1. Double Trouble: Diabetes and Tuberculosis
Kris Ernst, BSN, RN, CDE
Division of Diabetes Translation
Centers for Disease Control and Prevention

2. Disclaimer
This presentation represents the opinion of the author and is not the official opinion of CDC

4. Tuberculosis and Diabetes: Old Foes
Indian physician Susruta, in 600 A.D.
“phthisis frequently complicated diabetes”
Autopsy of diabetics in 1883 showed presence of TB granuloma I 50% of diabetics
Prior to the insulin era: Diagnosis of DM was a death sentence
Leading cause of death was: Tuberculosis

5. Definitions Latent Tuberculosis Infection (LTBI) Active TB Disease
Persons are infected with M. tuberculosis, but do not have active TB disease.
Active TB Disease
Persons infected with M tuberculosis bacteria that progress from latent TB infection.

6. Background
Diabetes increases risk for progression from latent TB infection (LTBI) to active TB disease and complicates treatment of active TB
Delays in diagnosis for both diabetes and TB
Globally, the number of people with diabetes is increasing

7. Number (in Millions) of Persons with Diagnosed Diabetes, United States, 1980–2007

8. Background
Pathophysiology – diabetes, especially when poorly-controlled, causes relative immunocompromise and increases likelihood of reactivation of TB
Epidemiology – dramatic increase of diabetes
Demographics – diabetes disproportionately affects lower socioeconomic groups and ethnic minorities that also have higher prevalence of TB

9. Background
Treatment considerations – hard to treat TB in the face of poor glucose control
Hidden epidemic – estimated that ¼ of people with diabetes don’t know they have it

10. TB Case Rates,* United States, 2008
D.C.
< 3.5 (year 2000 target)
3.6–4.2
> 4.2 (national average)
*Cases per 100,000.

11. Reported TB Cases by Age Group, United States, 2008
<15 yrs
(6%)
>65 yrs
(19%)
15–24 yrs
(11%)
25–44 yrs (33%)
45–64 yrs
(30%)

12. TB Case Rates by Race/Ethnicity* United States, 1993–2008**
Cases per 100,000
White
Black or African-American
Hispanic
American Indian/Alaska Native
Asian/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.

13. Reported TB Cases by Race/Ethnicity* United States, 2008
American Indian or
Alaska Native (1%)
White
(17%)
Asian
(26%)
Native Hawaiian or
Other Pacific Islander (<1%)
Hispanic or Latino
(29%)
Black or
African-American
(25%)
*All races are non-Hispanic. Persons reporting two or more races accounted for less than 1% of all cases.

14. Reported TB Cases* United States, 1982–2008
No. of Cases
Year
*Updated as of May 20, 2009.

15. TB Morbidity United States, 2003–2008
Year No Rate* , , ,
13,
13,
12,
*Cases per 100,000, updated as of May 20, 2009.

17. Transmission of M. tuberculosis
Spread by airborne route; droplet nuclei
Transmission affected by
Infectiousness of patient
Environmental conditions
Duration of exposure
Most exposed persons do not become infected

18. TB Pathogenesis (1) Latent TB Infection
Once inhaled, bacteria travel to lung alveoli and establish infection
2–12 wks after infection, immune response limits activity; infection is detectable
Some bacteria survive and remain dormant but viable for years (latent TB infection, or LTBI)

19. TB Pathogenesis (2) Latent TB Infection
Persons with LTBI are
Asymptomatic
Not infectious
LTBI formerly diagnosed only with TST
Now QFT-G can be used

20. Anergy
Anergy is the immune system’s failure to respond to injected reagents or antigens
Persons with compromised immunity may not react to tuberculin
A few persons with normal immunity also do not react
Thus, absence of TST reaction does not rule out LTBI or TB disease
Anergy testing not recommended as adjunct to TST, because TST results alone cannot guide clinical decision making

21. What’s New QuantiFERON-TB Gold test (QFT-G)
QFT-G is a type of blood assay for M. tuberculosis (BAMT)
Measures the patient’s immune system reaction to M. tuberculosis
Blood samples must be processed within 12 hours
Interpretation of QFT-G results is influenced by the patient’s risk for infection with M. tuberculosis
An alternative to TST

22. Clinical Diagnosis Obtain medical history and physical exam
Place patients with suspected or known infectious TB disease under AII precautions until determined to be noninfectious
Evaluate persons with extrapulmonary TB for concurrent pulmonary TB disease
Although normally not infectious, children should be evaluated for infectiousness

23. Diagnosis of Latent TB Infection
Persons with LTBI
Are asymptomatic
Do not feel sick
Cannot spread TB to others
Diagnostic procedures
Positive TST with medical evaluation to exclude TB
Evaluation includes assessing symptoms and signs, x-ray, and sputum tests
Blood assay for M. tuberculosis (BAMT) now available

24. Treatment for LTBI
Treating LTBI reduces the risk that M. tuberculosis infection will develop into TB disease
Certain groups have higher risk for developing TB disease after infection; should be treated
Before beginning treatment for LTBI
Exclude diagnosis of TB
Ensure patient has no history of adverse reactions resulting from prior LTBI treatment

25. Candidates for Treatment for LTBI
Give LTBI Treatment to
If M. tuberculosis Test Result Is
Highest risk groups
Immunocompromised
Recent contacts
X-ray indicates previous TB
≥5 mm
Other high-risk groups
≥10 mm
Patients with no risks
≥15 mm
The frequency of TB testing for HCWs will be determined by the risk classification for the setting.

26. TB Patient Characteristics That Increase Risk for Infectiousness (1)
Coughing
Undergoing cough-inducing or aerosol-generating procedure
Failing to cover cough
Having cavitation on chest radiograph

27. TB Patient Characteristics That Increase Risk for Infectiousness (2)
Positive acid-fast bacilli (AFB) sputum smear result
Disease of respiratory tract and larynx
Disease of respiratory tract and lung or pleura
Inadequate TB treatment

28. Characteristics of Infectiousness
Infectiousness related to
Cough >3 weeks
Cavitation on chest radiograph
Positive sputum smear results

29. Characteristics of Infectiousness
Respiratory tract disease involving lung, airway, or larynx
Failure to cover mouth and nose when coughing
Inadequate treatment
Undergoing cough- or aerosol-producing procedures

30. Antituberculosis Drugs
First-Line Drugs
Second-Line Drugs
Isoniazid
Rifampin
Pyrazinamide
Ethambutol
Rifabutin*
Rifapentine
Streptomycin
Cycloserine
p-Aminosalicylic acid
Ethionamide
Amikacin or kanamycin*
Capreomycin
Levofloxacin*
Moxifloxacin*
Gatifloxacin*
* Not approved by the U.S. Food and Drug Administration for use in the treatment of TB

31. Drug Abbreviations Ethambutol EMB Isoniazid INH Pyrazinamide PZA
Rifampin RIF
Rifapentine RPT
Streptomycin SM

32. Treatment Regiments for LTBI
Drugs
Months of Duration
Interval
Minimum Doses
INH 9*
Daily
270
2x wkly 76 6
180 52
RIF 4
120
*Preferred
INH=isoniazid; RIF=rifampin

33. Treatment for TB Disease
TB treatment regimens must contain multiple drugs to which M. tuberculosis is susceptible
Treating TB disease with a single drug can lead to resistance
Also, adding a single drug to a failing regimen can lead to drug resistance

34. Treatment for TB Disease
Preferred regimen
Initial phase: 2 months isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol
Continuation phase: 4 months INH and RIF
In patients with cavitary pulmonary TB and positive culture results at end of initiation phase, continuation phase should be 7 months
TB patients with HIV who are taking anti-retrovirals (ARVs) should be managed by TB/HIV disease experts
TB treatment regimens might need to be altered

35. Factors Guiding Treatment Initiation
Epidemiologic information
Clinical, pathological, chest x-ray findings
Microscopic examination of acid-fast bacilli (AFB) in sputum smears
Nucleic acid amplification test (when performed)

36. Persons at Higher Risk for Exposure to and Infection with M
Persons at Higher Risk for Exposure to and Infection with M. tuberculosis
HCWs unknowingly exposed to TB patient
Low-income, medically underserved groups
Locally defined high-risk groups
Young persons exposed to high-risk adults

37. When to Consider Treatment Initiation
Positive AFB smear
Treatment should not be delayed because of negative AFB smears if high clinical suspicion:
History of cough and weight loss
Characteristic findings on chest x-ray
Emmigration from a high-incidence country

38. Other Examinations to Conduct When TB Treatment Is Initiated
Counseling and testing for HIV infection
CD4+ T-lymphocyte count for HIV-positive persons
Hepatitis B and C serologic tests, if risks present

39. Other Examinations to Conduct When TB Treatment Is Initiated
Measurements of aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, alkaline phosphatase, serum creatinine, and platelet count
Visual acuity and color vision tests (when EMB used)

40. Algorithm to Guide Treatment of Culture-Negative TB
Is initial culture positive? NO
YES
Was there symptomatic or chest x-ray improvement after
2 months of treatment?
Continue treatment for culture-positive TB NO
YES
Discontinue treatment
Patient presumed to have LTBI
Treatment completed
Give continuation- phase treatment of INH/RIF daily or twice weekly for 2 months

41. Role of New Drugs
Rifabutin: For patients receiving medications having unacceptable interactions with rifampin (e.g., persons with HIV/AIDS)
Rifapentine: Used in once-weekly continuation phase for HIV-negative adults with drug-susceptible noncavitary TB and negative AFB smears at completion of initial phase of treatment

42. Role of New Drugs
Fluoroquinolones (Levofloxacin, Moxifloxacin, Gatifloxacin): Used when
-first-line drugs not tolerated;
-strains resistant to RIF, INH, or EMB; or
-evidence of other resistance patterns with fluoroquinolone susceptibility

43. Common Adverse Reactions to Drug Treatment
Signs and Symptoms
Any drug
Allergy
Skin rash
Ethambutol
Eye damage
Blurred or changed vision
Changed color vision
Isoniazid,
Pyrazinamide, or
Rifampin
Hepatitis
Abdominal pain
Abnormal liver function test
results
Fatigue
Lack of appetite
Nausea
Vomiting
Yellowish skin or eyes
Dark urine

44. Common Adverse Reactions to Drug Treatment
Signs and Symptoms
Isoniazid
Peripheral neuropathy
Tingling sensation in hands and feet
Pyrazinamide
Gastrointestinal intolerance
Arthralgia
Arthritis
Upset stomach, vomiting, lack of appetite
Joint aches
Gout (rare)
Streptomycin
Ear damage
Kidney damage
Balance problems
Hearing loss
Ringing in the ears
Abnormal kidney function test results

45. Common Adverse Reactions to Drug Treatment
Caused by
Adverse Reaction
Signs and Symptoms
Rifamycins
Rifabutin
Rifapentine
Rifampin
Thrombocytopenia
Gastrointestinal intolerance
Drug interactions
Easy bruising
Slow blood clotting
Upset stomach
Interferes with certain medications, such as birth control pills, birth control implants, and methadone treatment

46. Drug Interactions
Relatively few drug interactions substantially change concentrations of antituberculosis drugs
Antituberculosis drugs sometimes change concentrations of other drugs
-Rifamycins can decrease serum concentrations of many drugs, (e.g., most of the HIV-1 protease inhibitors), to subtherapeutic levels
-Isoniazid increases concentrations of some drugs (e.g., phenytoin) to toxic levels

47. Prevention of TB in persons with DM
Persons with diabetes mellitus (DM) who are at increased risk of tuberculosis (TB) should be screened for latent TB infection (LTBI)
TST or IGRA should be done at time of DM diagnosis
Patients with DM who are found to have LTBI should be encouraged to take INH for 9 months
Patients with DM on INH should receive vitamin B6 to prevent INH induced neuropathy

48. Screening for DM in persons with TB
Every patient with TB over the age of 18 should be screened for DM
A fasting plasma glucose > 125 mg/dl = DM
A random plasma glucose > 200 mg/dl = DM
A Hemoglobin A1c > 6.5% = DM
Abnormal glucose values should be repeated in patients who have no symptoms of DM

49. Screening for DM in persons with TB
Glucose should be repeated after 2-4 weeks of TB Rx or if symptoms of hyperglycemia develop
Rifampin and INH can markedly elevate glucose levels
Use the same criteria to diagnose DM as at initial evaluation
Ask about polyuria/polydipsia at TB clinic visits

50. Management of DM in patients receiving TB treatment
Use the frequent contact with the patient during TB treatment to help manage his/her DM in the TB clinic
There should be a glucose meter in every TB clinic and blood glucose should be frequently checked in the clinic for those with DM
All clinical staff should reinforce lifestyle changes at TB clinic visits
If available, refer persons with diabetes to a diabetes specialty clinic or clinician comfortable with treating DM

51. Management of DM in patients receiving TB treatment
DOT workers should encourage lifestyle changes at every encounter
Dietary changes and physical activity are most important in this effort
Use available structured diabetes education materials i.e. NDEP available at:
Consider delivering DM meds with TB meds via DOT

52. Treatment of TB in persons with DM
Ensure that TB treatment is appropriately adjusted in persons with DM
Check creatinine for diabetic nephropathy
May need to adjust frequency of PZA and EMB administration
Give B6 to prevent INH induced peripheral neuropathy

53. Treatment of TB in persons with DM
Ensure that TB treatment is appropriately adjusted in persons with DM
Persons with DM have a relative immune suppression and often a higher burden of disease
Consider extending treatment to 9 months for persons with DM and caviatary disease OR delayed sputum clearance.
Upon completion of therapy, obtain smear and culture for AFB
Follow up the patient at 6 months and one year after treatment completion

54. Treatment of TB in persons with DM
Observe closely for treatment failure
Be aware of poor absorpti0on of some TB meds in DM
Manage the many interactions between TB and DM meds
There may be a slight increase in diabetic retinopathy in persons with DM

55. Special Treatment Situations Renal Insufficiency and End-Stage Renal Disease
Renal insufficiency complicates management of TB because some antituberculosis medications are cleared by the kidneys
Dosage should not be decreased because peak serum concentrations may be too low; smaller doses may decrease drug efficacy

56. Special Treatment Situations Renal Insufficiency and End-Stage Renal Disease
Dosing interval of antituberculosis drugs should be decreased
Most drugs can be given 3 times weekly after hemodialysis; for some drugs, dose must be adjusted

57. Special Treatment Situations Hepatic Disease
Must consider regimens with fewer hepatotoxic agents for patients with liver disease
Recommended regimens:
Treatment without PZA Initial phase (2 months): INH, RIF, and EMB Continuation phase (7 months): INH and RIF
Treatment without INH Initial phase (2 months): RIF, PZA, and EMB Continuation phase (4 months): RIF, EMB, and PZA

58. Special Treatment Situations Hepatic Disease
Recommended regimens: (continued)
3) Regimens with only one potentially hepatotoxic drug
RIF should be retained
Duration of treatment is months
4) Regimens with no potentially hepatotoxic drugs
Duration of treatment is months

59. Treatment Failure
Defined as positive cultures after 4 months of treatment in patients for whom medication ingestion was ensured
Single new drug should never be added to a failing regimen; it may lead to acquired resistance to the added drug
Add at least three new drugs (e.g., fluoroquinolone, ethionamide, and an injectable drug: SM, amikacin, kanamycin, or capreomycin) to the existing regimen being cognizant of the possibility of drug resistance

60. References
Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, MMWR 2005; 54 (No. RR-17): 1–141.
Maj_guide/infectioncontrol.htm
Errata (August 2006) available online Errata_table.pdf

61. Division of Tuberculosis Elimination
Guidelines for Preventing the Transmission of M. tuberculosis in Health-Care Settings, 2005
Division of Tuberculosis Elimination
December 2006 note: Slide #123 has been edited.

62. Additional TB Guidelines
CDC. Prevention and Control of Tuberculosis in Correctional and Detention Facilities: Recommendations from CDC.MMWR 2006; 55 (No. RR-09): 1–44.
CDC. Guidelines for the investigation of contacts of persons with infectious tuberculosis: recommendations from the National Tuberculosis Controllers Association and CDC. MMWR 2005; 54 (No. RR-15): 1-37.
CDC. Guidelines for using the QuantiFERON-TB Gold Test for detecting Mycobacterium tuberculosis infection, United States. MMWR 2005; 54 (No. RR-15):
CDC. Controlling tuberculosis in the United States: recommendations from the American Thoracic Society, CDC, and the Infectious Diseases Society of America. MMWR 2005; 54 (No. RR-12): 1-81.
CDC. Guidelines for infection control in dental health-care settings—2003. MMWR 2003; 52 (No. RR-17).
CDC. Treatment of tuberculosis. American Thoracic Society, CDC, and Infectious Diseases Society of America. MMWR 2003; 52 (No. RR-11).
CDC. Guidelines for environmental infection control in health-care facilities: recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee (HICPAC).MMWR 2003; 52 (No. RR-10).

63. Additional Resources
For additional information on TB, visit the CDC Division of Tuberculosis Elimination website at

64. Thank You!