tuberculosis and diabetes christine s. ho md, mph margaret wheeler md

Tuberculosis and Diabetes

Christine S. Ho MD, MPHMargaret Wheeler MD

Overview

• Review the epidemiology of TB• Review the epidemiology of DM• Review the relationship between TB and DM• Implications of epidemiology and risk

– Screening, presentation, diagnosis, treatment• Issues in co-management of TB and DM• Cases

Tuberculosis in the United States - 2008

CDC/DTBE National Tuberculosis Surveillance System Highlights

Reported TB Cases* United States, 1982–2008

10,000

12,000

14,000

16,000

18,000

20,000

22,000

24,000

26,000

28,000

1984 1987 1990 1993 1996 1999 2002 2005 2008

• *Updated as of May 20, 2009.

*Updated as of May 20, 2009.

TB Case Rates,* United States, 2008

< 3.5 (year 2000 target)3.6–4.2

> 4.2 (national average)

D.C.

*Cases per 100,000.

Reported TB Cases by Race/Ethnicity* United States, 2008

Hispanic or Latino(29%) Black or

African-American(25%)

Asian(26%)

White(17%)

American Indian or Alaska Native (1%)

Native Hawaiian orOther Pacific Islander (<1%)

*All races are non-Hispanic. Persons reporting two or more races accounted for less than 1% of all cases.

Number of TB Cases inU.S.-born vs. Foreign-born Persons

United States, 1993–2008*

0

5000

10000

15000

20000

1993 1996 1999 2002 2005 2008

U.S.-born Foreign-born

No.

of

Cas

es


0

10

20

30

40

50

1993 1996 1999 2002 2005 2008

TB Case Rates by Race/Ethnicity* United States, 1993–2008**

Cas

es p

er 1

00,0

00

WhiteBlack or African-AmericanHispanic

American Indian/Alaska NativeAsian/Pacific Islander

*All races are non-Hispanic. In 2003, Asian/Pacific Islander category includes persons who reported race as Asian only and/or Native Hawaiian or Other Pacific Islander only.**Updated as of May 20, 2009.

Percentage of TB Cases Among Foreign-born Persons, United States*

>50%25%–49%

<25%

1998 2008

DC DC


Percent of Foreign-born with TB by Time of Residence in U.S. Prior to Diagnosis,

2008

0%

20%

40%

60%

80%

100%

All Mexico Philippines India

Missing* <1 yr 1–4 yrs >5 yrs

* Foreign-born TB patients for whom information on length of residence in the U.S. prior to diagnosis is unknown or missing.

TB in the US

Translated clinically• Risk factors for TB

– Exposure• Household contacts• Foreign-born from TB endemic regions• Congregate settings- shelters, prisons, hospitals• Poverty

– Impaired immunity (host factors)• Substance abuse: IVDA, Smoking,Heavy ETOH• Nutritional status: underweight, Vit D• Systemic disease: CA, silicosis, HIV, DM, renal dz; gastric

bypass, celiac sprue• Immune compromise: HIV, steroids, TNF inhibitors,

transplant• Age

Risk factors for Latent TB Infection

• Foreign born• Prisoners• Homeless/marginally housed• Injection Drug Users• Racial/ethnic minorities• Recent contact to TB

Risk Factors for Progression to Active TB

• Recent exposure/contact with TB case• Diabetes• HIV• Other medical conditions:

• Renal failure• Smoking• Immunosuppressants: s/p transplant, steroids. Anti-TNF• s/p gastrectomy/ jejuno-ileal bypass• Silicosis• Malnutrition

Epidemiology of DMin the United States

0

1

2

3

4

5

6

7

1958 61 64 67 70 73 76 79 82 85 88 91 94 97 00 03 06

Year

Per

cen

t w

ith

Dia

bet

es

0

2

4

6

8

10

12

14

16

18

20

Nu

mb

er w

ith

Dia

bet

es (

Mil

lio

ns)Percent with Diabetes

Number with Diabetes

Number and Percentage of U.S. Population with Diagnosed Diabetes, 1958-2008

CDC’s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics


Obesity (BMI≥30 kg/m2) Diabetes

<4.5%Missing data4.5 - 5.9% 6.0 - 7.4%7.5 - 8.9% ≥9.0%

18.0 -21.9%<14.0%Missing Data

14.0 - 17.9%22.0 - 25.9% ≥26.0%

Age-adjusted Percentage of U.S. Adults Who Were Obese or Who Had Diagnosed Diabetes

1994



<4.5%Missing data4.5 - 5.9% 6.0 - 7.4%7.5 - 8.9% ≥9.0%

18.0 -21.9%<14.0%Missing Data

14.0 - 17.9%22.0 - 25.9% ≥26.0%


1995



<4.5%Missing data4.5 - 5.9% 6.0 - 7.4%7.5 - 8.9% ≥9.0%

18.0 -21.9%<14.0%Missing Data

14.0 - 17.9%22.0 - 25.9% ≥26.0%


1996



<4.5%Missing data4.5 - 5.9% 6.0 - 7.4%7.5 - 8.9% ≥9.0%

18.0 -21.9%<14.0%Missing Data

14.0 - 17.9%22.0 - 25.9% ≥26.0%


1997



<4.5%Missing data4.5 - 5.9% 6.0 - 7.4%7.5 - 8.9% ≥9.0%

18.0 -21.9%<14.0%Missing Data

14.0 - 17.9%22.0 - 25.9% ≥26.0%


1998



<4.5%Missing data4.5 - 5.9% 6.0 - 7.4%7.5 - 8.9% ≥9.0%

18.0 -21.9%<14.0%Missing Data

14.0 - 17.9%22.0 - 25.9% ≥26.0%


1999



<4.5%Missing data4.5 - 5.9% 6.0 - 7.4%7.5 - 8.9% ≥9.0%

18.0 -21.9%<14.0%Missing Data

14.0 - 17.9%22.0 - 25.9% ≥26.0%


2000



<4.5%Missing data4.5 - 5.9% 6.0 - 7.4%7.5 - 8.9% ≥9.0%

18.0 -21.9%<14.0%Missing Data

14.0 - 17.9%22.0 - 25.9% ≥26.0%


2001



<4.5%Missing data4.5 - 5.9% 6.0 - 7.4%7.5 - 8.9% ≥9.0%

18.0 -21.9%<14.0%Missing Data

14.0 - 17.9%22.0 - 25.9% ≥26.0%


2002



<4.5%Missing data4.5 - 5.9% 6.0 - 7.4%7.5 - 8.9% ≥9.0%

18.0 -21.9%<14.0%Missing Data

14.0 - 17.9%22.0 - 25.9% ≥26.0%


2003



<4.5%Missing data4.5 - 5.9% 6.0 - 7.4%7.5 - 8.9% ≥9.0%

18.0 -21.9%<14.0%Missing Data

14.0 - 17.9%22.0 - 25.9% ≥26.0%


2004



<4.5%Missing data4.5 - 5.9% 6.0 - 7.4%7.5 - 8.9% ≥9.0%

18.0 -21.9%<14.0%Missing Data

14.0 - 17.9%22.0 - 25.9% ≥26.0%


2005



<4.5%Missing data4.5 - 5.9% 6.0 - 7.4%7.5 - 8.9% ≥9.0%

18.0 -21.9%<14.0%Missing Data

14.0 - 17.9%22.0 - 25.9% ≥26.0%


2006



<4.5%Missing data4.5 - 5.9% 6.0 - 7.4%7.5 - 8.9% ≥9.0%

18.0 -21.9%<14.0%Missing Data

14.0 - 17.9%22.0 - 25.9% ≥26.0%


2007



<4.5%Missing data4.5 - 5.9% 6.0 - 7.4%7.5 - 8.9% ≥9.0%

18.0 -21.9%<14.0%Missing Data

14.0 - 17.9%22.0 - 25.9% ≥26.0%


2008


Obesity (BMI ≥30 kg/m2)

Diabetes

1994

1994

2000

2000

No Data <14.0% 14.0-17.9% 18.0-21.9% 22.0-25.9% >26.0%

No Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0%


2008

2008

Prevalence DM by Age/Sex/Ethnicity US 2007

Increase in Prevalence DM by Ethnicity and Sex 1980-2007

Obesity & DM Prevalence in FB

• Increase with length of residenceOza-Frank, 2009

• Odds Ratio of DM among Foreign-born– Highest among East Indians (OR 3-4)– Latinos (OR 2)– Chinese

Oza-Frank, 2010Venkaya 2008

Percent Chronic Illness/Risk by Nativity and Ethnicity

Risk Native N. Hisp. N. Asia FB FB Hisp FB Asia

Obesity 23 30 11 16 21 5

cigs 24 20 15 14 14 12

DM 6 11 6 6 7 6

HTN 24 25 24 24 19 19

CV 8 8 7 6 5 5

Dey,CDC 2006

Tuberculosis and Diabetes

Audience response: TB increases the risk of DM

• True ?

• False ?

Not that we know of….

• No evidence to suggest that having tuberculosis or taking medications for tuberculosis increases the risk for diabetes

• Increased hyperglycemia with active disease and with rifampin-induced medicine interactions, but not development of DM

Audience response: Diabetes increases the risk of tuberculosis

• True ?

• False ?

Why increased risk?

Diabetes and Active TB – Evidence?• First described by the Romans..• 2008 Systematic review

– 13 observational studies show increased risk of TB in DM patients

– 3 prospective cohort studies showed RR 3.1 (CI 2.3-4.6)

– 8 case-control studies with OR 1.2-7.8 – Assoc’d with higher background TB incidence,

younger ageJeon, PLoS 2008

• Studies since 1995— OR 1.5-7.8 of TB in pts w/DM

Jeon et al. 2008

RR 1

Relative Risk Varying by TB Incidence

Variable RR 95% CI

Background TB Incidence ≥100 3.3 2.1-5.2

≥10 and<100 2.2 1.4-3.5

<10 1.9 1.1-3.2

Region C. America 6.0 5.0-7.2

Europe 4.4 2.5-7.8

Asia 3.1 2.3-4.3

N. Am Hispanics 2.7 2.3-3.2

N. Am Nat. Am. 1.9 0.3-10

N. Am Non-Hisp. 1.23 1.1-1.3

Diabetes and Active TB

• Contacts– Hong Kong prospective study of 4661 close contacts– RR 3.4 for both early ( 3month) and late ( within 5yrs)

diseaseLee MS, Int J

Tuberc Lung 2008

• Attributable Risk (India,2000) – 21 million DM; 900K pulm.TB– 15% excess pulmonary TB cases in DM pts– 20% excess smear positive cases in DM pts

Stevenson, BMC Pub Health 2007

Relative Risk - Progression to Active TB

Condition Relative Risk of TB

HIV 7-16

Healed TB 3-8

DM 2.3-4.8

Smoking 1.5-2.0

Renal Disease 2.1-52.5

Gastric bypass 1.7-2.0

Attributable Risk Depends on Relative Risk and Underlying

Prevalence

RR Prevalence Population Attributable Risk

HIV 8.3 1% 7%

DM 3.0 3.4% 6%

3.0 10% 17%

3.0 20% 29%

Raviglione, WHO

Implications : Screening

? Screen TB for DM– Tanzania study of OGT on all with TB

Mugusi, 1990

• Saipan experience– TB and DM epidemics – clinics cross-screening

Case #1

• 62 year old Salvadorean woman with DM who came to the US 4 years ago presents for primary care.

• Should she be screened with a TST?

• Yes• No

TB Case Rates in U.S.-born vs. Foreign-born Persons United

States, 1993–2008*

0

10

20

30

40

1993 1996 1999 2002 2005 2008

U.S. Overall U.S.-born Foreign-born

Case

s pe

r 100

,000


Global TB Incidence 2005

From WHO data (http://www.who.int/tb/publications/global_report/2007/)

80% of TB Cases

www.tbalert.org/worldwide/world

Countries Accounting for 80% TB Cases

1. Afghanistan2. Bangladesh3. Brazil4. Cambodia 5. China*6. Republic of Congo7. Ethiopia8. India*9. Indonesia*10.Kenya11.Mozambique

12. Myanmar13. Nigeria14. Pakistan15. Philippines16. Russia17. South Africa18. Tanzania19. Thailand20. Uganda21. Viet Nam22. Zimbabwe

An Approach to Immigrant Health: Risk Assessment

• Health risks of native country

• Health risks of travel– both initial and recurrent

• Health risks of adopted country

High Risk Travel Medicine• 50% of US residents traveling abroad are FB visiting home

• Higher risk of getting sick while traveling for FB

• Riskier behavior – Visits while pregnant, sick or with children– Longer stays, eat like hosts. – More often sex, rural areas, contact to sick relatives– Travel for health care or use health care– dentistry etc

• But less often vaccinated/prophylaxed/tested when back

Bacaber. JAMA. 2004;291:2856-2864.Deren S et al.. Am J Public Health.

2003;93:812-816.

New Immigrants and Risk of TB

Origin Time in U.S. Case Rate

U.S. Born 2.7

Foreign-Born Total 21.5

≦1 year 121.0

>1 and 5 years≦ 30.0

> 5 years 11.9

Cain et al. 2007 AJRCCM

Where do we go from here?TBESC foreign-born study: co-morbidities

N=264 respondents n %

Smoked more than 100 cigarettes in lifetime 89 33.7

Diabetes 53 20.1

Taking medicines that contain steroids 16 6.1

HIV/AIDS 11 4.2

Cancer 7 2.7

Kidney dialysis 4 1.5

Organ transplant 1 0.4

Silicosis or coal miner lung disease 1 0.4

Slide courtesy of Jenny Flood, M.D and CA DPH TB staff

Intersection of risks: TB infection; medical; and population risks

TB

AIDS, diabetes, renal dialysis…Foreign-born


1,835,000

185,00095,858

45,047 34,087

3,297

1

10

100

1,000

10,000

100,000

1,000,000

10,000,000

Nu

mb

er

of p

eo

ple

(lo

g s

cale

)

Diabetes RheumatoidArthritis

HIV/AIDS Renaldialysis

Crohn'sDisease

Organtransplantrecipients

Selected populations in CA with medical risk factors for TB, and LTBI estimates

636,000 (35%)

Foreign-born Foreign-born (FB):(FB):

31,450(17%)

13,551(14%)%)

11,27811,278(25%)(25%)

1,5071,507(4%)(4%)

730(22%)

FB with LTBI: 119,000 6,000 2,500 2,100 300 150


Case #1 Answer

• YES!• Born in TB-endemic region• New immigrant• DM• 3 overlapping risk factors

• Remote history of BCG-vaccination

Case #2

Dr. B is a retired physician from Russia who came to the US 10 years ago. She is screened and has 15mm of induration.

Do you believe her TST result?Would you get a chest x-ray?Would you get sputum specimens?Would you treat?

Dr. B

• Issues to consider– Immigrated from TB-endemic country– Healthcare worker– Exposure to drug-resistant TB– BCG vaccination effects on TST/Beliefs regarding

this

Active TB and Diabetes

Does DM affect presentation and treatment of active disease?

• Yes

• No

Case #3-Mr. W

• Mr. W is a 61 y.o. Chinese man referred from a local health dept clinic for an abnormal CXR

• PMH:– exercise-controlled DM with FS 120’s– chronic low back pain – h/o colon cancer s/p hemicolectomy

Mr. W (2)

• Pt well until fell off bike 2/20/09• In ED:

– L-S spine showing narrowed disk space L4-S1– Instructed to f/u with PCP regarding incidental

finding of low grade fever,

• Pt is meticulous & records temps at home: 99-100F consistently for over 1 month

Mr. W (3)

• No other remarkable symptoms at that time • PCP orders GI appointment for repeat

colonoscopy• Meanwhile patient develops scant cough, and

some fatigue, wonders about needing a CXR• Luckily, MD orders CXR 4/1/09

TB is more advanced at presentation in diabetics

• More often smear positive• More frequently present with hemoptysis• More often with cavitary lesions• More often with fever

Restrepo , Epi and Inf 2009

• More delayed diagnosis versus rapid disease progression?

DM and Presentation of TB

• Cavitary lesions – 51% of pts with DM – 39% of pts without DM (Shaikh, 2003)

• Lower lung lesions – 24% of pts with DM – 2.4% of pts without DM (Alisjahbana 2007)

• 20% of 280 CA TB pulmonary cases reported DM– 66% of smear-positive cases have DM– 31% of DM cases had cavitary disease vs. 14% non-

diabetics

• Not great studies…case-series, retrospective case-control – most do not look at DM

• EPTB mostly due to immunosuppression– HIV, ESRD known risk factors

DM?• Retrospective case-control study in Taipei with 75 pts

with EPTB– 20% with DM– TB peritonitis: 27% with DM vs. 7% without DM

(OR 5, CI 1.1-23.4) Weng 2009

DM Risk Factor for Extrapulmonary Disease- Not clear???

Audience response: Diabetics do just as well once treated

• True

• False

Treatment and Communication

• May have multiple providers—PCP/TB• Low-income, diverse pts with DM

– More than 50% low literacy/numeracy– Limited English proficiency– Sensory deficits: vision and hearing– Subtle cognitive impairments common in

longstanding DM– Use teach-back method

Mr.W (4)

• Empiric RIPE rx started for miliary TB • PCP contacted to start DM medicines to

optimize glucose control• 4/22 patient develops new R leg numbness• What might the pain/numbness from?• Would you have done anything differently?

Mr.W(5)

• DDx includes: ???– Mononeuritis multiplex– Paradoxical reaction– Other thoughts?

• B6 increased to 100mg, ibuprofen given• Pain/sciatica has worsened. Now unable to

negotiate stairs – has moved to downstairs bedroom.

• What is going on?

Mr.W (5)

• Post ED MRI on 3/5/09 shows reactive infiltrative process of L2, compression fx of L3, deg dz L3 through S1.

• Diagnosis – Pott’s disease

Case #4

• Mr. R is a 30 year old man with DM and has lived in the US for 10 yrs. He traveled to Chiapas 4 months ago and ran out of his DM meds. He presents with fatigue, 20 pound weight loss and cough with hemoptysis. He went to visit his ill sister, who had a respiratory illness.

• He lives in an apartment with 14 other day laborers.

Mr. R’s CXR

Mr. R

• Mr. R is started on INH, Rifampin, Pyrazinamide, Ethambutol and Vitamin B6

• His diabetic control worsens• He continues to lose weight• His AST and ALT are elevated into the 80s• His creatinine is normal

Treatment Issues - Rifampin

• Rifampin levels may be lower in diabetics– 17 age and sex-matched TB cases w/w/o DM– AUC 12.3 with DM; 25.9 no DM– Peak levels 50% as high in those with DM– Assoc’d with higher body weight and poor glucose

control– Consider rifampin levels for slow sputum

convertors Nijland, CID

2006

Treatment Issues – Rifampin cont’d

• Rifampin raises blood glucose even in non-diabetics

• Induces CYP450 enzyme system• Affects metabolism of sulfonylureas and

thiazolidinediones• Blood glucose control may worsen while

diabetics taking Rifampin

Treatment Issues Cont’d

• Diabetics at increased risk of hepatotoxicity• Screen with LFTs for INH,Rif or PZA-induced

hepatitis• At increased risk for INH-related neuropathy• EMB and PZA need dose adjustment in renal-

impaired patients• Chronic renal insufficiency or renal failure a

morbidity of DM – so check Cr!

Mr. R (2)

A. Increase DM managementB. Drug susceptibility testingC. Check rifampin levelsD. Assess adherenceE. Change TB drug regimenF. All except D

Mr. R (3)

• Insulin started. His cultures are pan-sensitive. He begins to gain weight. At 8 weeks his smears are still culture positive.

• Do you change his regimen in any way?

Risk of Relapse is associated with

• Culture status at 2 month

• Presence of Cavitations

Does DM Impact TB Treatment and Cure?

• Previously thought not to affect treatment• Four new studies from Baltimore, Texas,

Taiwan and Indonesia reveal:– Delayed culture conversion– Higher mortality

– Dooly, 2009; Restrepo 2008; Wang 2008; Alisahlanda,2007

• Culture conversion< 90 days in CA TB pts:– 86% in pts with DM– 92% in pts without DM

Response to Treatment

• Unclear if increased drug resistance in DM

• Relapse may be more frequent– Recent Shanghai study

• 20% relapse rate in pts with DM• 5% relapse rate in pts without DM

Zhang et al. Jpn J Infect Dis, 2009

Global Stance

IUATLD – Assumption to Evidence; 4 Recommendations

1. Collaboration between TB and DM care and control initiatives

2. Screening for active TB among DM people3. Screening for DM among TB patients4. Management of TB and DM co-morbidity

Domestic Stance – What makes sense now?

• Follow IUATLD recommendations in pertinent populations

• In Diabetics who have another risk for TB, (i.e. foreign-born) screen for TB with symptom review and TB test

• Screen for DM in all TB patients• Open communication between DM and TB

providers

Beyond Screening?

• Co-management of DM and TB through DOT?– Uncontrolled DM hampers the inflammatory

response in any infection– At SFDPH, uncontrolled diabetics are actively

managed with primary care providers to control hyperglycemia promptly

– Rifampin effects monitored closely; patients bring in glucose records to TB visits

Summary

• DM growing in prevalence world-wide• Uncontrolled DM may increase risk of TB• TB presents in more advanced stage in DM• Treatment time may be longer in DM pts to

“assure the cure”• Important implications in populations with high

prevalence for both diseases• Screening across clinics for DM and TB may be a

wave of the future

Thank you!

• Curry National TB Center• Gisela Schecter – CA DPH• Dean Schillinger – UCSF • Jenny Flood – CA DPH• Masae Kawamura – SFDPH• CDC Division of TB Elimination

tuberculosis and diabetes christine s. ho md, mph margaret wheeler md

Documents

united states

epidemiology of tb

reported tb cases

comanagement of tb

tb case rates

mph margaret wheeler

implications of epidemiology

alaska native