Double Trouble:Diabetes and Tuberculosis

Kris Ernst, BSN, RN, CDEDivision of Diabetes Translation

Centers for Disease Control and Prevention

Disclaimer

This presentation represents the opinion of the author and is not the

official opinion of CDC

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

Definitions

• Latent Tuberculosis Infection (LTBI)– 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.

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

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

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

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

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 Age Group, United States, 2008

25–44 yrs (33%)

<15 yrs(6%)

15–24 yrs(11%)

45–64 yrs (30%)

>65 yrs (19%)

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.

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.

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

Year

No.

of C

ases

*Updated as of May 20, 2009.

TB MorbidityUnited States, 2003–2008

Year No. Rate*

2003 14,836 5.12004 14,500 4.92005 14,067 4.72006 13,727 4.62007 13,288 4.42008 12,904 4.2

*Cases per 100,000, updated as of May 20, 2009.

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

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)

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

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

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

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

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

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

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.

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

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

Characteristics of Infectiousness

Infectiousness related to– Cough >3 weeks– Cavitation on chest radiograph– Positive sputum smear results

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

Antituberculosis Drugs

• Isoniazid

• Rifampin

• Pyrazinamide

• Ethambutol

• Rifabutin*

• Rifapentine

• Streptomycin

• Cycloserine

• p-Aminosalicylic acid

• Ethionamide

• Amikacin or kanamycin*

• Capreomycin

• Levofloxacin*

• Moxifloxacin*

• Gatifloxacin*

First-Line Drugs Second-Line Drugs

** Not approved by the U.S. Food and Drug Administration for use in the Not approved by the U.S. Food and Drug Administration for use in the treatment of TBtreatment of TB

Drug Abbreviations

Ethambutol EMBIsoniazid INHPyrazinamide PZARifampin RIFRifapentine RPTStreptomycin SM

Treatment Regiments for LTBI

DrugsMonths of Duration

IntervalMinimum

Doses

INH 9*Daily 270

2x wkly 76

INH 6Daily 180

2x wkly 52

RIF 4 Daily 120

*Preferred

INH=isoniazid; RIF=rifampin

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

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

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)

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

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

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

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)

Algorithm to Guide Treatment of Culture-Negative TB

Give continuation- phase treatment

of INH/RIF dailyor twice weekly for

2 months

NO YES

Wasthere

symptomaticor chest x-ray

improvement after2 months of treatment?

NO YES

Isinitial

culture positive?

Continue treatment for culture-

positive TB

• Discontinue treatment• Patient presumed to

have LTBI• Treatment completed

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

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

Common Adverse Reactions to Drug Treatment

Drug Adverse Reaction Signs and SymptomsAny drug Allergy Skin rash

Ethambutol Eye damage Blurred or changed visionChanged color vision

Isoniazid,Pyrazinamide,orRifampin

Hepatitis Abdominal painAbnormal liver function test resultsFatigueLack of appetiteNauseaVomitingYellowish skin or eyesDark urine

Common Adverse Reactions to Drug Treatment

Drug Adverse Reaction Signs and SymptomsIsoniazid Peripheral

neuropathyTingling sensation in hands and feet

Pyrazinamide Gastrointestinalintolerance

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

Common Adverse Reactions to Drug Treatment

Caused by Adverse Reaction Signs and SymptomsRifamycins

• 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

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

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

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

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

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

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: www.YourDiabetesInfo.org– Consider delivering DM meds with TB meds via DOT

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

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

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

Special Treatment SituationsRenal 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

• 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

Special Treatment SituationsRenal Insufficiency and End-Stage

Renal Disease

Special Treatment SituationsHepatic Disease

• Must consider regimens with fewer hepatotoxic agents for patients with liver disease

• Recommended regimens:1) Treatment without PZA

Initial phase (2 months): INH, RIF, and EMBContinuation phase (7 months): INH and RIF

2) Treatment without INHInitial phase (2 months): RIF, PZA, and EMBContinuation phase (4 months): RIF, EMB, and PZA

Special Treatment SituationsHepatic Disease

• Recommended regimens: (continued)

3) Regimens with only one potentially hepatotoxic drug

• RIF should be retained• Duration of treatment is 12-18 months

4) Regimens with no potentially hepatotoxic drugs

– Duration of treatment is 18-24 months

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

References• Centers for Disease Control and Prevention. Guidelines

for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005. MMWR 2005; 54 (No. RR-17): 1–141.

http://www.cdc.gov/nchstp/tb/pubs/mmwrhtml/ Maj_guide/infectioncontrol.htm

• Errata (August 2006) available onlinehttp://www.cdc.gov/nchstp/tb/pubs/mmwrhtml/ Errata_table.pdf

Guidelines for Preventing the Transmission of M. tuberculosis in Health-Care Settings,

2005

Division of Tuberculosis EliminationDecember 2006

note: Slide #123 has been edited.

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): 49-55.

• 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).

Additional Resources

For additional information on TB, visit the CDC Division of Tuberculosis Elimination website at

http://www.cdc.gov/tb

Thank You!kce0@cdc.gov