Misleading serology tests for tuberculosis could be worsening the epidemic in some high-burden countries. WHO will be issuing policy advice against their use in early 2011. Kelly Morris reports.
Although no international guideline recommends their use, scores of commercial serology tests for tuberculosis are being sold in high-burden countries. Some are laboratory-based tests, whereas others are rapid dipstick tests, which could fill a vital niche for a point-of-care tuberculosis diagnostic test. “If they worked, the problem of a gap in the pipeline for a point-of-care assay would have been solved decades ago”, comments Madhukar Pai, co-chair of the STOP-TB Partnership's new diagnostics working group. “The pity is that they don't work. In fact, they're inaccurate and useless.”
WHO is due to release a negative policy recommendation—the first of its kind for the organisation—on current commercial tuberculosis serodiagnostics. Results of several meta-analyses have indicated poor performance of these tests, and in 2008, an assessment of 19 commercial assays by TDR—the UN special programme for research and training in tropical diseases—found that none of the assays were good enough to replace sputum microscopy or as an add-on test to rule out tuberculosis. Manufacturers continue to claim that their tests are effective and fill a diagnostic niche, especially in sputum smear-negative patient groups.
Karin Weyer, WHO coordinator of TB diagnostics and laboratory strengthening, told The Lancet that “the negative policy process is a new concept in WHO”. But, she says, the process has been identical to that for positive recommendations, such as the endorsement announced on Dec 8 of a fully automated nucleic-acid amplification test (Xpert MTB/RIF, Cepheid) to improve tuberculosis diagnosis.
The available evidence on serodiagnostic kits has now been rigorously assessed, including meta-analyses when appropriate, and reviewed by an independent WHO expert group, says Weyer. “The expert group endorsed the findings from an updated systematic review since the TDR report in 2008 and essentially concluded that we should proceed with negative policy guidance based on the fact that the performance characteristics of these tests were way below what one would want and also because the quality of the data were so weak and so bad that it warranted a recommendation against the use of these tests”, she explains.
“Everyone is aware of the consequences of bad drugs and vaccines, but nobody really thinks about bad diagnostics and what impact they can have”, comments Pai. In their report, released at the end of December, the WHO Strategic and Technical Advisory Group for TB acknowledges “the adverse impact of misdiagnosis and wasted resources on patients and health services when using these tests for the diagnosis of active TB”, and recommends WHO to proceed with written guidance advising against current serodiagnostic kits. Further targeted research is strongly recommended since potential exists for research to develop accurate serologic assays, which could fill the point-of-care niche. WHO is being careful with preparation of the negative policy so as not to stifle innovation and research investment in tuberculosis diagnostics, says Weyer.
Commercial serodiagnostic kits are widely available, but the problem is probably greatest in India, where Pai estimates that serodiagnostic kits are used on at least 1·5 million people with suspected tuberculosis every year. Such testing is not done through the Revised National TB Control Programme (RNTCP) but through the unregulated private sector, which manages a substantial proportion of tuberculosis cases. Patients pay for serodiagnostic kits, and the market is estimated conservatively at over $US15 million in India alone, compared with $65 million for the entire RNTCP.
Despite country-wide DOTS coverage by the RNTCP, India continues to have more than 2 million new cases of tuberculosis every year. Ongoing transmission will not be reduced without intensified early case detection, which first relies on access to quality diagnosis. Writing in The New Yorker on Nov 15, journalist Michael Specter described how, in India, “for most patients, the choices are bleak”—overcrowded public hospitals versus unreliable tests at unregulated private laboratories or clinics.
Everyone in the private-sector chain gets a cut of patient fees—up to $10—30 per serodiagnostic kit—especially the referring doctors and private clinicians, who are often the same individual, Specter reports. Financial incentives perpetuate this system, Pai explains, since: “a private practitioner may not order sputum microscopy because you don't make much money out of a cheap test like sputum smears. The more expensive the test ordered, the more money you get back”, he explains.
The available evidence indicates that current tests lack either the necessary sensitivity or specificity or both to be an effective diagnostic test, and for many of these tests, false results far outnumber true results. Low sensitivity means increased false-negative results, which increase morbidity, mortality, and ongoing transmission of tuberculosis. Low specificity means more false-positive results; patients might then be given 6 months of potentially toxic treatment, while their underlying pathology remains uninvestigated and undiagnosed.
作者:admin@医学,生命科学 2011-01-14 00:45