What the Primary Physician Should Know about Tuberculosis Henry F. Chambers, M.D Professor of Medicine, UCSF Topics for Discussion Microbiology Epidemiology Common disease presentations Diagnosis of active disease Screening for latent infection Life Cycle of M. tuberculosis 1
Global Impact of TB - 2010 World population 6,891,695,457 Number infected with TB: 2,300,000,000 New reported cases of active TB: 10,000,000 (140 per 100,000) 500,000 new MDR cases per year Leading cause of death worldwide from any single infectious disease (AIDS and malaria are 2 and 3) US Tuberculosis Case Rates 2009 (per 100,000) MMWR Vol 59, No. 10, 2010 US Tuberculosis Case Rates 2009 (per 100,000) MMWR Vol 59, No. 10, 2010 2
Active Tuberculosis Pulmonary tuberculosis: 85% of all cases The infectious form of the disease Clinical suspicion based on Signs, symptoms, setting Chest x-ray 120 Sites of TB Infection Percent 100 80 60 40 20 Extrapulmonary Pulmonary Other Bone/jt Miliary GU Pleural Lymphatic 0 All cases Expul Case Presentation 63 y/o inmate transferred from jail for r/o TB No fever, cough, weight loss 12 mm + PPD, HIV negative Prior work-up 2/2001: AFB smear/culture neg x3 4/2005: AFB smear/culture neg x3 8/2005: AFB smear/culture neg x3 3/2010: AFB smear/culture neg x1 9/2010: AFB smear/culture neg x4 3
CXR: LUL nodular infiltrate, slight volume loss, maybe slightly worse since prior film What is your estimate of the likelihood of active TB in this case? 1. 75% or higher 2. 50-75% 3. 25-50% 4. 5-25% 5. < 5% Work-Up CXR: LUL nodular infiltrate, slight volume loss, maybe slightly worse since prior film? Sputum examination Routine: OF on culture and Gram-stain AFB x2 and BAL x1: no AFB GenProbe Amplified MTD test: negative 4
What is your revised estimate of the likelihood of active TB in this case? 1. 75% or higher 2. 50-75% 3. 25-50% 4. 5-25% 5. < 5% Diagnosis of TB Organism Burden in TB Cavitary TB Pulmonary infiltrate Lymphadenopathy 10 6-10 7 cfu/g 10 4-10 5 cfu/g 10 2-10 4 cfu/g 5
Detection Thresholds of Tests for TB Diagnosis Positive smear Positive NAA test Positive culture 10 4-10 5 cfu/ml 10 1-10 2 cfu/ml 10 1 cfu/ml Performance of Diagnostic Tests for Pulmonary TB Sensitivity Specificity AFB smear 60% 90% NAA test 85% 97% Culture 90% 99% PPD (or QTF) 60% 10% Performance of NAAT for Diagnosis of Pulmonary TB Pre-test PPV NPV probability 90% 100% 43% 75% 98% 69% 50% 96% 87% 25% 91% 95% 5% 57% 99% 6
Clinical Course Patient was discharged back to jail Treatment for tuberculosis withheld pending results of work-up 16 days after discharge, one sputum culture and the BAL specimen were reported positive for Mtb! Extrapulmonary TB Forms of Extrapulmonary Tuberculosis Cervical lymphadenitis Tuberculous pleuritis Other rarer birds 7
Differential Dx of Cervical Adenitis Tuberculosis Non-tuberculous mycobacterial infection Kikuchi-Fujimoto s syndrome (histiocytic necrotizing lymphadenitis) Staph or strep infection Cat scratch Lymphoma, other tumor Other: syphilis, HIV, tularemia, listeria, plague 8
Tuberculous Adenitis Clinically presentation not distinctive Constitutional symptoms not usually present Seen in children, young adults > adults PPD + in 75-80% Chest x-ray abnormality (15-20%) favors MTB Foreign-born patient more likely to have MTB Work-up of Suspected TB Adenitis Tuberculin test Check HIV serology Chest x-ray to r/o pulmonary TB Respiratory isolation for patients with pulmonary symptoms, pulmonary TB Notify tuberculosis control Diagnosis of TB Adenitis Tissue is the issue to exclude other etiologies for sensitivity testing FNA Characteristic granulomas in 80% Culture + in 40-70% Smear + < 50% Biopsy: partial vs. total excision 9
Treatment of TB Cervical Adenitis Responsive to medical therapy alone If excisional surgery performed, medical therapy still must be given Paradoxical worsening can occur; needle aspiration effective management Sinus track formation, non-healing wounds may benefit from surgery Similar Scenario for TB Pleuritis Unilateral, benign, lymphocytic effusion Primary infection, newly + PPD Fluid usually smear and culture negative Pleural biopsy culture positive ~60%, with granulomas ~80% Treat as for adenitis or pulmonary TB Principles of Therapy Start 4 drugs (RIPE) for suspected active TB Never use a single drug for treating active TB: resistance can emerge (1 mutant in 10 4 to 10 6 ) Never add a single drug to a failing regimen Consult and expert and/or local health department Francis Curry National TB Center: http:// www.nationaltbcenter.edu/ 10
Screening for Latent TB Infection (LTBI) Case Presentation LV is a 58 y/o female from Ukraine referred for treatment of hypertension and diabetes She is otherwise well She gives a history of BCG vaccination as a teen What is the best course of action? 1. The patient should be screened for LTBI with a tuberculin test 2. The patient should not be screened for LTBI because she is not a candidate for INH prophylaxis due to her age 3. The patient should not be screened because with prior BCG vaccination the tuberculin test will be false positive 4. The patient should be screened for LTBI by chest x-ray 11
LTBI: Goals of Screening Identify active cases Identify infected persons likely to benefit from treatment of latent TB infection (LTBI) Surveillance Who Should Be Screened? Persons with increased risk of TB infection Persons with increased risk of progression Not the general population Increased Risk of Infection Recent contacts of an active TB case About 30% are infected Foreign-born persons from high TB prevalence areas Asia, Mexico, Middle East, Central and South America, Africa, Eastern Europe Medically underserved, low-income, racial and ethnic minorities Others: HCW, residents of congregate living settings 12
Increased Risk of Progression Children < 5 years old Recent infection (contacts and converters HIV+ Prior TB Various medical conditions: Diabetes, hematologic and reticuloendotheial diseases, intestinal or gastric bypass, renal dialysis Malabsorption syndromes, malnutrition, silicosis, alcoholism, smokers Immunosuppression, anti-tnf agents > 15 mg prednisone QD for > 3 wks Risk of Progression Risk Factor Increase in risk (+TST) AIDS/Advanced HIV 9.9 Anti-TNF agent 7.9 Old TB, untreated 5.2 Diabetes 3.1 Smoker 2.7 Underweight 1.6 Flowchart: Evaluation and Treatment of LTBI TB Risk? Yes No STOP Tuberculin Test + symptom review Negative Positive Treatment not indicated Normal Chest x-ray Abnormal Candidate for Rx of LTBI R/o active TB 13
Diagnosis of LTBI TB Skin Test (TST) QuantiFERON Blood Test (QFT) Reading the TST Measure reaction in 48 to 72 hours Measure induration, not erythema Record reaction in millimeters, not as negative or positive Positive reactions can be read for up to 7 days Negative reactions can be read accurately for only 72 hours TST Positivity 5 mm + PPD HIV, immunocompromised, contacts, abnl CXR 10 mm + PPD Those at increased risk of infection: IVDU, health care workers, foreign born, children < 4 yo, high-risk medical conditions 15 mm +PPD Persons not at risk (why did you do the test?) 14
TST Conversion Signifies new infection > 10 mm increase within 2-year period Conversions may represent boosted reactions in some individuals Tuberculin Skin Test Should NOT be performed on someone with a documented history of a positive test Should be applied, read, and interpreted by a trained health professional RULE OUT active TB before treating for LTBI Interferon Gamma Release Assays (IGRA) Indirect test for M. tuberculosis infection using whole blood Tests for generation of interferon gamma by cell-mediated immunity (not antibody) Highly specific: not affected by prior BCG vaccination 15
Andersen, et al. Lancet 356:1099, 2000 FDA Approved Interferon Gamma Release Assays (IGRA) Quantiferon-TB Gold (Cellestis, Ltd) Uses ESAT-6 and CFP-10 as antigens Quantiferon-TB In-tube Uses ESAT-6, CFP-10 and TB7.7 (RD4) as antigens affixed to inside of tube T-Spot-TB (Oxford Immunotec) Uses ESAT-6 and CFP-10 IGRAS: Species Specificity of ESAT-6 and CFP-10 Mycobacterial species ESAT-6 CFP-10 M. tuberculosis + + M. africanum + + M. bovis + + BCG strains - - M. avium-intracellulare - - M. abscessus - - M. smegmatis - - M. kansasii + + M. marinum + + M. szulgai + + 16
Quantiferon-Gold Advantages Requires a single patient visit to draw a blood sample Results within 24 hours No boosting Is not subject to reader bias that can occur with TST Is not affected by prior BCG Performance of IGRA vs TST Performance characteristics TST IGRA Sensitivity 75-91% 80-95% Specificity 80-90% 95-100% Correlates with exposure Often no Yes Results change with Rx?? Usually yes When Should You Use QFT? QFT-G can be used in all circumstances in which the TST is currently used, including contact investigations evaluation of recent immigrants who have had BCG vaccination TB screening of health care workers others undergoing serial evaluation for M. tuberculosis Caution should be used when testing certain populations (i.e., children < 5 years old, immunocompromised) because of limited data in use of QFT 17
Current Guidelines for Treatment of LTBI Decision to test is decision to treat No 35 year-old cut-off 9 months of INH preferred over 6 months Baseline lab monitoring not routinely indicated How Long is Long Enough Comstock GW. Int J Tuberc Lung Dis 3:847, 1999 Efficacy of INH Treatment of LTBI Duration of INH 5-yr risk reduction Compliance Reduction if compliant 3 mo 21% 87% 31% 6 mo 65% 78% 69% 9 mo 75% 68% 93% Bull World Health Organ 60:555, 1982 18
What is the best course of action? 1. The patient should be offered a tuberculin test to screen for LTBI 2. The patient should not be screened for LTBI because she is not a candidate for INH prophylaxis due to her age 3. The patient should not be screened with tuberculin test because with prior BCG vaccination the test will be false positive 4. The patient should be screened for LTBI by chest x-ray 19