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: 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: 2010
12.0 million people living with TB 8.8 million new cases in the year 1.5 million people died of TB during the year
[WHO- Global TB Control 2011]

Global Distribution of DM and TB

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

Tuberculosis: 2010
South East Asia 40% Western Pacific 19% Africa 26%

80% in LIC and MIC

[IDF Diabetes Atlas 2011]

95% in LIC and MIC

[WHO- Global TB Control 2011]

Undiagnosed Cases
Diabetes Mellitus 2011 366 M with DM 183 M (50%) undiagnosed Tuberculosis 2010 8.8 M with TB 3.1 M (35%) undiagnosed

IDF Diabetes Atlas 2011

WHO Global Report 2011

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

HIV/AIDS Other causes of immune suppression (steroids) Silicosis Malnutrition Indoor air pollution Cigarette smoking Alcohol

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

Risk is 2 3 times higher than with normal people
Results confirmed in other publications 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 cellular immunity and have higher M.TB loads than normal mice Patients with DM have low levels of IFNgamma, reduced white cell killing activity
DM impairs immune responses to 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. Review new evidence - Harvard University commissioned to review the literature
2. Develop a prioritised research agenda

3. Decide on whether policy recommendations can be done

1. Updated systematic review:

focused 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 (risk of TB in DM = 2 3 times) Some evidence that poor DM control increases risk of TB 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

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

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

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; 15: 1436 - 1444

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

Launched in August 2011

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 To be reviewed and revised by 2015 To stimulate operational research and be guided by evidence

WHO / Union recommendations

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

Implementation of bi-directional screening activities in China

Screening of DM patients for TB in China __________________________

Approximately 100 million people with DM and 150 million with impaired fasting blood glucose (pre-diabetes)

Screening DM patients for TB

All confirmed DM patients Ask

Is there a current cough and has the cough lasted for > 2 weeks
Is there weight loss in last 4 weeks Has there been night sweats in last 4 weeks Has there been fever in last 4 weeks Is there a suspicion of tuberculosis

Refer to TB clinic for investigation if positive to any of the 5 symptoms

TB Screening in DM patients: Expected results

No. DM patients seen each quarter No. screened for TB at least once in quarter Number with positive screen (TB suspects) Number referred for TB tests Number diagnosed with TB Number referred for TB registration/treatment

Screening of DM for TB: all sites

Q3-2011 Q4-2011 Q1-2012

DM patients seen in each quarter

DM patients screened for TB TB already diagnosed

3174
2300 (72%) 0

7196
5669(79%) 1 39 19 20

4972
3361 (68%) 6 26 20 26

DM patients: +ve symptom screen 27 DM patients diagnosed with TB Total DM diagnosed with TB 9 9

Total DM started TB therapy

20

25

Types of TB diagnosed: all sites

All types of TB Category: New TB Category: Retreatment TB Type: Smear-positive PTB Type: Smear-negative PTB Type: EPTB 55 40 (73%) 15 (27%) 28 (51%) 24 (44%) 3 (5%)

TB case notification rates per 100,000 DM patients screened: all sites

Screening DM patients for TB
Q3-2011 TB case notification rate per 100,000 391 patients screened Q4-2011 Q1-2012

National Figure for 2010

352

774

78

Guiyang Medical College

Uniform patient flow chart Clear roles and responsibilities Special assigned staff for screening DM and TB clinic close to each other in same facility and on same floor

Screening of DM for TB: Guiyang Medical College

Q3-2011 DM patients seen in each quarter DM patients screened for TB DM patients diagnosed / registered with TB 899 899 (100%) 3 Q4-2011 1426 Q1-2012 714

1426 (100%) 714 (100%) 9 11

TB case notification rate per 100,000 DM patients screened

TB case notification rate per 100,000 in population in 2010

334

631
111

804

Challenges
DM doctors did not always screen their patients for TB:- too busy, new intervention, did not understand public health implications of TB Under-reported positive symptoms Not all patients referred attended the TB clinic There was a problem with the accurate recording of number of DM patients ever registered

Conclusion
Feasible to screen DM patients for TB TB case notification rates for screened DM patients always higher than general population Performance improved in last quarter in best performing clinic Special assigned staff, clear role and responsibility, and co-location of clinics are key factors for the successful screen.

Screening of TB patients for DM in China __________________________

Approximately 1 million TB cases per year in China

Screening: Two systems

RBG followed by FBG: All patients with RBG If RBG 6.1 mmol/l, then FBG FBG screen If FBG 7.0 mmol/l, then refer to DM clinic Confirm DM Enter to DM care Initial FBG test: FBG screen If FBG 7.0 mmol/l, then refer to DM clinic Confirm DM Enter to DM care

Results from the 6 TB facilities:

Number registered TB patients
Number diagnosed with DM:
Known DM New DM

8886
1090 (12.3%)
863 (9.7%) 227 (2.6%)

Number with impaired FBG (6.1 6.9) 575 (6.5%)

Prevalence of DM by site

TB Clinic (3)
No. TB patients % with DM 1254 8.5%

Hospital (3)
7297 13.5%

Rural Pop Urban Pop (2) (3)

2500 10.6% 5326 13.8%

Discussion (1)
High rates of DM in TB patients:
12.4% (cf 9.7% reported in NEJM study) translates to 124,000 DM patients per year 2.9% are new DM translates to ~30,000 new DM per year

High rates of Impaired FG in TB patients:

7.8% translates to 78,000 patients per year at risk

Discussion (2)
No particular challenges with screening each quarter about the same results achieved

Cost per patient for blood tests advocate for free RBG/FBG for TB patients Issue of TB causing stress-hyperglycaemia needs further research assessing when best to test and what type of test (e.g. HbA1C)

Conclusion
Feasible to screen, record and report on DM in the routine TB system High rates of DM and IFG compared with general population Scaling up screening should assist the country to detect more DM cases and lead to better DM and TB control