Tuberculosis Tools: A Clinical Update CAPA Conference 2014 JoAnn Deasy, PA-C. MPH, DFAAPA jadeasy@sbcglobal.net Adjunct Faculty Touro PA Program Learning Objectives Outline the pathogenesis of active pulmonary and extra-pulmonary tuberculosis and latent TB Differentiate between latent and active TB Outline the diagnostic work-up for patients with symptoms and signs of tuberculosis and for patients with a positive PPD or interferon-gamma release assay List the therapeutic regimens for active TB and latent TB Article in Sacramento Bee July 2, 2014 February 2014 a high school student diagnosed with active tuberculosis Subsequently 4 more students diagnosed with active TB (2 in lymph nodes) and 4 family and friends diagnosed with active TB 450 students and staff tested for TB and 116 tested positive Most of these = latent TB with 30 still pending further testing to rule out active TB If any concerns, contact your PCP Tuberculosis (TB) Causative agent: Mycobacterium tuberculosis One-third of world is latently infected 11 million in US latently infected In 90%, infection remains latent Infection spread limited by immune system Pathogenesis of TB M. tuberculosis = aerobic bacillus Neither gram positive or gram negative Acid fast bacilli Transmitted by inhalation (rarely ingestion) Cytokine and cellular activation Immune system tries to limit spread of infection Granuloma formation around bacilli Intracellular killing of bacilli Possible Outcomes of Infection with M. tuberculosis bacilli Active TB disease usually in first 2 years after infection Latent infection (chronic infection) Can develop active disease many years after infection (re-activation) usually when immune system wanes 1
75% Pulmonary Disease 25% Extrapulmonary Latent TB Infection (LTBI) vs TB Disease (Active TB) LTBI Infected with M. tuberculosis alive but not active Usually positive PPD or TB blood test No symptoms or signs Not contagious No infiltrate on CXR TB Disease Infected with M. tuberculosis alive and active Usually positive PPD or TB blood test Usually symptoms such as cough, fever, others Contagious Usually infiltrate on CXR or Other abnormality World Wide TB Disease (Active TB) 9,9445 cases of TB disease in 2012 in US World Health Organization. 2
Reported TB cases (CDC) United States, 1982-2010 TB Cases: United States 2010 Number of TB Cases in US-born vs. Foreign-born Person United States 2012-2014 Risk of Developing Active TB Persons at high risk for developing TB disease fall into 2 categories Those who have been recently infected Within past 2 years Those with clinical conditions that increase their risk of progressing from LTBI to TB disease Symptoms Cough - over weeks (>2-3 wks) to months Non-productive or productive Hemoptysis (blood streaked sputum) Chest pain Fatigue Anorexia Weight loss Fever with night sweats Dyspnea - extensive disease or pl effusions Physical Examination Few physical findings in pulmonary TB disease unless extensive disease Extensive: tubercular apical disease percussion to dullness along clavicles or wheezes in apices Extensive: may show wasting and use of accessory muscles 3
Radiologic Studies CXR : suspicious but does not confirm TB Multinodular infiltration superior segments of lower lobes apical segment of upper lobes Cavitation Hilar adenopathy Old (healed) TB Nodules (granulomas) calcified or not calcified Views posterior-anterior (PA) and lateral lordotic views CT scan of chest 45 yo man with cough and fever for 3-4 weeks Bacteriologic Evaluation AFB smear and culture X3 3 separate days or at least 8 hrs apart with one early morning Induction of sputum AFB sputum smears X3 5000-10000 bacilli/ml AFB cultures x3 as few as 10 bacilli/ml Solid media = 3-8 weeks Liquid culture systems = 7-14 days DNA probes of culture growth (2-4 hours) Nucleic amplification tests (PCR) on sputum Drug susceptibility on isolate Follow-up cultures : monthly until convert to negative AFB Smear AFB (shown in red) are tubercle bacilli Treatment of Active Disease (HIV negative adults) Adult patients = 4 drug regimen - Start: Isoniazid (INH) Rifampin Pyrazinamide (PZA) Ethambutol Obtain baseline CBC, liver enzymes, uric acid, bilirubin, creatinine If organism is susceptible to all meds, stop ethambutol PZA should be administered for 2 months INH and rifampin given for 6 months Most patients=noninfectious within 2 weeks after starting chemotherapy 4
Directly Observed Therapy (DOT) To optimize patient drug compliance and tolerability, directly observed therapy through the county or state health department is strongly recommended Patient Education and Follow-up Inform re: natural history of the disease Importance of adherence to med regimen Side effects of medications hepatitis rifampin may cause urine to become orange and stain contact lenses Follow-up cultures monthly until 2 neg CXR after treatment for baseline for further comparison Targeted Testing Decision to test = Decision to treat Latent Tuberculosis (Class II TB) Test patients at risk for active TB Patients with medical conditions that increase risk of active TB Patients in whom active TB is more prevalent health care workers nursing home residents / institutionalized recent arrival from high prevalence country (5 years) Contact with person with TB Old fibrotic lesion on CXR Risk Factors for Developing Active TB from Latent Infection High risk single test for latent TB regardless of age Persons with major immunocompromising conditions CXR shows fibronodular changes typical of healed TB Moderate risk - 65 single test for latent TB Diabetes mellitus Corticosteroid therapy Slightly increased risk - 50 single test for latent TB Underweight, smoker, small granulomas on CXR Diagnosis of LTBI Tuberculin skin test (TST, PPD) M. tuberculosis antigen-specific interferongamma release assay (IGRA) If either TST or IGRA positive CXR 5
Tuberculin Skin Test (TST) Intradermal injection of 0.1ml of 5 TU of PPD At 48-72 hrs report diameter of induration (not erythema) Positive at 3-7 weeks after infection False positives and false negatives do occur Reading the Tuberculin Skin Test Read reaction 48-72 hours after injection Measure only induration Record reaction in millimeters Problems with TST Return visit necessary Poor inter-reader reliability 9 mm vs 10 mm? False positive and false negatives Poor positive predictive value in low prevalence populations Factors that May Affect the Skin Test Reaction Type of Reaction Possible Cause False-positive Nontuberculous mycobacteria BCG vaccination Anergy False-negative Recent TB infection Very young age (< 6 months old) Live-virus vaccination Overwhelming TB disease LTBI Diagnosis with TST 5 mm = positive HIV positive, close contact to person with active TB, CXR consistent with old/healed TB, organ transplant or other immunosuppressed 10 mm = positive for most Foreign born, IVDU, residents of high risk settings or employees, listed co-morbidities 15 mm = positive No known risk factors for TB 6
Boosting (Booster Phenomenon) Some persons with LTBI may have negative TST when tested years after infection Initial skin test may stimulate (boost) ability to react to tuberculin Positive reactions to subsequent tests may be misinterpreted as a new infection Two-Step Testing Use two-step testing for initial skin testing of adults who will be retested periodically If first test positive, consider the person infected If first test negative, give second test 1-3 weeks later If second test positive, consider person infected If second test negative, consider person uninfected M. tuberculosis antigen-specific interferon-gamma release assay (IGRAs) Whole blood test for diagnosing LTBI QuantiFERON-TB GOLD and T-SPOT.TB Detect interferon-gamma release from previously sensitized memory T-cells via in vitro simulation by M. tuberculosis specific proteins No false positives due to BCG Cannot distinguish latent infection from active disease Immunocompromise conditions can give false negatives Interpretation of IGRA Results Laboratories provide both qualitative and quantitative results Qualitative: positive, negative and indeterminate (borderline) Quantitative Selecting a Test to Detect TB Infection New CDC Guidelines (2010) IGRAs preferred for: Unlikely to return for TST reading BCG vaccinated TST preferred: Children under 5 years Little specific guidance for immunocompromised patients Positive TST or IGRA What Next Chest x-ray All with positive TST or IGRA To differentiate between LTBI and TB disease Sputum AFB smear and culture Perform if positive TST or IGRA and abnormal CXR or negative CXR and respiratory symptoms 7
Treatment of LTBI in Adults (HIV negative) Tuberculosis Screening Flowchart. Drugs Duration Interval Isoniazid 9 months Daily or 2x week Isoniazid 6 months Daily or 2x week Isoniazid 3 months Once weekly + rifapentin Rifampin 4 months Daily Add pyridoxine (VitB6) for prevention of neuropathy in patients at risk Jasmer RM et al. N Engl J Med 2002;347:1860-1866. Take Home Points Prevent TB by assessing risk factors If risk present, perform TST or IGRA If TST or IGRA is positive, rule out active disease If active disease is ruled out, initiate treatment for LTBI If treatment is initiated, ensure completion 8