Smear-Negative Tuberculosis

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 HIV prevalent= HIV >1% in pregnant women or among Tb patients>5% Expert panel recognized the need for timely diagnosis and flexibity when it comes to HIV, especially those who are severely ill.HIV prevalent= HIV >1% in pregnant women or among Tb patients>5% Expert panel recognized the need for timely diagnosis and flexibity when it comes to HIV, especially those who are severely ill.

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. CXR can be normal in 14% of HIV patients with positive cultures Important issues: role of antibiotics, chest x-ray timing Takes 2 days to obtain one set of 3 specimens Best case here is 11-13 days to diagnosis.CXR can be normal in 14% of HIV patients with positive cultures Important issues: role of antibiotics, chest x-ray timing Takes 2 days to obtain one set of 3 specimens Best case here is 11-13 days to diagnosis.

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

11. Algorithm for the ambulatory HIV-positive patient Emphasis on timely diagnosis= ideally should not take more than 4 visits to arrive at a diagnosis; could get TB diagnosis on 1st visit, start tx on 2nd if smear positive. Emphasis on timely diagnosis= ideally should not take more than 4 visits to arrive at a diagnosis; could get TB diagnosis on 1st visit, start tx on 2nd if smear positive.

12. 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 Perhaps the most difficult part here is to determine likelihood of TB: cxr often atypical, but if abnormal, known exposures to TB, typical symptoms (NS, hemoptysis, wt loss, duration)Perhaps the most difficult part here is to determine likelihood of TB: cxr often atypical, but if abnormal, known exposures to TB, typical symptoms (NS, hemoptysis, wt loss, duration)

13. 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

14. 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 PPV 95%PPV 95%

15. Antibiotics trial “Non-response increases the likelihood of TB” PPV 73% “Response to antibiotics should not exclude TB” NPV 61% Sensitivity 55%, Specificity 77% Must maintain high clinical vigilance; patients advised to come back if symptoms return; must have good followupMust maintain high clinical vigilance; patients advised to come back if symptoms return; must have good followup

16. 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

17. 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.

18. 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

19. Algorithm for the seriously ill patient

20. 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.

21. 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 in systemic review most of the studies (81%) took a single sputum specimen and prepared processed and direct smears. Bleach method is not yet standardized: concentrationn, volume, distilled or tap water Fluorescence microscopy 10% increase in sensitivityin systemic review most of the studies (81%) took a single sputum specimen and prepared processed and direct smears. Bleach method is not yet standardized: concentrationn, volume, distilled or tap water Fluorescence microscopy 10% increase in sensitivity

22. 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

23. Diagnosis of extrapulmonary TB

24. 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

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

26. Pleural TB 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.

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

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

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

30. 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: www.who.int/entity/tb/publications/2006/tbhiv_recommendations.pdf