Commercial Serological Antibody Detection Tests for the Diagnosis of Pulmonary Tuberculosis: A Systematic Review

Background: The global tuberculosis epidemic results in nearly 2 million deaths and 9 million new cases of the disease a year. The vast majority of tuberculosis patients live in developing countries, where the diagnosis of tuberculosis relies on the identification of acid-fast bacilli on unprocessed sputum smears using conventional light microscopy. Microscopy has high specificity in tuberculosis-endemic countries, but modest sensitivity which varies among laboratories (range 20% to 80%). Moreover, the sensitivity is poor for paucibacillary disease (e.g., pediatric and HIV-associated tuberculosis). Thus, the development of rapid and accurate new diagnostic tools is imperative. Immune-based tests are potentially suitable for use in low-income countries as some test formats can be performed at the point of care without laboratory equipment. Currently, dozens of distinct commercial antibody detection tests are sold in developing countries. The question is “do they work?” Methods and Findings: We conducted a systematic review to assess the accuracy of commercial antibody detection tests for the diagnosis of pulmonary tuberculosis. Studies from all countries using culture and/or microscopy smear for confirmation of pulmonary tuberculosis were eligible. Studies with fewer than 50 participants (25 patients and 25 control participants) were excluded. In a comprehensive search, we identified 68 studies. The results demonstrate that (1) overall, commercial tests vary widely in performance; (2) sensitivity is higher in smear-positive than smear-negative samples; (3) in studies of smear-positive patients, Anda-TB IgG by enzyme-linked immunosorbent assay shows limited sensitivity (range 63% to 85%) and inconsistent specificity (range 73% to 100%); (4) specificity is higher in healthy volunteers than in patients in whom tuberculosis disease is initially suspected and subsequently ruled out; and (5) there are insufficient data to determine the accuracy of most commercial tests in smear microscopy–negative patients, as well as their performance in children or persons with HIV infection. Conclusions: None of the commercial tests evaluated perform well enough to replace sputum smear microscopy. Thus, these tests have little or no role in the diagnosis of pulmonary tuberculosis. Lack of methodological rigor in these studies was identified as a concern. It will be important to review the basic science literature evaluating serological tests for the diagnosis of pulmonary tuberculosis to determine whether useful antigens have been described but their potential has not been fully exploited. Activities leading to the discovery of new antigens with immunodiagnostic potential need to be intensified. Based on a systematic review, Madhukar Pai and colleagues conclude that none of the commercial immune-based tests for pulmonary tuberculosis so far evaluated perform well enough to replace sputum smear microscopy. Background.: Tuberculosis (TB) is, globally, one of the most important infectious diseases. It is thought that in 2005 around 1.6 million people died as a result of TB. Controlling TB requires that the disease is correctly diagnosed so that it can then be promptly treated, which will reduce the risk of infection being passed on to other individuals. The method normally used for diagnosing TB disease in poor countries (where most people with TB disease live) involves taking a sample of mucus coughed up from the lungs; this mucus is then spread thinly onto a glass slide, dyed, and viewed under the microscope. The bacteria responsible for TB take up the dye in a particular pattern and can be clearly seen under the microscope. Although this test (sputum smear) is relatively straightforward to carry out even where facilities are basic, it is not particularly good at identifying TB disease in children or amongst individuals who are HIV-positive. Finally, the sputum smear test is also not very sensitive; that is, many people who have TB disease may not give a positive reading. Therefore, there is an urgent need to develop and evaluate new tests that are suitable for use in poor countries, which will accurately diagnose TB disease, especially amongst children and people who are HIV-positive. Why Was This Study Done?: New tests for TB have become available which detect whether an individual has raised antibodies against particular proteins and other substances present on the surface of the TB bacterium. These tests are carried out on blood samples, once blood cells and other factors have been taken out. These antibody tests are often quite simple to carry out, so in principle they could be suitable for use in developing countries. Since the tests are available on the market and can be freely used in some developing countries without any need for government regulatory bodies to approve them, it is important to know how good these tests are at diagnosing TB disease. The researchers here wanted, therefore, to evaluate all of the available data relating to the accuracy of antibody detection tests for diagnosis of TB disease. What Did the Researchers Do and Find?: In order to evaluate all of the information available on commercial antibody detection tests for diagnosis of TB disease of the lungs, the researchers carried out a systematic review. First, they searched biomedical literature databases using specific terms to identify studies for inclusion. A study was included in their analysis if the commercial test was compared against one of two other standard tests (sputum smear microscopy, or growth of TB bacteria in culture). One researcher from the team then pulled out specific pieces of information from each published study: these included the type of study design; information on study participants; the type of test; what the test was compared against; and finally the results of evaluation of the test. A second researcher pulled out pieces of information from several of the same studies. The researchers then compared the information to ensure that it was recorded correctly. Each study was also assigned a quality rating, based on four distinct criteria. For each type of test, the researchers used the data in the published studies to work out the test's accuracy, both in terms of its ability to give a positive reading for people who have TB disease as well as its ability to give a negative reading for people who do not have TB disease. What Do These Findings Mean?: The results of this systematic review suggest that the commercial antibody detection tests considered here are not particularly useful in diagnosis of TB disease as compared to other tests, such as sputum smear and bacterial culture. Some people are concerned that there is pressure in certain developing countries to start using these tests, but the current data do not support greater use. This systematic review also highlights the fact that many studies evaluating commercial TB tests are of poor quality, and that further research needs to be done to evaluate the accuracy of different TB tests amongst children and HIV-positive patients. Additional Information.: Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040202.