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

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

Diagnosis: Blood glucose Treatment: diet, drugs,

insulin for life

Diagnosis: Smear for AFB Treatment: 6 months of

drugs

Global Burden of DM and TB

Diabetes Mellitus: 2011
366 million people living with DM 10 million new cases in the year 4.6 million people died of DM during the year
[IDF Diabetes Atlas 2011]

Tuberculosis: 2011
12.0 million people living with TB 8.7 million new cases in the year 1.4 million people died of TB during the year
[WHO- Global TB Control 2012]

Global Distribution of DM and TB

Diabetes Mellitus: 2011
South East Asia 20% Western Pacific Africa 36% 4%

Tuberculosis: 2011
South East Asia 40% Western Pacific 20% Africa 26%

80% in LIC and MIC

[IDF Diabetes Atlas 2011]

95% in LIC and MIC

[WHO- Global TB Control 2012]

India and China [2011]

India 60 million DM 2.2 million TB China 90 million DM 1.0 million TB

Undiagnosed Cases
Diabetes Mellitus 2011 366 M with DM 183 M (50%) undiagnosed Tuberculosis 2011 8.7 M with TB 2.9 M (33%) not-notified to NTPs

IDF Diabetes Atlas 2011

WHO Global Report 2012

The global increase in DM

2011 2030 366 million with DM 552 million with DM

[Diabetes Atlas: International Diabetes Federation, 2011]

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

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 dating back to 1965

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

Two other landmark studies confirming interaction of DM with 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 : 20% smear-positive PTB 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

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 CMI and have higher M.TB loads than normal mice

Patients with DM have low levels of IFNgamma, reduced white cell killing activity

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

Micronutrient Disturbances

Association between DM and TB

Not in doubt Biologically plausible BUT previous studies have limitations: Most are from industrialised countries Many are health facility-based and used old hospital records as data sources Many critical unanswered questions

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

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

Research studies (2011-12) reporting DM prevalence in TB patients

Karnataka 32%

Kerala 44%
Texas 39% Mexico 36% Nigeria 12%

Tanzania 17%
South Pacific ~40%

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

Screening TB patients for Diabetes (DM) in India: parallel register

Screening TB patients for DM in Hospitals and Health Centres in India: data combined for three quarters (Q1-Q3) for 2012
Indicator Number of patients with TB registered over the three quarters Number (%) with known diagnosis of DM Number needing to be screened with RBG TOTAL 8269 682 (8) 7587

Number (%) actually screened with RBG

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) Number (%) with known and newly diagnosed DM Number (%) with known / newly diagnosed DM referred to DM care
India TB-DM study group TMIH 2013: 18: 636-45

7467 (98)
2838 2703 (95) 402 (5) 1084 (13) 1033 (95)

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

Simple parameters for routine recording in quarterly reports

Number of TB patients registered
Number of TB patients screened for DM Number of TB patients diagnosed with DM

Back of the TB Treatment card used in India

Screening Diabetes patients for TB

TB Symptom Screen done every time the patient comes to clinic

If positive to any one of the symptom checks, this is a positive screen and referral is made to TB services

Screening Diabetes Patients for TB in India: Treatment Cards

Screening of Diabetes (DM) Patients for TB in quarter 2, 2012, for all sites combined, India
DM patients Seen in the quarter
Q2-2012 12237

Already diagnosed with TB from elsewhere Screened for TB symptoms in the quarter
Positive TB symptom screen

74 6393 (52%)
135 (2%)

Referred for TB investigations

Diagnosed with a new episode of TB Total number with new TB and TB from elsewhere Known to have started or to be on anti-TB Treatment TB cases per 100,000 DM patients seen per quarter
India DM-TB study group TMIH 2013; 18: 646-654

128 (95%)
11 85 80 695

Many questions
Need for better individualised data analysis Co-determinants of TB risk e.g., smoking Cost-efficient screening / diagnostic methods Optimum time to screen TB patients for DM Better data management systems for DM Integration of DM and TB care

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

Study

Country

8 studies: RR 0.8 3.2

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

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

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%)

23 studies: Pooled RR 1.85 [1.5-2.4]

RR (95% CI)
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

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

5 Studies: Pooled RR 3.89 [2.4 6.2]

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 liver toxicity with TB drugs

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

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 the case fatality increasing the risk of failure or relapse

Framework for collaborative activities exists but needs to be guided by better evidence