New Diagnostics for Latent and Active Tuberculosis: State of the Art and Future Prospects

 

 Buy Article Permissions and Reprints

ABSTRACT

Tuberculosis (TB) continues to be the world's most important infectious cause of morbidity and mortality among adults. Nearly 9 million people develop TB disease each year, and an estimated 1.6 million die from the disease. Despite this enormous global burden, case detection rates are low, posing serious hurdles for TB control. Conventional TB diagnosis continues to rely on antiquated tests such as sputum smear microscopy, culture, tuberculin skin test, and chest radiography. These tests have several limitations and perform poorly in populations affected by the HIV epidemic. Conventional tests for detection of drug resistance are time consuming, tedious, and inaccessible in most settings. In this review, we describe recent advances in the diagnosis of latent and active TB, and detection of drug resistance. Although the perfect test will not be ready for large-scale roll-out and integration into routine TB care services for some time, substantial progress has been made in expanding the TB diagnostic product pipeline. With the resurgence of interest in the development of new tools for TB control, and the recent influx of funding and political support, it is likely that the next few years will see the introduction of new diagnostic tools into routine TB control programs.

REFERENCES

• 1 World Health Organization .Global Tuberculosis Control: Surveillance, Planning, Financing. WHO Report 2007. WHO/HTM/TB/2007.376. Geneva, Switzerland; World Health Organization 2007
  Google Scholar
• 2 Perkins M D, Cunningham J. Facing the crisis: improving the diagnosis of tuberculosis in the HIV era.  J Infect Dis. 2007;  196(Suppl 1) S15-S27
  CrossrefPubMedGoogle Scholar
• 3 Keeler E, Perkins M D, Small P et al.. Reducing the global burden of tuberculosis: the contribution of improved diagnostics.  Nature. 2006;  444(Suppl 1) 49-57
  PubMedGoogle Scholar
• 4 Raviglione M C, Uplekar M W. WHO's new Stop TB Strategy.  Lancet. 2006;  367 952-955
  CrossrefPubMedGoogle Scholar
• 5 Stop TB Partnership and World Health Organization .The Global Plan to Stop TB 2006–2015. Geneva, Switzerland; World Health Organization 2006
  Google Scholar
• 6 World Health Organization .New Technologies for Tuberculosis Control: A Framework for Their Adoption, Introduction and Implementation WHO/HTM/STB/2007.40. Geneva, Switzerland; World Health Organization 2007
  Google Scholar
• 7 Perkins M D, Roscigno G, Zumla A. Progress towards improved tuberculosis diagnostics for developing countries.  Lancet. 2006;  367 942-943
  CrossrefPubMedGoogle Scholar
• 8 Pai M, Kalantri S, Dheda K. New tools and emerging technologies for the diagnosis of tuberculosis, I: Latent tuberculosis.  Expert Rev Mol Diagn. 2006;  6 413-422
  CrossrefPubMedGoogle Scholar
• 9 Pai M, Kalantri S, Dheda K. New tools and emerging technologies for the diagnosis of tuberculosis, II: Active tuberculosis and drug resistance.  Expert Rev Mol Diagn. 2006;  6 423-432
  CrossrefPubMedGoogle Scholar
• 10 Menzies D, Pai M, Comstock G. Meta-analysis: new tests for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research.  Ann Intern Med. 2007;  146 340-354
  CrossrefPubMedGoogle Scholar
• 11 Pai M, Zwerling A, Menzies D. Systematic review: T-cell based assays for the diagnosis of latent tuberculosis infection—an update.  Ann Intern Med. 2008;  149 177-184
  CrossrefPubMedGoogle Scholar
• 12 Pai M, Dheda K, Cunningham J, Scano F, O'Brien R. T-cell assays for the diagnosis of latent tuberculosis infection: moving the research agenda forward.  Lancet Infect Dis. 2007;  7 428-438
  CrossrefPubMedGoogle Scholar
• 13 Andersen P, Doherty T M, Pai M, Weldingh K. The prognosis of latent tuberculosis: can disease be predicted?.  Trends Mol Med. 2007;  13 175-182
  CrossrefPubMedGoogle Scholar
• 14 Arend S M, Franken W P, Aggerbeck H et al.. Double-blind randomized phase I study comparing rdESAT-6 to tuberculin as skin test reagent in the diagnosis of tuberculosis infection.  Tuberculosis (Edinb). 2008;  88 249-261
  CrossrefPubMedGoogle Scholar
• 15 Steingart K R, Ramsay A, Pai M. Optimizing sputum smear microscopy for the diagnosis of pulmonary tuberculosis.  Expert Rev Anti Infect Ther. 2007;  5 327-331
  CrossrefPubMedGoogle Scholar
• 16 Steingart K R, Henry M, Ng V et al.. Fluorescence versus conventional sputum smear microscopy for tuberculosis: a systematic review.  Lancet Infect Dis. 2006;  6 570-581
  CrossrefPubMedGoogle Scholar
• 17 Steingart K R, Ng V, Henry M et al.. Sputum processing methods to improve the sensitivity of smear microscopy for tuberculosis: a systematic review.  Lancet Infect Dis. 2006;  6 664-674
  CrossrefPubMedGoogle Scholar
• 18 Mase S R, Ramsay A, Ng V et al.. Yield of serial sputum specimen examinations in the diagnosis of pulmonary tuberculosis: a systematic review.  Int J Tuberc Lung Dis. 2007;  11 485-495
  PubMedGoogle Scholar
• 19 World Health Organization .Reduction of Number of Smears for the Diagnosis of Pulmonary TB. 2008. Accessed January 27, 2008 at http://www.who.int/tb/dots/laboratory/policy/en/index2.html
  Google Scholar
• 20 Anthony R M, Kolk A H, Kuijper S, Klatser P R. Light emitting diodes for auramine O fluorescence microscopic screening of Mycobacterium tuberculosis.  Int J Tuberc Lung Dis. 2006;  10 1060-1062
  PubMedGoogle Scholar
• 21 Foundation for Innovative New Diagnostics .FIND and Zeiss Team Up to Develop an Affordable Fluorescence Microscope for the Diagnosis of TB and Other Infectious Diseases. Press release, 2007. Accessed February 1, 2008 at http://www.finddiagnostics.org/news/press/zeiss_nov07.shtml
  Google Scholar
• 22 Marais B J, Brittle W, Painczyk K et al.. Use of light-emitting diode fluorescence microscopy to detect acid-fast bacilli in sputum.  Clin Infect Dis. 2008;  47(2) 203-207
  CrossrefPubMedGoogle Scholar
• 23 Cruciani M, Scarparo C, Malena M, Bosco O, Serpelloni G, Mengoli C. Meta-analysis of BACTEC MGIT 960 and BACTEC 460 TB, with or without solid media, for detection of mycobacteria.  J Clin Microbiol. 2004;  42 2321-2325
  CrossrefPubMedGoogle Scholar
• 24 World Health Organization .The Use of Liquid Medium for Culture and DST. 2008. Accessed January 27, 2008 at http://www.who.int/tb/dots/laboratory/policy/en/index3.html
  Google Scholar
• 25 Moore D A, Evans C A, Gilman R H et al.. Microscopic-observation drug-susceptibility assay for the diagnosis of TB.  N Engl J Med. 2006;  355 1539-1550
  CrossrefPubMedGoogle Scholar
• 26 Flores L L, Pai M, Colford Jr J M, Riley L W. In-house nucleic acid amplification tests for the detection of Mycobacterium tuberculosis in sputum specimens: meta-analysis and meta-regression.  BMC Microbiol. 2005;  5 55
  CrossrefPubMedGoogle Scholar
• 27 Greco S, Girardi E, Navarra S, Saltini C. The current evidence on diagnostic accuracy of commercial based nucleic acid amplification tests for the diagnosis of pulmonary tuberculosis.  Thorax. 2006;  61 783-790
  CrossrefPubMedGoogle Scholar
• 28 Ling D, Flores L, Riley L, Pai M. Commercial Nucleic-Acid Amplification Tests for Diagnosis of Pulmonary Tuberculosis in Respiratory Specimens: Meta-Analysis and Meta-Regression. PLoS ONE.  2008;  3(2) e1536
  CrossrefPubMedGoogle Scholar
• 29 Pai M, Flores L L, Hubbard A, Riley L W, Colford Jr J M. Nucleic acid amplification tests in the diagnosis of tuberculous pleuritis: a systematic review and meta-analysis.  BMC Infect Dis. 2004;  4 6
  CrossrefPubMedGoogle Scholar
• 30 Pai M, Flores L L, Pai N, Hubbard A, Riley L W, Colford Jr J M. Diagnostic accuracy of nucleic acid amplification tests for tuberculous meningitis: a systematic review and meta-analysis.  Lancet Infect Dis. 2003;  3 633-643
  CrossrefPubMedGoogle Scholar
• 31 Daley P, Thomas S, Pai M. Nucleic acid amplification tests for the diagnosis of tuberculous lymphadenitis: a systematic review.  Int J Tuberc Lung Dis. 2007;  11 1166-1176
  PubMedGoogle Scholar
• 32 Pai M, Ling D I. Rapid diagnosis of extrapulmonary tuberculosis using nucleic acid amplification tests: what is the evidence?.  Future Microbiol. 2008;  3 1-4
  CrossrefPubMedGoogle Scholar
• 33 Boehme C C, Nabeta P, Henostroza G et al.. Operational feasibility of using loop-mediated isothermal amplification for diagnosis of pulmonary tuberculosis in microscopy centers of developing countries.  J Clin Microbiol. 2007;  45 1936-1940
  CrossrefPubMedGoogle Scholar
• 34 Raja S, Ching J, Xi L et al.. Technology for automated, rapid, and quantitative PCR or reverse transcription-PCR clinical testing.  Clin Chem. 2005;  51 882-890
  CrossrefPubMedGoogle Scholar
• 35 Ling D, Zwerling A, Pai M. GenoType MTBDR assays for diagnosis of multidrug-resistant tuberculosis: a meta-analysis.  Eur Resp Journal. 2008;  , Published ahead of print, July 9, 2008
  PubMedGoogle Scholar
• 36 Barnard M, Albert H, Coetzee G, O'Brien R, Bosman M E. Rapid molecular screening for MDR TB in a high volume public health laboratory in South Africa.  Am J Respir Crit Care Med. 2008;  177 787-792
  CrossrefPubMedGoogle Scholar
• 37 Steingart K R, Ramsay A, Pai M. Commercial serological tests for the diagnosis of tuberculosis: do they work?.  Future Microbiol. 2007;  2 355-359
  CrossrefPubMedGoogle Scholar
• 38 Steingart K R, Henry M, Laal S et al.. A systematic review of commercial serological antibody detection tests for the diagnosis of extra-pulmonary tuberculosis.  Thorax. 2007;  62 911-918
  PubMedGoogle Scholar
• 39 Steingart K R, Henry M, Laal S et al.. Commercial serological antibody detection tests for the diagnosis of pulmonary tuberculosis: a systematic review.  PLoS Med. 2007;  4 e202
  CrossrefPubMedGoogle Scholar
• 40 Lyashchenko K P, Greenwald R, Esfandiari J et al.. PrimaTB STAT-PAK assay, a novel, rapid lateral-flow test for tuberculosis in nonhuman primates.  Clin Vaccine Immunol. 2007;  14 1158-1164
  CrossrefPubMedGoogle Scholar
• 41 Boehme C, Molokova E, Minja F et al.. Detection of mycobacterial lipoarabinomannan with an antigen-capture ELISA in unprocessed urine of Tanzanian patients with suspected tuberculosis.  Trans R Soc Trop Med Hyg. 2005;  99 893-900
  CrossrefPubMedGoogle Scholar
• 42 Tessema T A, Hamasur B, Bjun G, Svenson S, Bjorvatn B. Diagnostic evaluation of urinary lipoarabinomannan at an Ethiopian tuberculosis centre.  Scand J Infect Dis. 2001;  33 279-284
  CrossrefPubMedGoogle Scholar
• 43 Pai M, Ramsay A, O'Brien R. Evidence-based tuberculosis diagnosis.  PLoS Med. 2008;  5(7) e156
  CrossrefPubMedGoogle Scholar
• 44 Pai M, Kalantri S, Pascopella L, Riley L W, Reingold A L. Bacteriophage-based assays for the rapid detection of rifampicin resistance in Mycobacterium tuberculosis: a meta-analysis.  J Infect. 2005;  51 175-187
  CrossrefPubMedGoogle Scholar
• 45 Kalantri S, Pai M, Pascopella L, Riley L, Reingold A. Bacteriophage- based tests for the detection of Mycobacterium tuberculosis in clinical specimens: a systematic review and meta-analysis.  BMC Infect Dis. 2005;  5 59
  CrossrefPubMedGoogle Scholar
• 46 Nahid P, Pai M, Hopewell P C. Advances in the diagnosis and treatment of tuberculosis.  Proc Am Thorac Soc. 2006;  3 103-110
  CrossrefPubMedGoogle Scholar

Madhukar PaiM.D. Ph.D. 

Department of Epidemiology, Biostatistics & Occupational Health, McGill University

1020 Pine Ave. West, Montreal, Quebec, Canada H3A 1A2

Email: madhukar.pai@mcgill.ca