Diabetes Mellitus and Tuberculosis:

current status and implications for tuberculosis control

__________________________Anthony D Harries

“The Union”

Paris, France

Global Burden of DM and TBDiabetes 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%

70% in LIC and MIC

[World Diabetes Foundation 2009]

Tuberculosis: 2009

• South East Asia 35%

• Western Pacific 20%

• Africa 30%

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]

M.tuberculosis bacteria

2.0 billion people carry this bacteria in their bodies

TUBERCULOSIS

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

THE TUBERCLE BACILLUS

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 IFN-gamma, reduced white cell killing activity

DM impairs innate and immune responses to TB

Diabetes Mellitus associated with:

• Pulmonary microangiopathy

• Renal failure

• Micronutrient Deficiency

ALSO:-

Increased risk of TB

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 [Bacakoglu et al, 2001]– Saudi Arabia [Shaikh et al, 2003] – Pakistan [Jabbar et al 2006]– Taiwan [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

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

Adjusted odds of death for diabetic patients with TB compared to non-diabetic patients with TB

[adjusted for age and other confounders]

Weights are from random effects analysis

Summary

Wang (2009)

Dooley (2009)

Oursler (2002)

Study

Fielder (2002)

Taiwan

USA

USA

USA

13/74 (17.6%)

6/42 (14.3%)

8/18 (44.4%)

13/22 (59.1%)

11/143 (7.7%)

20/255 (7.8%)

14/108 (13.0%)

29/152 (19.1%)

4.95 (2.69, 9.10)

5.20 (1.77, 15.25)

6.50 (1.11, 38.20)

6.70 (1.57, 28.52)

OR (95% CI)

3.80 (1.42, 10.16)

11 4.95 15 40

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

DM Deaths/Total DM

Non-DM Deaths/Total Non-DM

Country

3.3. Increased risk of recurrent TB

• 5 studies assessed risk of relapse or drug-resistant 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)

Weights are from random effects analysis

Summary

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

Wada, 2000

Singla, 2006

Zhang, 2009

Study

Mboussa, 2003

Maalej, 2009

Japan

Saudi Arabia

China

Country

Congo

Tunisia

7/61 (11%)

2/130 (2%)

33/165 (20%)

6/17 (35%)

4/55 (7%)

4/284 (1%)

3/367 (1%)

9/170 (5%)

9/77 (12%)

1/82 (1%)

3.89 (2.43, 6.23)

8.15 (2.46, 26.97)

1.88 (0.32, 11.14)

3.78 (1.87, 7.65)

RR (95% CI)

3.02 (1.24, 7.35)

5.96 (0.68, 51.95)

3.89 (2.43, 6.23)

8.15 (2.46, 26.97)

1.88 (0.32, 11.14)

3.78 (1.87, 7.65)

RR (95% CI)

3.02 (1.24, 7.35)

5.96 (0.68, 51.95)

1.3 1 3.89 15 60

Population with DM Relapse/ Total

Population without DM Relapse/ Total

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

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

Weighted prevalence

(adults 22 HBCs)

Population Attributable

Fraction (adults)

HIV infection 20.6/26.7* 0.8% 16%Malnutrition 3.2** 16.7% 27%Diabetes 3.1 5.4% 10%

Alcohol use (>40g / d)

2.9 8.1% 13%

Active smoking 2.0 26% 21%Indoor Air Pollution

1.4 71.2% 22%

1

1 1

P RRPAF

P RR

Sources: Lönnroth 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

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

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