What the Primary Physician Should Know about Tuberculosis Henry F. - PDF document

What the Primary Physician Should Know about Tuberculosis Henry F. Chambers, M.D Professor of Medicine, UCSF Disclosures of Financial Relationships with Relevant Commercial Interests • None

Topics for Discussion • Epidemiology • Diagnosis of active TB • Latent TB infection Definitions • Multi-drug resistant TB (MDR-TB): Resistance to both INH and rifampin • Extensively drug-resistant TB (XDR-TB): Resistance to INH + rifampin + any fluoroquinolone + at least one injectable second line anti-TB agents

Global Impact of TB – 2018 • World population 7,700,000,000 • Number infected with TB: 2,500,000,000 • Incident cases of active TB: 10,000,000 (~140 per 100,000) – US rate 2.8/100,000 in 2018 • ~500,000 new rifampin-resistant cases per year – 3.4% of new cases, 18% of previously treated cases – 78% MDR (~6% of these are XDR) – India (27% of total), China (14%), Russian federation (9%) • Mortality – 1.2 million deaths in HIV-neg – 250,000 deaths in HIV-pos (1/3 of all HIV-related deaths) 2019 WHO Global Tuberculosis Report Countries with Highest TB Incidence – 2018 2019 WHO Global Tuberculosis Report

US Trends in TB – 2018 • 9,025 cases (0.7% decrease from 2017) • US rate 2.8/100,000 (1.3% decrease from 2017) • 515 deaths from TB in 2017 (565 in 2016) • 70% of US cases occurred in non-US-born people • 13,000,000 latent TB infections (LTBI) • Drug resistance – 9.4% of cases with INH resistance – 98 MDR cases (1.5%) – 1 XDR case https://www.cdc.gov/tb/publications/factsheets/statistics/tbtrends.htm US Trends in TB – 2018 Race/ % US Incidence Ethnicity cases per 100,000 Native American 1.2 4.3 Asian 35.3 17.0 50% of US Cases Black or African 19.9 4.4 American Native Hawaiian, 1.3 20.0 Pacific Islander Hispanic, Latino 29 4.4 White 11.9 0.5 https://www.cdc.gov/tb/publications/factsheets/statistics/tbtrends.htm

Demographic Groups with Higher Rates of TB • Foreign-born other than Western Europe • Incarcerated persons • Homeless, marginally housed • HIV positive • Children < age 5 with positive TB test Active Tuberculosis • Pulmonary tuberculosis: ~80% of all cases • The infectious form of the disease • Clinical suspicion based on – Signs, symptoms, setting – Chest x-ray

Diagnosis of TB 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 – 2/2012: AFB smear/culture neg x3 – 4/2014: AFB smear/culture neg x3 – 8/2015: AFB smear/culture neg x3 – 3/2017: AFB smear/culture neg x1 – 9/2018: AFB smear/culture neg x4

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 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%

Performance of Diagnostic Tests for Pulmonary TB Sensitivity Specificity AFB smear 60% 99% NAAT* 85% 99% Culture 90% 99% PPD (or QTF) 60-70% 10% *NAAT = Nucleic Acid Amplification Test

Xpert MTB/RIF Test Performance – Pulmonary TB Sensitivity Specificity Smear pos. TB 95-98% 99% Smear neg. TB* 70-90% Rifampin “R” 98-99% 99-100% * Lower value for single specimen, higher for 3 specimens Organism Burden in TB 10 6 - 10 7 cfu/g Cavitary TB 10 4 - 10 5 cfu/g Pulmonary infiltrate 10 2 - 10 4 cfu/g Lymphadenopathy

Detection Thresholds of Tests for TB Diagnosis 10 4 - 10 5 cfu/ml Positive smear 10 1 - 10 2 cfu/ml Positive NAAT 10 1 cfu/ml Positive culture 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%

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

Case Presentation • 45 yo M from India with 2 weeks of fever and non- productive cough • Chest x-ray: right pleural effusion, otherwise negative • HIV-negative, TST = 20 mm • Pleural fluid – 1200 cells/mm 3 , 65% lymphs – Glucose 90 mg%, Protein 3.5 g/dL, LDH 540 IU/L – Gram-strain, AFB smear negative, cultures pending – Nucleic acid amplification test negative – Pleural adenosine deaminase 9.2 U/L (normal < 9.4) Which of the following is the best approach 1. Treat for latent TB infection with INH or Rifampin 2. Perform quantiferon test and if positive, treat for latent TB infection with INH or Rifampin 3. Start 4-drug therapy for active TB 4. Perform pleural biopsy, start 4-drug therapy for active TB 5. Perform pleural biopsy, start 4-drug therapy for active TB if cultures are positive

Active TB Cases by Site All Cases Extrapulmonary 120 100 80 Percent 60 40 20 0 Lymphatic Pleural Bone/jt Pulmonary Extrapulmonary Peritoneal GU CNS Other Work-up of Suspected Extrapulmonary TB • Tuberculin test (negative does not it rule out) • Check HIV serology (also true for any TB) • Chest x-ray to r/o pulmonary TB • Get tissue for histopathology, culture (and NAAT)

Diagnosis of Extrapulmonary TB • Tissue is the issue – to exclude other etiologies – for sensitivity testing • FNA (lymph node) or biopsy Characteristic granulomas in 80% – Culture + in 40-70% – Smear + < 50% Performance of NAAT for Extrapulmonary TB Sensitivity Specificity Lymphadenitis 90% 92% Meningitis 53% 100% Pleural 30% 100% Peritoneal 32% 100% Tedesse, et al. Clin Microbiol Infect 2019; 25:1000-1005 Cochrane Data base Syst Rev. 2018 Aug 27;8:CD012768

When to Use NAAT for TB Diagnosis in Addition to Culture Suspected pulmonary tuberculosis Suspected tuberculous lymphadenitis Suspected tuberculous meningitis Children (nasophyngeal aspirate) Principles of Therapy • Start 4 drugs (RIPE) for suspected active TB – INH 300 mg once daily – Rifampin 600 mg once daily – Pyrazinamide 25 mg/kg once daiky – Ethambutol 15-25 mg/kg once daily • 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: https://www.currytbcenter.ucsf.edu/

Treatment of Extrapulmonary TB • Same as for pulmonary TB although 9-12 months for CNS, bone, joint • Responsive to medical therapy alone • Paradoxical “worsening” can occur Latent TB Infection (LTBI)

Case Presentation • Lev P is a 58 y/o male from Ukraine referred for treatment of hypertension and diabetes • He is overweight, otherwise well • He 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

Who Should Be Screened? • Persons likely to have 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 (new CDC guidance*), residents of congregate living settings *MMWR / May 17, 2019 / Vol. 68 / No. 19/ page 439

Increased Risk of Progression • Children < 5 years old • Recent infection (contacts and converters) – Recent = within 2 years of documented prior negative – Conversion: a positive TST of ≥ 10 mm and an increase of at least 6 mm in induration compared with the last TST • HIV+ • Prior TB • Various medical conditions: – Diabetes, hematologic/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, others Mabs 7.9 Old TB, untreated 5.2 Diabetes 3.1 Smoker 2.7 Underweight 1.6

Flowchart: Evaluation and Treatment of LTBI TB Risk? STOP No Yes Tuberculin Test + symptom review Negative Positive Chest x-ray Treatment not indicated Normal Abnormal Candidate for Rx R/o active TB of LTBI Diagnosis of LTBI TB Skin Test (TST) Interferon-gamma Release Assay (IGRA)