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Smear-Negative Tuberculosis. Daniel Park, MD, MPH Infectious Diseases Fellow University of California, San Diego. Learning Objectives .

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Smear-Negative Tuberculosis

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    1. Smear-Negative Tuberculosis Daniel Park, MD, MPH Infectious Diseases Fellow University of California, San Diego

    2. Learning Objectives • To review the significance of smear negative tuberculosis in HIV-prevalent, resource-constrained settings and diagnostic difficulties and ways to improve diagnosis. • To review World Health Organization algorithms for the diagnosis of smear-negative TB and extrapulmonary TB

    3. Introduction • Algorithms developed for the diagnosis of ambulatory, seriously ill, and extrapulmonary tuberculosis • Review Algorithms • Compare methods of performing sputum microscopy

    4. Background • Disproportionate increase in rates of smear-negative pulmonary and extrapulmonary tuberculosis in HIV-prevalent and resource-constrained settings • Higher mortality in HIV-infected, especially smear negative • Over twice the risk of death in Malawi study with 7 years of follow-up data (Kang’ombe CT, et al. Int J Tuberc Lung Dis 2004;8:829-36.) • Smear negative status leads to delayed diagnosis and may contribute mortality. • Cultures frequently not available Getahun H, et al. The Lancet; 369:2042 - 2049

    5. Background • Infectivity of smear-negative tuberculosis • 22% relative transmission rate compared to smear positive Siddiqi K, et al. Lancet Infect Dis 2003;3:288-296.

    6. Background • Clinical features not sensitive or specific to distinguish TB from non-TB • Retrospective multivariate logistic regression analysis • 182 patients (~70% HIV) with negative AFB smears; 41 had TB, 141 other diagnosis. • Mostly community acquired pneumonia; KS, cryptococcosis, PCP infrequent • cough >21 days, chest pain>15 days, absence of expectoration, absence of dyspnea • 2 criteria= sensitivity 85%, specificity 67% • 3 criteria= sensitivity 49%, specificity 86% • adding cervical lymphadenothy increased sensitivity and specificity • Samb B, et al. Int J Tuberc Lung Dis 1997;1:25-30

    7. Examples of national guide- lines for the diagnosis of smear negative TB. Getahun H, et al. The Lancet; 369:2042 - 2049

    8. Major Recommendations • Revised Case Definitions (HIV only) • Smear-positive pulmonary tuberculosis only requires one positive smear result. • Smear-negative pulmonary TB: • At least two sputum exams negative for AFB and • X-ray consistent with active TB and • Decision by clinician to treat with full course for TB • OR • AFB smear-negative sputum with cultures that are positive

    9. Case definition • Extrapulmonary Tuberculosis • One specimen from an extrapulmonary site culture-positive • OR • Histological or strong clinical evidence consistent with active extrapulmonary tuberculosis and decision by clinician to treat with full course for TB

    10. Algorithm for the ambulatory HIV-positive patient DANGER SIGNS Respiratory Rate>30/minute T>39 Celsius Pulse>120/min Unable to walk unaided

    11. Algorithm for the ambulatory HIV-positive patient • HIV assessment includes HIV clinical staging, CD4 count, referral for HIV care • Attempt to get CXR, sputum AFB and culture, clinical assessment all in same visit • Likely won’t have results until 3rd visit • At least one of the sputum should be early morning • Clinical assessment: • Evaluating pt with unknown HIV status • Assess likelihood of TB and starting empiric therapy • Empiric PCP and/or Bacterial therapy

    12. Antibiotics Trial • Primary role should not be as a diagnostic aid • Treat concomitant bacterial infection • Common both with and without tuberculosis • Non-response increases the likelihood of TB but a response to antibiotics should not exclude TB • Antibiotic choice should cover typical causes of community acquired pneumonia but should NOT INCLUDE FLUOROQUINOLONE

    13. Antibiotics trial • Validation of antibiotic algorithm • Patients TB suspects • respiratory symptoms>3 weeks, abnormal CXR consistent with TB OR • acute pneumonia and failed outpatient antibiotics • Patients with Negative AFB smears treated with amoxicillin x 5 days and erythromycin x 5 days if not improved. • 120 patients evaluated Wilkinson D, et al. 2007. Int J tuberc Lung Dis;4:513-518

    14. Antibiotics trial • “Non-response increases the likelihood of TB” PPV 73% • “Response to antibiotics should not exclude TB” NPV 61% • Sensitivity 55%, Specificity 77%

    15. Algorithm for the ambulatory HIV-positive patient • 3rd visit will have results of CXR, sputum • Decide if likely to have TB • If unlikely to have TB based on negative AFB, clinical assessment, CXR • PCP and/or bacterial treatment

    16. Algorithm for the ambulatory HIV-positive patient • If rapid response to PCP or bacterial treatment must remain vigilant • If unsatisfactory response should be re-assessed clinically and bacteriologically for tuberculosis • No algorithm provided or further recommendations.

    17. Etiology of pneumonia • Prospective study to evaluate etiology of AFB sputum smear negative pneumonia in HIV-infected patients • BAL in 71% and 75% in Senegal and CAR

    18. Algorithm for the seriously ill patient DANGER SIGNS Respiratory Rate>30/minute T>39 Celsius Pulse>120/min Unable to walk unaided

    19. Algorithm for the seriously ill patient • If immediate referral no possible • Finish antibiotic course even if AFB smear positive and start TB treatment • If no response to antibiotics in 3-5 days, TB treatment should be initiated and finish initial antibiotic course. • Refer to higher level of care if possible to confirm diagnosis of TB and for HIV care.

    20. Improving diagnosis of TB through better smear microscopy • Processing methods: • sputum liquefaction • by sodium hypochlorite (bleach), NaOH, N-acetyl-L-cysteine-sodium-hydroxide, ammonium sulphate, sodium hydroxide • Concentration • sedimentation or centrifugation • Systemic review: Steingart K. Lancet Infect Dis 2006;6;664-74. • bleach and centrifugation increased sensitivity by 18% • chemical and overnight sedimentation increased sensitivity by 23% (small number of studies) • Could not evaluate HIV-infected given small numbers

    21. Extrapulmonary TuberculosisBackground • One in five registered TB patients has extrapulmonary TB • Lymph nodes, pleural, disseminated most common • Meningeal, pericardial also common • Disseminated TB cases one-third of deaths in HIV-positive Africans. • Only half of these diagnosed before death. • Most patients have no bacteriological or histological confirmation except in lymph node involvement

    22. Diagnosis of extrapulmonary TB

    23. Diagnosis of extrapulmonary TB • Maintain high clinical vigilance for ETB • Assess clinical response to TB treatment after one month and seek alternative diagnosis if no improvement. • ETB is indication for antiretroviral therapy • Start co-trimoxazole preventive therapy

    24. Aspiration high yield, up to 85% confirmatory TB Lymphadenitis

    25. High mortality (>20%) in first two months of therapy. Clotting indicates high protein content and increased likelihood of TB >30g/L >50% lymphocytes If no thoracentesis available, start empiric TB treatment. Pleural TB

    26. Clinicians must be vigilant for disseminated TB High rates of undiagnosed disseminated TB in febrile, HIV-positive inpatients Disseminated TB

    27. 90% of HIV-related pericardial effusions is TB 50-70% in non-HIV Pericardial Effusion

    28. Cryptococcal meningitis is more common than TB in HIV patients LP is essential Measure opening pressure TB Meningitis

    29. Samb B, Henzel D, Daley CL, et al. Methods for diagnosing tuberculosis among in-patients in eastern Africa whose sputum smears are negative. Int J Tuberc Lung Dis 1997;1:25-30 • Wilkinson D, Newman W, Reid A, Squire SB, et al. Trial-of-antibiotic algorithm for the diagnosis of tuberculosis in a district hospital in a developing country with high HIV prevalence. Int J Tuberc Lung Dis 2000;4:513-518 • Getahun H, Harrington M, O'Brien R, Nunn P. Diagnosis of smear-negative pulmonary tuberculosis in people with HIV infection or AIDS in resource-constrained settings: informing urgent policy changes. The Lancet 2007; 369:2042 – 2049 • Steingart KR, Ng V, Henry M, Hopewell PC, et al. Sputum processing methods to improve the sensitivity of smear microscopy for tuberculosis: a systematic review. Lancet Infect Dis 2006;6:664-74. • World Health Organization. Improving the diagnosis and treatment of smear-negative pulmonary and extrapulmonary tuberculosis among adults and adolescents: Recommendations for HIV-prevalent and resource-constrained settings. Accessed December 5, 2008: