaber-Fiebert et al, International Journal Epidemiology 2011

Is this biologically plausible?

YES: Animal models diabetic mice have impaired CMI and have higher M.TB loads than normal mice Patients with DM have low levels of IFNgamma, reduced white cell killing activity
DM impairs innate and immune responses to TB

ALSO:Diabetes Mellitus associated with: Pulmonary microangiopathy Renal failure Increased risk of TB

Micronutrient Deficiency

Association between DM and TB

Not in doubt Biologically plausible BUT previous studies have limitations:Most are from industrialised countries Almost none from Africa Many are health facility-based and are secondary analyses of routine data sources Many critical unanswered questions

Expert Meeting convened in November 2009

(WHO, Union, WDF, IDF, Academia, Ministries of Health)

Objectives of Meeting
1. Discuss an updated systematic review conducted by Harvard University between May Aug 2009, and identify knowledge gaps
2. Develop a prioritised research agenda 3. Decide on policy recommendations

1. Updated systematic review:

focus on issues related to TB control

PUBMED, EMBASE, Bibliographies, Conference proceedings from IUATLD in 2007 and 2008

1.Linkage between DM and TB

Strong evidence from 16 age-adjusted studies (summary OR = 2.2) Some evidence that poor DM control increases risk of TB (HbA1c >7% = RR 2.56)
[USA,UK, Canada, Mexico, Russia, India, Taiwan, South Korea, Indonesia]

Knowledge gaps:
Little evidence from low-income countries, especially Africa Need more data on the effect of DM control on risk of TB

2. Diagnosis of TB and DM
Two main problems: In patients with TB, DM is not suspected or recognised In patients with DM, TB may present differently and may not be diagnosed

(2.1.) Is DM under-diagnosed in TB patients?

Tanzania 506 consecutive PTB patients 9 known to have DM Other patients given a 75G OGTT 11 had sustained high blood glucose levels = DM
DM missed in over half the patients
Mugusi et al, Tubercle 1990

(2.2.) Does TB present differently in patients with DM?

Most consistent difference is infiltrates more common in lower lung fields
Turkey Saudi Arabia Pakistan Taiwan [Bacakoglu et al, 2001] [Shaikh et al, 2003] [Jabbar et al 2006] [Wang et al, 2008]

TYPICAL CHEST X-RAY

ATYPICAL CHEST X-RAY

3. Effect of DM on treatment outcomes of TB

DM associated with: possible delay in sputum culture conversion increased risk of death increased risk of recurrent TB

BUT many limitations to these studies

3.1. Delay in sputum culture conversion at 2-3 months

8 studies comparing DM with non-DM Relative risks from 0.8 3.2

Five of eight studies had RR > 2

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

Study

Country

RR (95% CI)

Kitahara (1994) Hara (1995) Wada (2000)

Japan Japan Japan

11/71 (15.5%) 32/93 (34.4%) 14/90 (15.6%) 7/41 (17.1%) 8/69 (11.6%)

33/449 (7.3%) 43/301 (14.3%) 16/334 (4.8%) 68/372 (18.3%) 10/68 (14.7%) 13/85 (15.3%) 88/262 (33.6%) 50/163 (30.7%)

2.11 (1.12, 3.98) 2.41 (1.62, 3.57) 3.25 (1.65, 6.40) 0.93 (0.46, 1.90) 0.79 (0.33, 1.88) 2.01 (0.77, 5.24) 2.17 (1.69, 2.78) 0.98 (0.54, 1.77)

Alisjahbana (2007) Indonesia Banu Rekha (2007) India Blanco (2007) Guler (2007)* Dooley (2009)

Canary Islands,Spain 4/13 (30.8%) Turkey USA 32/44 (72.7%) 9/30 (30%)

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

Weights are from random effects analysis

.3

3.2. Increased risk of death

23 studies comparing risk of death in DM and non-DM patients Pooled RR = 1.85 (95% CI, 1.5 2.3) 4 studies adjusted for age /other confounders: pooled OR = 4.95 (95% CI, 2.7 9.1)

Risk of death for DM patients with TB compared to non-DM patients with TB

DM Deaths/ Total DM Study
Kitahara (1994)

Non-DM Deaths/ Total Non-DM RR (95% CI)

Country
Japan 3/71 (4.2%) 3/32 (9.4%) 4/50 (8.0%) 1/40 (2.5%) 5/56 (8.9%) 7/50 (14%) 2/40 (5%) 13/22 (59.1%) 8/18 (44.4%) 8/32 (25%) 34/172 (19.8%) 5/20 (25%) 8/44 (18.2%) 8/73 11.0%) 14/449 (3.1%) 29/746 3.9%) 19/773 (2.5%) 43/667 (6.4%) 49/1044 (4.7%) 1/105 (0.95%) 26/852 (3.1%) 29/152 (19.1%) 14/108 (13.0%) 8/100 (8%) 61/409 (14.9%) 87/440 19.8%) 175/1872 (9.3%) 97/1438 (6.7%) 3/383 (0.8%) 0/540 (0%) 86/537 (16.0%) 112/1022 (11%) 6/44 (13.6%) 137/886 (15.5%) 20/255 (7.8%) 0/82 (0%) 11/143 (7.7%)

1.36 (0.40, 4.60) 2.41 (0.78, 7.50) 3.25 (1.15, 9.20) 0.39 (0.05, 2.74) 1.90 (0.79, 4.59) 14.70 (1.86, 116.27) 1.64 (0.40, 6.66) 3.10 (1.92, 4.99) 3.43 (1.68, 6.98) 3.13 (1.28, 7.65) 1.33 (0.91, 1.94) 1.26 (0.58, 2.76) 1.94 (1.02, 3.70) 1.62 (0.82, 3.21) 0.95 (0.10, 9.08) 28.47 (1.38, 588.46) 1.49 (0.99, 2.26) 1.07 (0.78, 1.48) 3.67 (1.23, 10.93) 1.40 (1.05, 1.86) 1.82 (0.78, 4.27) 7.16 (0.35, 146.29) 2.28 (1.08, 4.85) 1.85 (1.50, 2.28)

Ambrosetti (1995 Report) Italy Ambrosetti (1996 Report) Italy Ambrosetti (1997 Report) Italy Centis (1998 Report) Bashar (2001) Centis (1999 Report) Fielder (2002) Oursler (2002) Mboussa (2003) Ponce d Leon (2004) Kourbatova (2006) Mathew (2006) Pina (2006) Singla (2006) Alisjahbana (2007) Vasankari (2007) Fisher-Hoch (2008) Hasibi (2008) Chiang (2009) Dooley (2009) Maalej (2009) Wang (2009) Italy USA Italy USA USA Congo Mexico Russia Russia Spain

Saudi Arabia 1/134 (0.7%) Indonesia Finland USA Iran Taiwan USA Tunisia Taiwan 2/94 (2.1%) 22/92 (23. 9%) 46/391 (11.8%) 3/6 (50.0%) 52/241 (21.6%) 6/42 (14.3%) 2/57 (3.5%) 13/74 (17.6%)

Summary Heterogeneity I-squared = 44% (9, 66) Weights are from random effects analysis .3 1 1.85 7

Adjusted odds of death for diabetic patients with TB compared to non-diabetic patients with TB
[adjusted for age and other confounders]

Study

Country

DM Deaths/ Non-DM Deaths/ Total DM Total Non-DM

OR (95% CI)

Fielder (2002)

USA

13/22 (59.1%) 29/152 (19.1%)

3.80 (1.42, 10.16)

Oursler (2002) USA

8/18 (44.4%)

14/108 (13.0%)

6.70 (1.57, 28.52)

Dooley (2009) USA

6/42 (14.3%)

20/255 (7.8%)

6.50 (1.11, 38.20)

Wang (2009)

Taiwan

13/74 (17.6%) 11/143 (7.7%)

5.20 (1.77, 15.25)

Summary

4.95 (2.69, 9.10)

Heterogeneity I-squared = 0% (0, 85)

Weights are from random effects analysis

4.95

15

40

3.3. Increased risk of recurrent TB

5 studies assessed risk of relapse or drugresistant recurrent TB For Relapse, pooled RR = 3.89
(95% CI, 2.1 7.5)

For drug-resistant recurrent disease, there was no evidence of any association

(pooled OR = 1.24, 95% CI 0.7 2.2)

Risk of TB relapse for DM patients with TB compared to non-DM patients with TB

Population with DM Relapse/ Total Population without DM Relapse/ Total

Study

Country

RR (95% CI)

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)

Summary

3.89 (2.43, 6.23)

Heterogeneity I-squared = 0% (0,79) Weights are from random effects analysis .3 1 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 hepatic toxicity with TB drugs Immune-suppressive effects of DM

4. 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

Summary: DM-TB is similar to HIV-TB

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

Int J Tuberc Lung Dis 2011; 6 September epub ahead of print

Proportion of TB burden attributable to some major risk factors in high TB burden countries
Relative risk for active TB disease
HIV infection Malnutrition Diabetes Alcohol use (>40g / d) Active smoking Indoor Air Pollution

PAF

P RR 1 P RR 1 1

Weighted prevalence (adults 22 HBCs)

Population Attributable Fraction (adults)

20.6/26.7* 3.2** 3.1 2.9 2.0 1.4

0.8% 16.7% 5.4% 8.1% 26% 71.2%

16% 27% 10% 13% 21% 22%

Sources: Lnnroth K, Castro K, Chakaya JM, Chauhan LS, Floyd K, Glaziou P, Raviglione M. Tuberculosis control 2010 2050: cure, care and social change. Lancet 2010 DOI:10.1016/s0140-6736(10)60483-7.

2. Prioritised research agenda

Tropical Medicine & International Health 2010; 15: 659-663

Highly prioritised Research:

Bi-directional screening: active TB in DM patients and DM in TB patients Treatment outcomes in DM patients (focus on mortality and strategies to reduce mortality Use of the DOTS model to manage DM POC diagnostic and monitoring tests for DM (glycosylated haemoglobin HbA1c)

3. Policy Recommendations

Collaborative Framework for Care and Control of TB and Diabetes

The recommendations

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

Summary: Diabetes and Tuberculosis

Rapidly growing pandemic of diabetes This could threaten tuberculosis control by:increasing the number of cases increasing the case fatality increasing the risk of relapse after treatment

We have a framework for action and now need to implement