Diagnostic Tests Chest x-ray –Patchy or nodular infiltrate –Apical or sub-apical posterior aspects of UPPER LOBES (or superior segment of lower lobes) –Cavity usually without an air-fluid level –pneumonic lesion with enlarged hilar nodes consider primary TB

Clinical Manifestations Pulmonary –Non-HIV: 85% –HIV+: 38% pulmonary only 30% extrapulmonary only 32% pulmonary and extrapulmonary X-ray findings

Clinical Manifestations: Pulmonary TB Coughing > sneezing, speaking –correlates with infectiousness –“The principal risk for acquiring infection with M.Tb. is breathing” Bloom and Murray, 1992 Fever (about 80%), Weight loss, malaise –Probably cytokine mediated

Infectiousness of Source Case Transmission highly likelyLess efficient transmission Cavitary disease: billions of bacilli Sputum AFB smear +++ Coughing (& sneezing & talking) Household contact Non-cavitary disease Sputum AFB smear negative Not coughing Casual contact Outdoor contact very unlikely

Epidemiology: Who Gets TB? Who gets TB infection? Who gets TB disease? Definitions: –TB infection: TB exposure that leads to local induration in response to intradermal injection of purified protein derivative (PPD) –TB disease = tuberculosis = active TB

Who Gets TB infection? In the world - ubiquitous –~ 1/3 of the world’s population infected –80% in developing countries Immigrants from these other countries to U.S. –major source of recent increase in U.S. TB

Who Gets TB infection in the U.S.? Exposure medically underserved –urban (& in NC, rural) poor minority populations** –Southeast Asian, African-American, Hispanic

Annual Case Rates by Race/Ethnicity 1990 Annual New-case Rate per 100,000 in U.S. 42.6in Asian/Pacific Islanders 33.0in blacks 21.4in Hispanics 18.9in Native Americans 4.2in U.S.-born whites 2/3 of cases occur in racial or ethnic minorities

Laboratory Processing: mucolysis, homogenization, bacterial contamination and concentration Smear staining: –Ziehl-Neelsen acid-fast stain –auramine 0 fluorescence

Laboratory Reading the slide: –Examined an equivalent of 300 oil immersion fields = negative –Quantitated: 1-4+ or # bacilli/field –A positive smear = ,000 acid-fast bacilli/ml sputum –TB or non-TB mycobacterium???

Making the Definitive Diagnosis Smear: Auramine-rhodamine –Increased sensitivity Confirmed by Ziehl-Neelson AFB + does not = TB –at Duke, AFB+ smear is MOTT 2x >TB –at CMC, Charlotte, AFB+ smear is TB 5x > MOTT

Making the Definitive Diagnosis Cultures: Broth-based growth systems –average time to detection: days, e.g. BACTEC days, conventional –Susceptibilities: additional ~ 7 days if not at Duke, always order on first specimen

Expectations of TB Therapy: Pre-chemotherapy Era Therapy: Improve nutrition Bed rest and isolation, high altitude preferred Surgical intervention in some Mortality rate at 5 years: 40-50%

History of TB Therapy 1940’s - Streptomycin [SM] 1952: Isoniazid [INH] & p-aminosalacylic acid [PAS] –determined combination prevented rapid emergence of INH resistance 1960’s: Rifampin [RIF], Pyrazinamide [PZA] & Ethambutol [EMB]

History of TB Therapy ’s: large clinical trials world-wide –1977: 9 mos vs 18 mos INH, RIF, Streptomycin [SM] Cure rates 95% in 9 mos –1982: 6 mos total - 2 mos INH, RIF, PZA, SM, then drop PZA for last 4 mos –1990: 6 mos INH, RIF, PZA (1st 2 mos) better than 9 mos INH & RIF [Cure rates 95%]

Recommended Treatment Regimens: Rationale INH during entire duration of Rx < 6 months: unacceptably high failure rate < 12 month regimens: must use INH and RIF, 2 mos at least Initial PZA makes < 9 mos possible Intermittent dosing (2-3 x/week) and daily dosing - equal efficacy

Treatment Option 1 Option 2Option 3 Daily INH, RIF, EMB or SM & PZA for 8 weeks, then INH & RIF for 16 weeks more (daily or 3x/wk DOT) (total 24 weeks) Daily INH, RIF, EMB or SM & PZA for 2 weeks, then Same drugs 2x/week for 6 weeks (DOT), then INH & RIF 2x/week for 16 weeks more (total 24 weeks) DOT 3x/week INH, RIF, EMB or SM & PZA (total 24 weeks) Start with Four Drug Therapy/DOT; TOTAL RX 6 months

Expectations of TB Therapy: Post-chemotherapy Era Therapy: Specific, potent anti-tuberculous drugs in combination Improve nutrition Brief period of isolation Success rate at 5 years: 95%

Anti-TB Drugs: Resistance Naturally occurring mutations result in drug resistance at predictable rate: RIF: 1 in 10 8 organisms INH,PZA,EMB,SM: 1 in 10 6 organisms TB cavitary lesion has ~ 1 x 10 8 orgs IF INH alone, 100 orgs resistant on day 1

MDR-TB: Contributing Factors MDR TUBERCULOSIS 1. Patient non-compliance 2. Patient non-compliance 3. Patient non-compliance Anti-tuberculous drugs available without prescription/management Immune deficiency (e.g., AIDS) Antidote: Directly Observed Therapy

Other Management Issues respiratory isolation while waiting ID or pulmonary consultation if sending home on TB meds: –contact county health department –before 4:45 Friday afternoon –request DOT

Services available at North Carolina County Health Depts (vary state to state) –NC will provide all TB meds free to all people with TB, –plus DOT, –plus monitoring for symptoms, –plus contact tracing and testing, –plus nutritional support, housing and other support during therapy Other Management Issues

Relationship of HIV and TB Risk for M.TB-infected person (e.g., + PPD) to develop active TB HIV-seronegative: 10-15% LIFETIME risk HIV-seropositive: ANNUAL 7-10% ANNUAL risk HIV-infected-113 fold increase AIDS-170 fold increase Other IC* fold increase Relative Risks

+PPD skin test: when to give preventive therapy? Age in Years 35 yrs Risk of INH hepatitis 2.3% 1.3%.1 Risk of active TB HIV positive steroid therapy/other IC recent conversion to +PPD healthy, nl CXR, +PPD unk time Unlikely* High risk* *Risk categorized in Figure 1