World TB DAY 2007 The Trouble With TB Pitfalls in the Diagnosis and Treatment of Tuberculosis Jon Warkentin, M.D., M.P.H. State TB Control Officer Tennessee Dept. of Health Ph: (615)253-1364 Jon.Warkentin@state.tn.us March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC Objectives Explain why TB remains a critical public health issue Describe the epidemiology of TB in Tennessee List challenges to TB diagnosis and treatment Identify resources to improve TB diagnosis and treatment March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC Objective TB as a critical public health issue March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC History of TB The brilliance of Robert Koch Koch’s Postulates March 24, 1882 - First description of slow-growing “tubercle bacillus” Life cycle of tubercle bacilli entailed in human-to-human transmission Lungs as portal of entry “…my studies have been done in the interest of public health, and I hope that this will derive the largest profit from them.” March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC History of TB Adventures in treatment of TB Rest, dietary enrichments, religious rituals, exocism, fasting, bleeding, purging, emetics, expulsion, execution Manipulating climatological variables Collapse therapies – “plomage” 1885 to WWII – Edward Livingston Trudeau’s “Little Red Cottage” at Saranac, NY – the age of “sanataria” March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC History of TB Curative chemotherapy 1944 – Lehmann – para-aminosalicylate 1944 – Waksman, Schatz, Hinshaw, Feldman – streptomycin 1952 – Domagk, Fox, Bernstein – isoniazid 1954 – first combination therapy with INH, PAS and streptomycin produced nearly universal, lifetime cures of TB March 13, 2007 East Tennessee State University - VAMC

TB as a critical public health issue Biological factors Cellular structure Resilience in an intracellular habitat Latency and active replication Interpersonal transmission through air Socioeconomic factors Associations with poverty, limited access to health care, on every continent HIV/AIDS Politics and the “cycle of neglect” March 13, 2007 East Tennessee State University - VAMC

TB as a critical public health issue 2007: Tools for effective TB control Effective multi-drug therapeutics Diagnostics tools – rapid culture techniques, NNA, susceptibility testing, genotyping, etc. Standards of care (ATS/CDC guidelines) 2007: Resurgence of TB HIV co-infection, multi-drug resistance Immigration and migration “Out of sight, out of mind” The “cycle of neglect” – public health resources March 13, 2007 East Tennessee State University - VAMC

Breaking the Cycle of TB Transmission “The best way to prevent TB is to treat and cure people who have it.” - The STOP TB Partnership March 13, 2007 East Tennessee State University - VAMC

TB as a critical public health issue Worldwide Impact of TB 8,000,000 people develop active TB every year Each one can infect between 10-15 people in one year just by breathing March 13, 2007 East Tennessee State University - VAMC

TB as a critical public health issue Worldwide Impact of TB Someone dies of TB every 15 seconds Worldwide, over 2,000,000 people die annually from TB, mostly in less developed countries March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC March 13, 2007 East Tennessee State University - VAMC

Breaking the Cycle of TB Transmission Recall: The best way to prevent TB is to treat and cure people who have it. Therefore, Emergence of MDR-TB represents a failure of public health systems to effectively treat TB And, if the system FAILS….? March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC TB emergency declared in Africa African health ministers have announced a regional tuberculosis emergency due to a sharp rise in the number of cases. The declaration was made in Mozambique at a meeting of the World Health Organization's (WHO) African region. WHO Regional Director for Africa Dr Luis Gomes Sambo appealed for "urgent and extraordinary" action to prevent the situation from getting worse. Tuberculosis, or TB, kills half a million people a year in Africa, a quarter of the global total. 'Unprecedented proportions' The Aids epidemic is increasing the spread of TB, which affects people in their most productive years and kills some 1,500 Africans every day. Published: 2005/08/25 23:57:01 GMT March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC Objective The epidemiology of TB in Tennessee March 13, 2007 East Tennessee State University - VAMC

Reported TB Cases United States, 1982–2004 No. of Cases Slide 2. Reported TB Cases, United States, 1982–2004. The resurgence of TB in the mid-1980s was marked by several years of increasing case counts until its peak in 1992. From 1992 until 2002, the total number of TB cases decreased 5%–7% annually, and 2004 marked the twelfth year of decline in the total number of TB cases reported in the United States since the peak of the resurgence. From 2002 to 2003, however, the total number of TB cases decreased by only 1.4%, the smallest annual decrease during the past decade. In 2004, a total of 14,517 cases were reported from the 50 states and the District of Columbia. This represents a decline of 2.3% from 2003 and of 46% from 1992. (Note: A provisional total of 14,511 was reported in the MMWR in March 2005.) 1982 1987 1991 1995 1999 2004 Year Source: CDC All case counts and rates for 1993–2003 have been revised based on updates received by CDC as of April 1, 2005. March 13, 2007 East Tennessee State University - VAMC

Are We On Track? “Without question the major reason for the resurgence of tuberculosis was the deterioration of the public health infrastructure essential for the control of tuberculosis.” - Institute of Medicine March 13, 2007 East Tennessee State University - VAMC

Tennessee Public Health Regions Lake OBION DYER LAUDERDALE TIPTON 1 FAYETTE HAYWOOD CROCKETT GIBSON WEAKLEY CARROLL HENRY 2 HARDEMAN MCNAIRY CHESTER HENDERSON HARDIN WAYNE LAWRENCE GILES LINCOLN FRANKLIN MARION 4 BRADLEY POLK PERRY LEWIS DECATUR HICKMAN MAURY MARSHALL BEDFORD MOORE COFFEE GRUNDY SEQUATCHIE BLEDSOE RHEA MEGS MCMINN MONROE LOUDON BLOUNT ROANE SEVIER 5 MORGAN ANDERSON SCOTT CAMPBELL CLAIBORNE GRAINGER UNION HAMBLEN JEFFERSON COCKE STEWART HOUSTON HUMPHREYS MONTGOMERY DICKSON WILLIAMSON 3 CHEATHAM ROBERTSON SUMNER MACON TROUSDALE WILSON RUTHERFORD CLAY PICKETT JACKSON OVERTON FENTRESS SMITH DEKALB CANNON WARREN VAN BUREN WHITE PUTNAM CUMBERLAND HANCOCK GREENE UNICOI 6 CARTER JOHNSON BENTON Hawkins WASHINGTON ● West Tennessee Region ● Mid Cumberland Region ● South Central Region ● Upper Cumberland Region ● Southeast Tennessee Region ● East Tennessee Region ● North East Tennessee Region Metro Reporting Areas 1. Memphis/Shelby County 2. Jackson/Madison County 3. Nashville/Davison County 4. Chattanooga/Hamilton County 5. Knoxville/Knox County 6. Sullivan County March 13, 2007 East Tennessee State University - VAMC

Tuberculosis Cases and Case Rates Tennessee Regions, 2006 100,000 Population Case Rate§ per Number of Cases Region * Case Rates using July 2005 population estimates (2006 County level pop. estimates not yet available). March 13, 2007 East Tennessee State University - VAMC

Tuberculosis Cases and Case Rates Tennessee, 2002-2006 Number of Cases 100,000 Population Case Rate per Year *Case Rates using population estimates from July of each year, respectively. March 13, 2007 East Tennessee State University - VAMC

Tuberculosis Cases by Gender Tennessee, 2002-2006 Percent of Cases Year March 13, 2007 East Tennessee State University - VAMC

Tuberculosis Cases by Age Group Tennessee, 2002-2006 Percent of Cases Year March 13, 2007 East Tennessee State University - VAMC

Tuberculosis Cases by Race/Ethnicity Tennessee, 2002-2006 Percent of Cases Year *Data do not include missing information; Race is Non-Hispanic and Hispanic is of all races. March 13, 2007 East Tennessee State University - VAMC

National Origin of Foreign-born Tuberculosis Cases Tennessee, 2006 March 13, 2007 East Tennessee State University - VAMC

Foreign-born Tuberculosis Cases Tennessee, 1997-2006 Number of Cases Percent of Cases Year March 13, 2007 East Tennessee State University - VAMC

Risk Factors Associated with TB Infection Tennessee, 2002-2006 TB Risk factor 2002 N (%) 2003 2004 2005 2006 Foreign-born 50 (16) 52 (18) 49 (18) 64 (21) 69 (25) HIV Infection 30 (10) 30 (11) 23 (8) 26 (9) 21 (8) Homeless† 28 (9) 27 (10) 32 (11) 15 (5) Residing in correctional facility‡ 13 (4) 19 (7) 11 (4) 10 (4) Residing in a long-term facility‡ 12 (4) 13 (5) 4 (1) Injection drug user 9 (3) 7 (3) 0 (0) 6 (2) Non-injection drug user 31 (10) 38(13) 28 (10) 37 (12) Excessive alcohol use 61 (20) 62 (22) 61 (22) 57 (19) 37 (13) † Homeless within past year ‡ Residing in facility at time of TB diagnosis March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC in TN R MDR M TB D March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC MDR-TB in Tennessee - 2007 March 13, 2007 East Tennessee State University - VAMC

Summary of TB Epidemiology TB is a burgeoning global epidemic Rate of decline in TB case rate in U.S. has slowed, increasing in some states Pediatric TB disease is sentinel for ongoing TB transmission Migration/immigration link every corner of the globe with Tennessee Increasing percentage of cases among blacks, hispanics and foreign-born in TN Substantial racial/ethnic disparities in TN March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC Objective Challenges to diagnosis and treatment of TB March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC Case Study 72 y.o. female presents to local hospital c/o… March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC The Cycle of TB Transmission March 13, 2007 East Tennessee State University - VAMC

Challenges to Diagnosis and Treatment of TB S: Subjective O: Objective A: Assessment P: Plan Key to diagnosis is “Thinking TB”! March 13, 2007 East Tennessee State University - VAMC

Challenges to Diagnosis and Treatment of TB S: Subjective Chief complaint History of present illness Past medical history Current medications Social history Review of systems March 13, 2007 East Tennessee State University - VAMC

Challenges to Diagnosis and Treatment of TB S: Subjective Chief complaint “Classical” vs atypical presentations Mental status changes in elderly History of present illness Cluster of key symptoms Index of suspicion with respiratory symptoms Corroborating history by significant others March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC March 13, 2007 East Tennessee State University - VAMC

Challenges to Diagnosis and Treatment of TB S: Subjective Past medical history History of “positive skin test,” recent or remote Recurrent “bronchitis” or “community acquired pneumonia,” especially in past 6 months, refractory UTIs in elderly Initial improvement, worse recurrence Treatment with fluoroquinolones Conditions with high risk of LTBI progression March 13, 2007 East Tennessee State University - VAMC

Conditions with Increased Risk of Progression to TB Disease HIV infection / AIDS Substance abuse Recent infection Previous TB Diabetes Silicosis Corticosteroid tx Imm. therapy CA of head/neck Hemato./RE diseases ESRD Certain GI surgeries Malabsorption synd. Low body wt. (10%) March 13, 2007 East Tennessee State University - VAMC

Challenges to Diagnosis and Treatment of TB S: Subjective Current medications Antibiotics, especially fluoroquinolones Levofloxacin, Moxifloxicin Development of FQ-resistant TB strains Preemption of FQ use as first-line TB therapy Immunosuppressive agents (e.g., chronic systemic steroids, TNF-alpha blockers, Methotrexate High risk for progression from LTBI to active TB March 13, 2007 East Tennessee State University - VAMC

Challenges to Diagnosis and Treatment of TB S: Subjective Social history Known TB exposures? Work history Travel to countries with endemic TB Health status of household contacts, work and social network Substance abuse (esp. Etoh, crack) March 13, 2007 East Tennessee State University - VAMC

Challenges to Diagnosis and Treatment of TB S: Subjective Review of systems Constitutional symptoms Organ systems CNS – TB meningitis, esp. in young children, HIV Pulmonary – may have minimal cough Lymph nodes, especially cervical Urinary tract – refractory UTIs “TB can affect any organ of the body” March 13, 2007 East Tennessee State University - VAMC

Challenges to Diagnosis and Treatment of TB O: Objective Physical examination Labs Radiography Special procedures March 13, 2007 East Tennessee State University - VAMC

Challenges to Diagnosis and Treatment of TB O: Objective Physical examination Vital signs – fever, tachypnea Inspection – wasting (“consumption”), dyspnea on exertion Auscultation – rales, rhonchi, decreased breath sounds Percussion – dullness Palpation – lymphadenopathy Non-specific findings are common March 13, 2007 East Tennessee State University - VAMC

Challenges to Diagnosis and Treatment of TB O: Objective Labs TST – false-positives, false-negatives Sputums for AFB smear and culture Always collect under supervision Strongly consider induction (comparable AFB yield to bronchoscopy) MTD available at State Laboratory on AFB+ spec. CBC with diff, CMP, U.A. U.A. HIV status – critical! (see MMWR 9/22/06) March 13, 2007 East Tennessee State University - VAMC

Challenges to Diagnosis and Treatment of TB O: Objective Radiography CXR (PA and lateral) – infiltrates, nodules, calcifications, effusions, pleural thickening, tracheal deviation with volume loss, cavitation, perihilar adenopathy CXR may be normal in HIV/AIDS or other immunocompromised patients CT scan – helpful for small cavities March 13, 2007 East Tennessee State University - VAMC

Challenges to Diagnosis and Treatment of TB O: Objective Special procedures Bronchoscopy – BAL with washings for AFB smear, culture, cytology; biopsy Other biopsies – specimens should be cultured for Mtb (not placed in formalin!), State Lab can probe with MTD Laryngoscopy CT-guided FNA – cytology confirming carcinoma does not rule out concurrent TB March 13, 2007 East Tennessee State University - VAMC

Challenges to Diagnosis and Treatment of TB A: Assessment Problem list Differential diagnosis P: Plan Further diagnostics? Resp. isolation Medications? Notify local health department Discharge planning March 13, 2007 East Tennessee State University - VAMC

Challenges to Diagnosis and Treatment of TB A: Assessment Problem list Organ systems Acute + chronic signs, symptoms linked? Differential diagnosis Is active TB disease on the differential dx? Must have a low index of suspicion for TB March 13, 2007 East Tennessee State University - VAMC

Challenges to Diagnosis and Treatment of TB P: Plan Further diagnostic tests Respiratory isolation Medications Notify local health department Discharge planning March 13, 2007 East Tennessee State University - VAMC

Treatment of TB Disease Standard DOT: 6-9 months Initial phase: 4-drugs (INH, RIF, PZA, ETH) for 8 wks (daily x2 wks, then 2-3x/wk) Continuation: 2-drugs (INH, RIF) for 16 weeks (daily or 2-3x/wk) Drug changes: depend on culture sensitivity, clinical response, pt. factors Clin. monitoring: ESSENTIAL! March 13, 2007 East Tennessee State University - VAMC

Challenges to Diagnosis and Treatment of TB Physicians are obliged to treat the patient AND protect the public health Suspicion or confirmatin of active TB must be reported by telephone to local health dept. within 12 hours (statutory requirement of physicians, labs, hospitals in TN) AFB+ patients should be considered to have active TB until proven otherwise “TST- and AFB-” does NOT rule out TB! March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC New Anti-TB Drugs Problems with std. 4-drug regimen for TB dz (INH, RIF, PZA, EMB): toxicities, drug interactions, long tx course, many “pills” challenges for completing full tx course increasing drug resistance Growing int’l awareness of need for new Rx Will we say goodbye to Isoniazid? March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC Single-drug & MDR-TB Primary: infected with a resistant TB organism Secondary: developed drug resistance due to (a) inadequate regimen, (b) sporadic treatment, or (c) both Cure? Tx is long, expensive, toxic, difficult, and impossible in certain cases March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC Impact of HIV/AIDS HIV is the strongest risk factor for development of TB disease if infected:  7-10% chance per year of developing active TB disease  100x greater risk than person with a normal immune system  TB is the leading killer of persons with HIV/AIDS worldwide March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC Pearls That Work THINK TB! Induce & witness sputum collection Poor specimens yield unreliable results One neg. MTD does not rule out TB R/O active pulmonary TB even in context of confirmed extra-pulmonary TB HIV+, PPD-, normal CXR, with symptoms of active TB is active TB (not MAI) until proven otherwise Four-drug therapy for initiation phase March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC Pearls That Work THINK TB! Nothing grows in formalin… Biopsy specimens need to be cultured for TB Sensitivity testing requires live TB bugs Recurrent “CAP” – risk factors for TB? Inappropriate FQ use can… Delay dx of TB disease Increase severity of TB before dx made Create drug resistant TB organisms Contribute to ongoing TB transmission March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC Pearls That Work Rapid reporting of TB suspect to LHD TN Statute requires provider phone report to LHD within 12 hrs. Contact investigation starts only after report Discharge planning starts on Hosp. Day #1 LHD case manager works with ICN and SW NEVER release a homeless TB pt. from the hospital before consulting the LHD March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC Objective Resources in the fight against TB March 13, 2007 East Tennessee State University - VAMC

TB Resources for the Clinician ATS website TB diagnosis and classification TB treatment Community Acquired Pneumonia (CAP) CDC website – DTBE Infection control in healthcare facilities Contact investigation TDH website – TB Elimination Program Dr. Jay Mehta – ETSU March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC Acknowledgements Dr. Jay Mehta Dr. Michael Iseman Dr. Timothy Sterling Staff of the Sullivan County Health Dept. Staff of Northeast TN Regional Office - TDH Staff of Tennessee TB Elimination Program Erin Holt, MPH – epidemiologist American Thoracic Society Centers for Disease Control & Prevention March 13, 2007 East Tennessee State University - VAMC

East Tennessee State University - VAMC Questions? March 13, 2007 East Tennessee State University - VAMC