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Ward 86 Management Recommendations

Diagnosis of Tuberculosis and Latent Mycobacterium tuberculosis Infection

updated October 2018

Contributors: Gabriel Chamie, MD
Annie Luetkemeyer, MD
Diane Havlir, MD

  1. The risk of exposure to Mycobacterium tuberculosis leading to latent infection is the same for people who are coinfected with HIV and those who are not. However, the risk of developing clinical tuberculosis after initial M tuberculosis infection is 20-fold higher for individuals who are HIV coinfected compared with those who are not. HIV-infected persons who are not on antiretroviral therapy (ART) and especially those with low absolute CD4 cell counts are at much higher risk. The risk of developing tuberculosis after M tuberculosis infection for the general population is 10% over a lifetime, whereas the risk for those with HIV infection is 10% per year after initial M tuberculosis infection. This accelerated progression to disease following exposure has resulted in outbreaks of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis in HIV-coinfected populations. Not only does HIV infection increase the risk of developing tuberculosis and thus the risk of transmitting it, tuberculosis also increases T-cell activation, plasma levels of HIV RNA, the rate of HIV disease progression, and AIDS-related mortality. Thus, vigilance in diagnosing and treating tuberculosis is important for both patient and public health. Of note, treatment of latent M tuberculosis infection (LTBI) in the HIV-infected patient decreases the risk of tuberculosis disease by more than 50% and the risk of death by more than 25%.

  2. Diagnosis of tuberculosis in the HIV-infected patient

    1. When to suspect tuberculosis:
      The classic symptom complex of pulmonary tuberculosis (prolonged cough, fevers, weight loss, night sweats) should always instigate a workup for this disease in any HIV-infected patient. Subclinical disease (a positive sputum culture for M tuberculosis in a patient who is asymptomatic) increasingly is being reported in resource-limited settings. Any HIV-infected patient who has had a known close contact exposure to tuberculosis or a positive skin or serologic test for latent M tuberculosis infection should be evaluated for tuberculosis (eg, chest X ray at a minimum) and monitored carefully afterward for development of disease.

    2. Chest X-ray findings: A majority of HIV patients with pulmonary tuberculosis have an abnormal chest X-ray result, although up to 20% (particularly those with absolute CD4 counts of <50 cells/µL) may have no abnormal findings. Typical X-ray findings of pulmonary tuberculosis (upper lobe location, cavitation) usually are not seen when the CD4 count is <200 cells/µL. Enlarged mediastinal or hilar lymph nodes, middle or lower lobe consolidation, or pleural effusion may occur in HIV-infected patients.

    3. Extrapulmonary manifestations of tuberculosis occur more frequently in HIV-infected patients than in HIV-uninfected patients, especially among those with low absolute CD4 counts.(1) Lymphadenitis and meningitis are the most common extrapulmonary manifestations. Most cases of tuberculous meningitis occur in non-U.S.-born patients with advanced HIV disease, and pulmonary tuberculosis is often present as well. Tuberculous meningitis can present in 3 phases: prodromal, meningitic, and paralytic (the latter with advanced disease characterized by seizures, hemiplegia, paraplegia and/or coma), and mass lesions (tuberculomas or abscesses) may account for some of the clinical manifestations.(2)

    4. Microbial confirmation of the diagnosis

      Culture of M tuberculosis from a patient specimen is the gold standard for diagnosing tuberculosis. However, M tuberculosis grows slowly; laboratories do not consider a culture negative until 6-8 weeks of incubation have passed. Up to 20% of pulmonary tuberculosis is culture negative, with diagnosis made on the basis of clinical presentation and improvement on antimycobacterial therapy in the absence of an alternative diagnosis.

      The sensitivity of a sputum acid-fast stain in HIV-infected patients with pulmonary tuberculosis is suboptimal--only 50% in patients with advanced disease who are deficient in the immune responses that lead to cavitation and a subsequent large mycobacterial lung burden. Also, positive sputum stains sometimes indicate atypical mycobacterial colonization or disease rather than tuberculosis, particularly in areas of low prevalence for tuberculosis such as the United States.

      Microbial confirmation of tuberculous meningitis is even more challenging, as the cerebrospinal fluid (CSF) acid-fast mycobacterial stain result is almost always negative. Thus, the diagnosis of tuberculous meningitis is often made empirically (without a confirmatory CSF smear, culture, or PCR result) on the basis of CSF white blood cell (WBC), protein, or glucose abnormalities. While CSF pleocytosis is common and the WBC differential can be variable, lymphocytic predominance is typical. CSF protein is often elevated, and CSF glucose may be low. CSF abnormalities may be minimal in patients who have a very low CD4 cell count. The concomitant presence of pulmonary tuberculosis can support the diagnosis of tuberculous meningitis. To confirm the diagnosis by culture requires large-volume CSF specimens (10 mL).

      These issues of suboptimal sensitivity and specificity and delay in confirming a diagnosis of pulmonary tuberculosis can be addressed in part by testing sputum for M tuberculosis nucleic acid. The Xpert MTB/RIF assay is a rapid (results are available in approximately 2 hours), specific test for M tuberculosis (ie, negative in the presence of atypical mycobacterial colonization or disease).(3,4,5,6) Sensitivity of Xpert MTB/RIF assay sputum testing for pulmonary TB is quite high, with one test reported to detect 80% of all culture-positive specimens among persons with HIV infection and 60% of culture-positive specimens that are acid-fast bacilli smear-negative. Sensitivity may be improved by obtaining more than one specimen. For CSF specimens, sensitivity of this test is higher when using concentrated or centrifuged large-volume CSF specimens. This assay also can rapidly identify M tuberculosis that is resistant to rifampin. As rifampin monoresistance is very rare, rifampin resistance is a good marker for MDR tuberculosis (defined as resistance to isoniazid and rifampin). Of note, the World Health Organization (WHO) has recommended using the next-generation Xpert MTB/RIF assay (Xpert® MTB/RIF Ultra) as a replacement for the current Xpert MTB/RIF assay in countries in which regulatory agencies have approved its use. In the United States, approval for the MTB/RIF Ultra assay is pending.

    5. Mycobacteremia in patients with tuberculosis is more common in patients with HIV coinfection than in those without HIV coinfection. Positive blood cultures have been reported to occur in half of HIV-infected patients who have active tuberculosis and an absolute CD4 count of <100 cells/µL. In order to maximize the likelihood of obtaining a culture isolate that can be used to identify the presence of antimycobacterial drug resistance, blood always should be cultured for mycobacteria in an HIV-infected patient with tuberculosis, before starting treatment (unless M tuberculosis already has been isolated from a patient specimen).

  3. Diagnosis of latent M tuberculosis infection (LTBI) in the HIV-infected patient

    1. Skin testing

      Tuberculin antigen skin testing (TST) detects a cell-mediated immune response to a purified protein derivative of M tuberculosis. A positive result (defined for HIV-infected persons as ≥5 mm of induration at 48-72 hours after intradermal injection) is considered diagnostic of LTBI. However, false-positive results can occur owing to nontuberculous mycobacterial infection (eg, Mycobacterium avium complex) or prior Bacillus Calmette-Guérin (BCG) vaccination, and false-negative results may be caused by the anergy associated with HIV disease, particularly among patients with low CD4 counts. A major problem with employing TST for screening is the failure of patients to return for skin test reading at 48-72 hours.

    2. Blood interferon-gamma release assay (IGRA)

      Blood IGRA (eg, the QuantiFERON-TB Gold In-Tube or T-SPOT.TB assays) detects a cell-mediated immune response to M tuberculosis-specific antigens. These assays have similar sensitivity and are more specific than the TST (ie, the problem of false positives is reduced). Use of IGRA also avoids the need for the patient to return for skin test reading. Given that current evidence suggests IGRAs perform similarly to the TST in identifying HIV-infected individuals with LTBI, a blood IGRA is our test of choice for screening HIV-infected patients at risk of LTBI.(7) As with the TST, blood IGRA can be falsely negative or indeterminate as a result of anergy in patients with a very low CD4 cell count.

    3. We recommend yearly screening of all HIV-infected patients not already known to have LTBI. Despite the low incidence of tuberculosis in San Francisco, we consider the adverse personal and public health consequences of M tuberculosis transmission in our urban clinic population, many of whom are homeless, live in congregate housing programs, or were born in higher TB-prevalence countries, to shift the cost-benefit ratio in favor of such yearly screening.


  1. Jones BE, Young SM, Antoniskis D, et al. Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am Rev Respir Dis. 1993 Nov;148(5):1292-7.
  2. Chamie G, Marquez C, Luetkemeyer A. HIV-associated central nervous system tuberculosis. Semin Neurol. 2014 Feb;34(1):103-15.
  3. Steingart, KR, Sohn H, Schiller I, et al. Xpert MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev. 2013 Jan 31;1:CD009593.
  4. Luetkemeyer AF, Firnhaber C, Kendall MA, et al. Evaluation of Xpert MTB/RIF versus AFB smear and culture to identify pulmonary tuberculosis in patients with suspected tuberculosis from low and higher prevalence settings. Clin Infect Dis. 2016 May 1;62(9):1081-8.
  5. Lawn SD, Brooks SV, Kranzer K, et al. Screening for HIV-associated tuberculosis and rifampicin resistance before antiretroviral therapy using the Xpert MTB/RIF assay: a prospective study. PLoS Med. 2011 Jul;8(7):e1001067.
  6. Boehme CC, Nicol MP, Nabeta P, et al. Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study. Lancet. 2011 Apr 30;377(9776):1495-505.
  7. Cattamanchi A, Smith R, Steingart KR, et al. Interferon-gamma release assays for the diagnosis of latent tuberculosis infection in HIV-infected individuals: a systematic review and meta-analysis. J Acquir Immune Defic Syndr. 2011 Mar 1;56(3):230-8.