Guest post by Madhukar Pai, David W. Dowdy and Karen R Steingart, tuberculosis (TB) researchers at McGill University, Johns Hopkins Bloomberg School of Public Health, and University of Washington School of Public Health. MP, DD and KS are co-authors of two studies published in this week’s PLoS Medicine that underpinned a historic first negative policy recommendation in the field of TB, from the World Health Organization, advising against the use of inaccurate antibody-based serological diagnostic tests for active TB.
On 20 July 2011, the World Health Organization (WHO) published a policy recommendation against the use of currently available commercial blood (serological) antibody-detection tests to diagnose active tuberculosis (TB).
While serological tests work well for several infectious diseases (e.g., HIV, hepatitis B), existing serological tests for TB (both ELISA and rapid lateral flow tests) are not accurate or consistent enough to be useful. Even though many of these tests are manufactured in the developed world, none are approved for use by those countries’ regulatory authorities (e.g., FDA). A 2007 meta-analysis published in PLoS Medicine found that TB serological tests are not accurate, and an independent evaluation of 19 commercial rapid tests by TDR (Special Programme for Research and Training in Tropical Diseases) the following year confirmed those findings.
Unfortunately, the evidence from these studies was never translated into policy. While most regulatory bodies have mechanisms to withdraw or ban dangerous drugs and vaccines, there is little awareness of the consequences of bad diagnostics. Furthermore, there are few published data on the human and economic impact of inaccurate diagnostics, although common sense tells us that inaccurate tests lead to mismanagement of disease, with adverse consequences for patients and health systems.
Another reason for the initial inaction on commercial serological TB tests was possibly the perception that these tests were rarely used. In reality, these tests are widely abused in the private sector in countries such as India, with at least 1.5 million serological tests performed in India every year. At $10-$30 per test, the cost of testing, plus the cost of TB drugs wasted on treating hundreds of thousands of patients with false-positive results, rival the entire Indian TB TB control program annual budget of $65 million. Every major private laboratory in India offers TB serological tests, mostly ELISA kits imported from developed countries that do not allow these tests to be used on their own TB patients.
The problem extends far beyond India. These tests are available in at least 17 of 22 highest TB burden countries, from China to South Africa to Afghanistan. In all these countries, the tests are used only in the private medical sector. Weak regulation of diagnostics allows inappropriate tests to enter the market, where financial gains to doctors, laboratories, and diagnostic companies provide a strong incentive to keep such tests profitable. The losers in this economically-driven cycle are patients and public health.
In 2010, recognizing the importance of tackling this widespread problem, WHO convened an Expert Group to review the evidence and formulate a policy. The Expert Group considered an updated meta-analysis of test performance and a cost-effectiveness analysis. The meta-analysis, published in this week’s PLoS Medicine, synthesized evidence from 92 studies. The conclusion: commercial serological tests remain inconsistent and inaccurate, supported only by data of exceedingly low quality.
The cost-effectiveness study, also published in this week’s PLoS Medicine, found that serology results in more human suffering, secondary infections, and false-positive diagnoses than sputum smear microscopy, while increasing per-patient costs to the Indian TB control sector. Where high-quality sputum microscopy is available, adding WHO-recommended automated liquid culture is cheaper and more effective than adding serology.
Based on the WHO Expert Group report and STAG-TB’s recommendation, the WHO released a first-of-its-kind “negative policy” on 20 July 2011, concluding that, since the “the harms/risks [of commercial serodiagnostic tests] far outweigh any potential benefits (strong recommendation)…these tests should not be used in individuals suspected of active pulmonary or extra-pulmonary TB, irrespective of their HIV status.”
It is important to clarify three points:
(1) The WHO policy encourages research to develop new serological tests for TB based on antigen/antibody biomarkers. The negative recommendation only applies to existing commercial tests.
(2) The WHO policy does not include commercially available blood-based tests (interferon-gamma release assays) for latent TB infection. It only applies to antibody-based (serological) tests for active TB.
(3) The WHO policy does not call for a ban on the technology platforms used for antibody or antigen detection (ELISA or rapid immunochromatography). They are excellent for many diseases, just not currently for TB.
The WHO policy against serological TB testing provides much-needed guidance at the global level. Now, it is up to high-burden countries to implement this policy by tightening regulations and educating doctors, laboratories and consumers to prevent continued abuse of such diagnostics.
India has already shown leadership in this area. Immediately following the WHO policy announcement, the Indian Revised National TB Control Program (RNTCP) issued an advisory against TB serological tests, and the National Laboratory Committee of the RNTCP endorsed the WHO policy recommendations. The challenge is now the Indian private sector, which manages nearly half of all TB cases in India. The private sector is strong in many other countries, including South Africa, Brazil, Indonesia, Philippines, Bangladesh, Kenya, Nigeria and Pakistan – all of these have serological tests on the market. The economic incentives that drive the private sector must be aligned with the health incentives of TB patients, which would push private doctors and laboratories to switch from serology to validated WHO-endorsed tests.
Lastly, intensive research is urgently needed to develop accurate and reliable point-of-care tests, offering more accurate and accessible diagnosis than is currently possible. This will require resources, scientific collaboration, industry engagement, and serious commitment from governments and donors.
None of the authors have any financial/industry conflicts to declare. All authors participated as observers (not involved in developing policy recommendations) in the WHO Expert Group meeting on TB serological tests held in July 2010. All 3 authors contributed to the cost-effectiveness analysis of serological tests in India. KRS and MP have contributed to previously published and updated meta-analyses on TB serological tests. KRS and MP are affiliated with the Stop TB Partnership’s New Diagnostics Working Group (NDWG). KRS serves as co-chair of the Evidence Synthesis& Policy subgroup of Stop TB Partnership’s New Diagnostics Working Group, while MP serves as Co-chair of the WorkingGroup. MP also serves as a consultant to the Bill & Melinda Gates Foundation (BMGF). NDWG and BMGF had no involvement in the two PLoS publications. MP serves on the editorial boards of PLoS Medicine and PLoS One.
The views expressed in this article are the authors’ own and do not necessarily reflect those of NDWG or BMGF or WHO.