T
uberculosis (TB) is a serious global problem.Resources are readily available for TB diagnosis in developed countries, but creating a quick, accurate, and cost-effective mass TB screening method in limited-resource countries has stymied the medical community for a century. In developing countries, chronic underfunding sustains the use of inadequate, outdated diagnostic tests that fail to detect TB in about half of all patients.1 Global travel, difficulty in accurately diagnosing and treating TB, increase worldwide of TB incidence related to HIV infection, TB’s growing drug resistance, and its easy spread by cough or sneeze mean that TB requires immediate attention.
According to Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, “… TB research has suffered enormous neglect over the past several decades. Generations of research advances and technologies have largely bypassed … TB research, particularly in … product development. It is time to transform … TB research and begin to apply new technologies using a comprehensive approach.”2
In developed countries, TB diagnosis is often done via a combination of tuberculin skin test, X-ray, and culture, the latter two, however, are beyond the means for mass use in 22 countries (e.g., India, China, Nigeria, and South Africa) with 80% of global TB cases.3 In such countries, standard TB-screening tests, recommended by the World Health Organization (WHO), continue to be sputum microscopy and the tuberculin skin test (TST) — both largely unchanged for 100 years and incapable of identifying drug-resistant strains. Low-cost sputum microscopy by itself is inadequate. Trained microscopists review slides looking for Mycobacterium tuberculosis (MTB)bacillus — a time-consuming, labor-intensive process with low sensitivity, high specificity, and inaccurate diagnosis almost half the time.
Sensitivity significantly decreases with HIV co-infection, since TB/HIV patients typically have fewer bacilli in their sputum. Advanced HIV can cause MTB’s morphology to be highly variable and, therefore, less recognizable among extensive debris often present in sputum samples. Microscopists tend to err on the conservative side in diagnosing TB in HIV co-infected cases. Since HIV-positive people are 20+ times more likely than HIV-negative people to develop TB,4 a test that eliminates human variability during diagnosis is needed. Increasing numbers of requests in high-risk areas for sputum microscopy coupled with staff shortages have created test-interpretation backlogs, delaying diagnostic results. During this time, a large portion of TB smear-positive patients drop out of the diagnostic pathway before receiving their diagnosis and treatment initiation.5
The low-cost, fast TST has a 30% false-positive rate. Most positives in low-risk individuals are false, particularly among those who previously received the Bacillus Calmette-Gu’erin TB vaccine; it tends to produce false-negatives for individuals who are immunologically compromised (i.e. HIV or low CD4 T-cell counts).
Few major diagnostics companies allocate funding for low-cost TB diagnostics, and government funding to fill the gap has not been forthcoming. In a recently published report,4 the Centers for Disease Control and Prevention (CDC) acknowledged numerous global problems tied to funding. Missing is up-to-date knowledge of what constitutes appropriate lab capabilities and capacities or the appropriate use of tests. Absent is a well-trained, stable lab workforce, as well as TB lab services with the capacity to identify, characterize, and track MDR- and XDR-TB strains at local public-health labs. Further, highly sensitive, sophisticated, and technically challenging diagnostic tests are not universally available, nor are resources for building/maintaining infrastructure and competencies necessary to provide consistently high-quality diagnostic services. All of this results in substantial delays in TB diagnosis/treatment.
The main criteria for effective new TB tests include diagnosis at point of care. Within the past five years, several new diagnostic technologies have shown promise. In December 2010, a new nucleic-acid amplification diagnostic technology was approved by WHO for rollout. It offers high sensitivity, including for HIV co-infected individuals, and automates the complex, labor-intensive process of detecting resistance to rifampicin, a first-line TB-drug treatment. The automated echnology platform based on real-time PCR amplification integrated most of the preparation of the sputum sample and delivers results within 120 minutes. In 2010, the Foundation for Innovative New Diagnostics (FIND) announced subsidies to offset the high costs for machine and test cartridges for heavy burden countries, reducing cartridge pricing to about $176 — lower than conventional culture and dual skin test for diagnosis of MDR-TB. It provides faster, more accurate results than conventional culture for testing HIV-positive individuals, and requires minimal training for healthcare workers for a near-point-of-care diagnosis.
Now in Phase II clinical trials, imaging-analysis technology being developed jointly by a U.S. company and South African government-healthcare groups uses traditional sputum-smear microscopy slides. The fully automated slide-management system digitally photographs samples, employs image-analysis algorithms to automatically detect the MTB bacilli within the image, and, with its 200-slide capacity, enables operation 24/7 with minimal human interaction to maximize lab and personnel resources. Early trials indicate improved sensitivity and specificity, including for HIV co-infection and where few bacilli are present, as in early stages of the disease. The analysis is complete within five minutes at $3 to $5 per test review with results integrated into a patient’s electronic medical records. This eliminates problematic human variation in microscopy; standardization of operation and results; and provision of computer-based workstation. Healthcare workers also can realize an improved workflow and work environment.
Within the past five years, improved interferon-gamma release assays (IGRAs) received U.S. Food and Drug Administration (FDA) approval. IGRAs measure interferon-gamma released from white blood cells that are then mixed with antigens derived from MTB to diagnose both latent TB infection and disease.7 The test has improved specificity over tuberculin skin tests but does not differentiate between active or latent infection. Despite the addition of new IGRAs, the Tuberculosis Network European Trials Group, in collaboration with the European Centre for Disease Control and Prevention documented that these tests have limited value for the diagnosis of active TB when performed on blood alone8; immuno-compromised patients are more likely to have indeterminate results. IGRA results are available with 24 hours, but the test is expensive.9
No test is perfect or appropriate for all situations. That there are several distinctly different diagnostic systems so close to the end of the development pipeline is encouraging. A need for multiple methods of detection will always exist, and these new technologies complement current diagnostics methods.
Fleming Lure is VP of Product Management for Signature Mapping Medical Sciences in Herndon, VA, a subsidiary of Applied Visual Sciences. He is overseeing the development of Signature Mapping TBDx, a new CAD technology that automates fluorescence sputum microscopy for the diagnosis of TB. For information, visit, www.SignatureMapping.com.
References
- M’edecins Sans Fronti`eres. Tuberculosis: New MSF report sheds light on neglect that costs lives. http://www.msf.org.uk/tb_underfunding_europe_20091021.news.
Published October 21, 2009. Accessed February 7, 2011. - Fauci A. Opinion: Fighting TB should Be Priority. MSNBC. http://www.msnbc.msn.com/id/33890464/ns/health-infectious_diseases. Updated November 17, 2010. Accessed November 27, 2009.
- Stop TB Partnership. Tuberculosis in Countries. http://www.stoptb.org/countries/tbdata.asp. Accessed Published 2009. February 4, 2011.
- Centers for Disease Control and Prevention. Plan to Combat XDR-TB Recommendations of the Federal TB Task Force. MMWR.. February 13, 2009;58(RRo3):1-43.
- Squire SB, Belay AK, Kashoti A. Salaniponi FM, Mundy CJ, Theobald S. Kemp J. ‘Lost’ smear-positive pulmonary tuberculosis cases: where are they and why did we lose them?
Int J Tuberculc Lung Dis. 2005;9:25-31. - World Health Organization. “Roadmap for rolling out Xpert MTB/RIF for rapid diagnosis of TB and MDR-TB” http://www.who.int/tb/features_archive/new_rapid_test/en/index.html.
Published December 6, 2010. Accessed February 7, 2011. - Centers for Disease Control and Prevention. Fact Sheet — Interferon-Gamma Release Assays (IGRAs). http://www.cdc.gov/tb/publications/factsheets/testing/IGRA.htm.
Updated June 25, 2010. Accessed February 7, 2011. - Interferon-Gamma Assays Limited in TB Diagnosis, T-SPOT.TB the Best Available. Reuters Health. http://www.medscape.com/viewarticle/729853?src=rss.
Published October 16, 2010. Accessed February 7, 2011. - Madariaga M, Jalali Z, Swindells S. Clinical Utility of Interferon Gamma Assay in the Diagnosis of TB. J Am Board Fam Med. http://www.medscape.com/viewarticle/565794.
Published November 16, 2007. Accessed February 7, 2011.
