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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 l.jpg

Smear-Negative Tuberculosis

Daniel Park, MD, MPH

Infectious Diseases Fellow

University of California, San Diego

Learning objectives l.jpg
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

Introduction l.jpg

  • Algorithms developed for the diagnosis of ambulatory, seriously ill, and extrapulmonary tuberculosis

  • Review Algorithms

  • Compare methods of performing sputum microscopy

Background l.jpg

  • 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

Background5 l.jpg

  • Infectivity of smear-negative tuberculosis

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

Background6 l.jpg

  • 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

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Examples of national guide-

lines for the diagnosis of smear

negative TB.

Getahun H, et al. The Lancet; 369:2042 - 2049

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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

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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

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Algorithm for the ambulatory HIV-positive patient


Respiratory Rate>30/minute

T>39 Celsius


Unable to walk unaided

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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

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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

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Antibiotics trial

  • Validation of antibiotic algorithm

    • Patients TB suspects

      • respiratory symptoms>3 weeks, abnormal CXR consistent with TB


      • 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

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Antibiotics trial

  • “Non-response increases the likelihood of TB”

    PPV 73%

  • “Response to antibiotics should not exclude TB”

    NPV 61%

  • Sensitivity 55%, Specificity 77%

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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

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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.

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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

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Algorithm for the seriously ill patient


Respiratory Rate>30/minute

T>39 Celsius


Unable to walk unaided

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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.

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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

  • Extrapulmonary tuberculosis background l.jpg
    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

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    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

    Pleural tb l.jpg

    High mortality (>20%) in first two months of therapy.

    Clotting indicates high protein content and increased likelihood of TB


    >50% lymphocytes

    If no thoracentesis available, start empiric TB treatment.

    Pleural TB

    Disseminated tb l.jpg

    Clinicians must be vigilant for disseminated TB

    High rates of undiagnosed disseminated TB in febrile, HIV-positive inpatients

    Disseminated TB

    Pericardial effusion l.jpg

    90% of HIV-related pericardial effusions is TB

    50-70% in non-HIV

    Pericardial Effusion

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    Cryptococcal meningitis is more common than TB in HIV patients

    LP is essential

    Measure opening pressure

    TB Meningitis

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    • 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: