What you need to know about diagnosing and treating TB: a preventable, fatal disease. Bob Belknap M.D. Denver Public Health November PDF Free Download

What you need to know about diagnosing and treating TB: a preventable, fatal disease Bob Belknap M.D. Denver Public Health November 2013

Case 1: 52 y/o male Born in the Pacific Islands; some travel in the U.S. military Known (+) TST (h/o BCG) 1 month of cough, fever, weight loss Refused admission

Case 1: 52 y/o male Hospitalized 2 weeks later QuantiFERON negative Lung bx shows granulomas, AFB smear (-) Presumed to have hypersensitivity pneumonitis or sarcoidosis

Case 1: 52 y/o male Clinically worse after 1 month on steroids Died shortly after readmission Preventable Disease and a Preventable Death

Objectives - After this talk you should be able to describe: 1. TB epidemiology risk factors for infection and progression 2. The steps for diagnosing TB Sensitivity of AFB smears Role of newer molecular tests and the interferongamma release assays (IGRAs) 3. Drugs for treating TB infection and disease

Global TB Incidence WHO Global TB Report 2013

Global TB Mortality WHO Global TB Report 2013

U.S. TB Cases, 1982 2012 9,945 No. of Cases Year CDC Reported TB in U.S. 2012

Risk Factors for Infection 1. Being born or living where TB is common 2. Being a close contacts to someone with active pulmonary TB 3. Older U.S. born persons (>75 years)

Transmission and Pathogenesis of Tuberculosis No infection (70%) Early progression (5%) Exposure Infection (30%) Late progression (5%) Containment (95%) Continued containment (90%)

Transmission and Pathogenesis of Tuberculosis Affect of HIV No infection (<70%?) No infection (70%) Early progression (40%) Early progression (5%) Exposure Infection (30%) Infection (>30%?) Late progression (5-10%/yr) Late progression (5%) HIV positive HIV negative Containment (95%) Containment (60%) Continued containment (90%) Continued containment (0%?)

Risk Factors for Progression HIV Fibrotic CXR c/w prior TB Immunosuppression (transplants, TNFalpha inhibitors) Recent close contact to active TB Diabetes Chronic renal failure Silicosis Leukemia / lymphoma Head/neck cancer Wt loss > 10% gastric bypass surgery

Global TB Incidence WHO Global TB Report 2013

Percentage of TB Cases Among Foreign-born Persons, United States 2002 2012 DC DC >50% 25% 49% <25% CDC Reported TB in U.S. 2012

Brief history of TB diagnostics 400 BC Hippocrates had clinical deduction 1761 Auenbrugger describes auscultation 1816 Laennec invents the stethoscope 1882 Koch identifies TB using smears 1895 Roentgen discovers x-rays 1907 von Pirquet describes hypersensitivity to PPD 1910 Mantoux describes intradermal injection

Case 2 : 23 y/o male Originally from Botswana, in U.S. for 3 years Presents to the ED: cough for 5 days, subjective fevers and chills Rx: 5 day course of azithromycin Symptoms did not improve and one week later he presented to the ED again

Case 2 : 23 y/o male ED #2 Dx: pneumonia RX: amoxicillinclavulanate x 7d

Case 2 : 23 y/o male ED #3 T 40.9 C Diaphoretic, enlarged cervical lymph nodes Rapid HIV test positive, CD4 67 cells/µl Rx: CTX + azithro

Case 2 : 23 y/o male Ceftriaxone + azithro AFB smears (-) x 3 TST (-) QFT (-) Vanco, Cefepime Mediastinoscopy Meropenem, linezolid and voriconazole

Case 2 : 23 y/o male AFB smears (-) x 3 TST (-) QFT (-) Mediastinoscopy on hospital day 13 AFB smear (+) INH, RIF, PZA, ETH started 29 days after initial presentation

Medical Evaluation for Active TB 1. History (including travel) 2. Physical examination (non-specific) 3. Chest x-ray 4. Bacteriologic /histologic AFB smears 5. AFB Culture * TB Skin Test (aka TST, PPD) or Interferon- Release Assay (IGRA) can be useful adjuncts

TB Symptoms Typical Cough > 3 weeks Weight loss Night sweats Fever Hemoptysis Atypical Recurrent pneumonia or UTIs (cx neg) Pleuritic chest pain Swollen lymph nodes Headache or altered mental status Pathologic fractures Unexplained anemia Infertility * NOTE: FQs are extremely active against TB

TB Symptoms and HIV Symptom/sign HIV positive (%) HIV negative (%) Dyspnea Fever Sweats Weight loss Diarrhea Hepatomegaly Splenomegaly Lymphadenopathy 97 79 83 89 23 41 40 35 81 62 64 83 4 21 15 13 Chest 1994;106:1471-6

Case 3-25 yr old female Radiology reading: Fibrotic opacity in the right upper lobe with pleural thickening consistent with scarring from old TB

Case 3-25 yr old female AFB smear (-) x 3 All 3 grew MTB Sensitivity of Sputum Smears = 50%

Interferon-gamma Release Assays Blood test for detecting TB infection Requires 1 visit (TST requires 2 visits) Results less subject to reader bias and error More specific with less cross-reaction with non-tuberculosis mycobacterium and BCG than the TST

2 Commercially Available IGRAs

TST and IGRA: Sensitivity for Active TB Meta-analysis Data presented for TST and the commercially available assays (QFT-GIT and T-SPOT) Results: % (95% CI) TST 70( 67-72) QFT-GIT 84 (81-87) T-SPOT 88 (85-90) Diel, Chest April 2010 137(4): 952 31

Case 4-18y/o male Born in Somalia, moved from Chicago Empty bottle of rifampin 600 mg, #30 filled at Chicago health dept 2 months earlier Says his chest X-ray was abnormal & sputum cultures negative Denies any symptoms or signs of TB

Case 4-18y/o male Is this active TB? Is it drug resistant?

Culture and Susceptibility Testing Method Time to Detection Time to Susceptibility Comments Solid 3-4 weeks 3-4 weeks Gold standard Media Broth 10-14 d 5-10 days Molecular 1 day 1 day Newer technologies are making this more feasible

Molecular Diagnostics RT-PCR w/ molecular beacon GeneXpert Performed on direct specimens Detects rifampin resistance only Automated so requires much less lab capabilities NEJM Sept 2010; 363: 1005

Case 1: 52 y/o male Hospitalized 2 weeks later QuantiFERON negative Lung bx shows granulomas, AFB smear (-)

Empirical TB treatment without a positive smear or culture Clinical reasons at risk for life-threatening TB, including ones often never confirmed (e.g. < 50% of TB meningitis is culture positive) Public health reasons return to work/school while cultures are pending, children at home, staying in a congregate setting (nursing home or homeless shelter)

First-line TB Therapy Medication Rifampin (Rif) Isoniazid (INH) Pyrazinamide (PZA) Ethambutol (EMB) Side Effects P450 inducer,hepatitis, rash, flu-like symptoms, hypersensitivity Fatigue, peripheral neuropathy, hepatitis GI upset, rash, hepatitis, uric acid elevation (rare gout attack) Rare optic neuritis

Standard Treatment of Tuberculosis 1. Intensive Phase INH, Rifampin, Pyrazinamide and Ethambutol x 2 months First 2 to 3 weeks are spent in home isolation can t work, go to school or be out in public places 2. Continuation Phase INH and Rifampin x 4 months

Timing of ART in TB-HIV co-infection Trial CAMELA. Blanc FX, et al., NEJM 2011. 365(16): 1471 81 STRIDE. Havlir DV, et al., NEJM 2011. 365(16):1482 91 Targeted TB HIV Median infected population Location CD4 Pulmonary (PTB) and extrapulmonary (EPTB); CD4 count 25 <200 cells/µl Cambodia cells/µl PTB and EPTB; CD4 count <250 cells/µl multisite 77 cells/µl Timing of ART initiation 2 weeks vs. after 8 weeks 2 weeks vs. 8 12 weeks Outcome Decreased mortality; rates of IRIS 2X higher Decreased mortality only seen if CD4 <50 cells/µl SAPiT. Abdool Karim SS et al., NEJM 2010. 362 (8): NEJM 2011 365(16): 1492 501 pulmonary CD4 <500cells/µL South Africa 150 cells/µl 4 weeks vs. 8 12 weeks vs. end of TB treatment Decreased mortality seen at 4 weeks if CD4 < 50 cells/µl Bottom line: if CD4 < 50 cells/µl ART in 2 weeks. If >= 50 cells/µl or CNS disease, risk of IRIS may outweigh benefit 8-12 weeks

Case 4-18y/o male Is this active TB? Is it drug resistant?

Case 4-18y/o male Confirmed TB resistant to INH and Rif in 72 hours Cx (+) MTB resistant to INH, Rifampin, PZA, EMB and streptomycin Is this XDR-TB?

Drug Resistant Tuberculosis Multi-drug Resistant (MDR) Resistant to at least INH and Rifampin Extensively Drug Resistant (XDR) Resistant to INH and Rifampin plus Fluoroquinolones Second-line injectable agent (amikacin, kanamycin, or capreomycin)

Treatment of Suspected Drug-resistant TB Consider when a patient has a prior history of TB treatment and appears to have relapsed Never add a single drug to a failing regimen (eg. fluoroquinolones) Treat with 4-6 drugs known or likely to be effective, daily therapy directly observed for 18-24 months

TB Prevention The best way to keep TB in the differential is to diagnose and treat latent TB 1965: American Thoracic Society recommended treatment of LTBI for those with previously untreated TB, tuberculin skin test (TST) converters, and young children 1967: Recommendations expanded to include all TST positive reactors

Online TB Risk Calculator http://www.tstin3d.com/

Before Initiating Treatment for LTBI Rule out active TB CXR on everyone sputum collection if the CXR is abnormal or the person is symptomatic Determine prior history of treatment for LTBI or TB disease Assess risks of toxicity Determine current and previous drug therapy If you collect sputum cultures, wait for the results before beginning LTBI therapy

Isoniazid Regimens Preferred INH daily for 9 months Acceptable Alternatives INH twice/week for 9 months by DOT INH daily for 6 months INH twice/week for 6 months by DOT

Rifampin Regimens Rifampin (RIF) given daily for 4 months is an acceptable alternative when treatment with INH is not feasible In situations where RIF cannot be used (e.g., HIV-infected persons receiving protease inhibitors), rifabutin may be substituted

Rifampin vs INH Treatment completion 78% Rifampin vs 60% INH Grade 3/4 adverse events 7/418 (1.7%) vs. 17 / 422 (4.0%) INH Menzies Ann Int Med 2008; 149:689

Phase 3 Clinical Trial 9 months of daily, self-administered INH vs 3 months of INH/Rifapentine once weekly by directly observed therapy (DOT) > 8,000 patients Proved both safe and effective

A previously healthy student died of a preventable & treatable illness News Alerts POSTED: 1:16 pm June 11, 2007 Colorado Springs Student From Nepal Dies From TB COLORADO SPRINGS, Colo. -- Tuberculosis was confirmed as the cause of death of a patient who died shortly after arriving at the emergency room on Friday.

Why do people still die of TB in 2013 Failure to diagnose and treat latent infection Delays considering TB in the differential Delays working up symptomatic patients Misperception about the accuracy of our diagnostic tests Empiric use of fluoroquinolones Failure to report suspect cases to the health department and to start empiric TB treatment Failure to monitor appropriately while on treatment

Contact Information Denver Metro TB Clinic 602-7240 Bob Belknap MD (Director) 602-7244 CDC Division of TB Elimination - guidelines http://www.cdc.gov/nchstp/tb/default.htm

Resources CDC www.cdc.gov/tb/ Francis J Curry Center www.currytbcenter.ucsf.edu/ Stop TB Partnership www.stoptb.org WHO http://www.who.int/tb/en/

What you need to know about diagnosing and treating TB: a preventable, fatal disease. Bob Belknap M.D. Denver Public Health November 2013