Double Trouble: Diabetes and Tuberculosis Kris Ernst, BSN, RN, CDE Division 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) 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.

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 D.C. < 3.5 (year 2000 target) 3.6–4.2 > 4.2 (national average) *Cases per 100,000.

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%)

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.

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.

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

TB Morbidity United States, 2003–2008 Year No. Rate* 2003 14,836 5.1 2004 14,500 4.9 2005 14,067 4.7 13,727 4.6 13,288 4.4 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 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

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

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

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 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 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

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 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

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

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

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 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

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

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

Special Treatment Situations Hepatic 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 online http://www.cdc.gov/nchstp/tb/pubs/mmwrhtml/ Errata_table.pdf

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.

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