Diagnostic Tools

TB Screening

In resource-constrained settings

The World Health Organization (WHO) guidelines for people living with HIV (PLWHIV) in resource-constrained settings recommend that all PLWHIV, wherever they receive care, should be regularly screened for TB using a clinical algorithm.1

  • TB screening should occur at every visit to a health facility or contact with a health worker, regardless of whether the individual has received, or is receiving isoniazid preventive therapy (IPT) or ART1

In other settings

The Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America recommend:2

  • All persons should be tested for latent TB infection (LTBI) at the time of HIV diagnosis regardless of their TB risk category
  • Persons with negative diagnostic tests for LTBI, advanced HIV infection (CD4+ count <200 cells/μL), and without indications for initiating empiric LTBI treatment should be re-tested for LTBI once they start ART and attain a CD4+ count >200 cells/μL
  • Annual testing for LTBI in HIV-infected persons who are or remain in a “high-risk” category for repeated or ongoing exposure to persons with active TB, such as people who
    • are, or who have been incarcerated
    • live in congregate settings
    • are active drug users
    • have other sociodemographic risk factors for TB

Procurement of tissue/fluid samples for TB diagnosis

  • The most accessible fluid or tissue should be procured for histopathological, cytopathological and microbiological diagnosis3
  • Sputum samples can be analysed to diagnose pulmonary TB
    • bronchoscopy may be necessary3
  • Urine, pleural fluid, pericardial fluid and cerebrospinal fluid analysis can provide an indication of the presence of extrapulmonary TB in addition to definitive diagnosis by conventional diagnostic tests using molecular or culture techniques (see Table 1).3
  • Fine needle aspiration cytopathology (FNAC) biopsy will provide lymph node tissue for diagnosis.
    • a CT scan is helpful for localising intrathoracic and intra-abdominal lymphadenopathy
    • radiologically guided FNAC and biopsy may be necessary3
  • Video-assisted thoracoscopic surgery is a minimally invasive procedure that can be used to collect tissue for TB diagnosis in patients with intrathoracic lymphadenopathy and pleural disease3
  • Laparoscopy will facilitate visual inspection and biopsy of intra-abdominal lesions.3

For further information on diagnosis of extrapulmonary TB, refer to this review from Sharma SK, Mohan A. (2004) Extrapulmonary tuberculosis.3

Molecular Methods

The Xpert MTB/RIF (M. tuberculosis [MTB] rifampin resistance [RIF] assay) is a new rapid TB test endorsed by the WHO in December 2010.5

  • The Xpert MTB/RIF is an automated molecular test for identification of M. tuberculosis and rifampin resistance.4 The assay identifies:
    • > 97% of patients with culture-confirmed TB
    • > 90% of TB-infected individuals with smear-negative disease
    • rifampicin resistant TB strains (95% of which will also be isoniazid resistant)4
  • Rapid results from the Xpert MTB/RIF assay allow for prescription of appropriate treatment on the same day5
    • however, if the assay is performed in a centralised laboratory, results may not be available on the same day
  • The WHO strongly recommends that the Xpert MTB/RIF rapid test should be used as the initial diagnostic test in individuals suspected of multidrug-resistant TB or HIV/TB coinfection4
    • the Xpert MTB/RIF assay is certified and approved by the Regulatory Authority in Europe (CE-Marked)10
    • the Xpert MTB/RIF assay is undergoing FDA review and approval is pending10

For practical advice and further information, see WHO Rapid Implementation of the Xpert MTB/RIF Test Technical and Operational ‘How-to’ Practical considerations.13

Microscopic Smear

  • Microscopic examination of sputum smears for acid-fast bacilli (AFB) is the primary method for diagnosing pulmonary TB in most countries.7
    • smear microscopy is considered to be relatively insensitive compared with culture6
    • sensitivity in diagnosing pulmonary TB ranges between 25–65% and is dependent on multiple factors; nonetheless, the technique has a sensitivity of 90% in identifying community-based infection sources6
  • Results can be available on the same day4
  • Drug-resistant TB cannot be distinguished from drug-sensitive TB7
  • AFB concentration in the sputum of individuals co-infected with TB and HIV is lower than that in TB-infected individuals not infected with HIV14
    • AFB density falls with decreasing CD4 count
  • Individuals with advanced HIV infection with an impaired delayed-type hypersensitivity immune response may have decreased sputum expression despite large numbers of bacilli in the lungs14
  • Smear microscopy may be less sensitive in diagnosing TB when HIV infection is present than in HIV-uninfected individuals14
    • ​particularly in severely immunocompromised individuals.14
    • sputum examination remains an important diagnostic tool for pulmonary TB in PLWHIV with a CD4 count > 200 but there is an urgent need for better diagnostic methods in PLWHIV with a CD4 count < 200.15

Culture

  • Culture for M. tuberculosis is the gold standard for diagnosing TB7
    • highly sensitive
    • can differentiate between drug-sensitive and drug-resistant strains7
  • Unfortunately, results may take between 2–6 weeks and laboratories must have a level of biosafety infrastructure that may not be easily implemented in resource-poor settings
    • access to culture facilities is relatively restricted in most developing countries7
  • Liquid culture methods are available, and these tests can confirm diagnosis of TB in 7–28 days4,7
  • However, although liquid culture methods may provide a faster diagnosis, they are human resource-intensive, costly, infrastructure resource-demanding and prone to contamination, and therefore access remains restricted in most developing countries7

Chest Radiography

  • Apical infiltrates or cavities may be visible on a chest radiograph from an individual with TB, but the absence of cavities does not exclude diagnosis16
  • In PLWHIV, the radiographic appearances of TB are dependent on the degree of immunodeficiency17
    • ​with preserved immune function, the classic findings of upper lobe disease, cavitation and fibrosis are likely to be observed
    • in patients with advanced HIV, appearances may be atypical and radiographs can be normal in up to half of all microbiologically proven cases17

If the Xpert MTB/RIF test is not available, diagnosis of TB in PLWHIV should include analysis of sputum smear, mycobacterial culture and chest radiograph.16

Urine lipoarabinomannan analysis (LAM)

  • Sensitivity of LAM for detecting TB ranges from 8–93%, with a specificity of 87%–99%18
    • in five studies with results stratified by HIV status, LAM sensitivity was 3–53% higher in HIV-positive compared with HIV-negative subgroups
    • sensitivity was highest in PLWHIV with advanced immunosuppression18
  • LAM may be a useful TB screening tool among PLWHIV with low CD4 cell counts18–21
    • further studies are needed to evaluate the potential value of the LAM assay in individuals with advanced HIV18

Serodiagnostic Tests

  • The WHO does NOT recommend the use of commercial serodiagnostic tests for the diagnosis of active pulmonary or extrapulmonary TB.8 These tests:
    • provide inconsistent and imprecise results
    • have high proportions of false-positive and false-negative results
    • are associated with inconsistent and imprecise estimates of sensitivity and specificity in the literature8,9

Diagnostic Tests for Latent TB

Tuberculin Skin Testing (TST) and Interferon-γ Release Assays (IGRAs) test for an immune response that indicates exposure to M. tuberculosis. These tests do not detect M. tuberculosis and do not distinguish between latent and active TB.22

  • High false-negative rates have been reported for TST in PLWHIV, particularly in individuals with low CD4 counts.4
    • both TST and IGRAs are adversely affected by low CD4+ counts22
  • TST and IGRAs show similar sensitivities in detecting TB infection or disease in children
    • with reduced sensitivity in young or HIV-infected children22
  • In low- and middle-income countries, TST is the recommended screening method for latent TB infection as it is more cost-effective than IGRA22
  • There are limited data regarding IGRA performance in PLWHIV, but based on current data, the British HIV Association guidelines recommend the use of IGRAs rather than TST when screening PLWHIV for latent TB infection4

IGRAs are considered more specific than TST in Bacillus Calmette-Guérin (BCG)-vaccinated individuals.4

References

  1. World Health Organization. Guidelines for Intensified Tuberculosis Case-finding and Isoniazid Preventive Therapy for People Living with HIV in Resource-constrained Settings.  Accessed 25 November 2011.
  2. Centers for Disease Control and Prevention. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR 2009;58(No. RR-4):1–217. Accessed 17 February 2012.
  3. Sharma SK, Mohan A. Extrapulmonary tuberculosis. Indian J Med Res 2004;120:316–353. 
  4. British HIV Association. Guidelines for the Treatment of TB/HIV Coinfection 2011. Accessed 25 November 2011.
  5. World Health Organization. Diagnostics - Xpert MTB/RIF Test - fact sheet. Accessed 26 November 2011.
  6. World Health Organization. Laboratory Services in Tuberculosis Control: Organization and Management. Accessed 26 November 2011.
  7. Van Rie A, Page-Shipp L, Scott L, Sanne I, Stevens W. Xpert(®) MTB/RIF for point-of-care diagnosis of TB in high-HIV burden, resource-limited countries: hype or hope?
  8. World Health Organization. Tuberculosis Serodiagnostic Tests Policy Statement 2011. Accessed 26 November 2011.
  9. Steingart KR, Flores LL, Dendukuri N, et al. Commercial serological tests for the diagnosis of active pulmonary and extrapulmonary tuberculosis: an updated systematic review and meta-analysis. PLoS Med 2011;8:e1001062.
  10. World Health Organization. Policy statement: automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF system 2011.  Accessed 15 February 2012.
  11. Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detection of tuberculosis and rifampin resistance.  N Engl J Med 2010;363:1005–1015.
  12. 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;377:1495–1505.
  13. World Health Organization. Rapid Implementation of the Xpert MTB/RIF Test Technical and Operational ‘How-to’ Practical considerations.  Accessed 26 November 2011.
  14. Mugusi F, Villamor E, Urassa W, et al. HIV co-infection, CD4 cell counts and clinical correlates of bacillary density in pulmonary tuberculosis. Int J Tuberc Lung Dis 2006;10:663–669. 
  15. Singhal S, Mahajan SN, Diwan SK, et al. Correlation of sputum smear status with CD4 count in cases of pulmonary tuberculosis and HIV co-infected patients--a hospital based study in a rural area of Central India. Indian J Tuberc 2011;58:108–112. 
  16. Martinson NA, Hoffman CJ, Chaisson RE. Epidemiology of Tuberculosis and HIV: recent advances in understanding and responses. Proc Am Thorac Soc 2011;8:228–293.
  17. Dawson R, Masuka P, Edwards DJ, et al. Chest radiograph reading and recording system: evaluation for tuberculosis screening in patients with advanced HIV. Int J Tuberc Lung Dis 2010;14:52–58. 
  18. Minion J, Leung E, Talbot E, et al. Diagnosing tuberculosis with urine lipoarabinomannan: systematic review and meta-analysis. Eur Respir J 2011;38:1398–1405. 
  19. Shah M, Variava E, Holmes CB, et al. Diagnostic accuracy of a urine lipoarabinomannan test for tuberculosis in hospitalized patients in a High HIV prevalence setting. J Acquir Immune Defic Syndr 2009;52:145–151. 
  20. Lawn SD, Kerkhoff AD, Vogt M, et al. Diagnostic accuracy of a low-cost, urine antigen, point-of-care screening assay for HIV-associated pulmonary tuberculosis before antiretroviral therapy: a descriptive study. Lancet Infect Dis 2012;12:201–209.
  21. Lawn SD, Edwards DJ, Kranzer K, et al. Urine lipoarabinomannan assay for tuberculosis screening before antiretroviral therapy diagnostic yield and association with immune reconstitution disease. AIDS 2009;23:1875–1880.
  22. World Health Organization. Tuberculosis IGRA TB Tests Policy Statement 2011. Accessed 26 November 2011.