Tuberculosis

Tuberculosis Blood Tests Often Inaccurate, WHO Warns Against Use

Commercially available blood tests for active tuberculosis (TB) may not be accurate and can lead to misdiagnosis and mistreatment, according to a systematic review and meta-analysis published online August 9, 2011, in PLoS Medicine.

Karen Steingart from the University of Washington and colleagues performed an updated systematic review on behalf of the World Health Organization (WHO) to assess the diagnostic accuracy of commercial serological tests for pulmonary and extrapulmonary TB, with a focus on their relevance in low- and middle-income countries.

Serological tests look for TB antigens or antibodies in the blood. They are typically less expensive than examination of sputum under a microscope, bacterial laboratory cultures, or chest x-rays, especially in resource-limited settings. But cheaper does not necessarily mean more cost-effective, if the tests are not accurate.

The researchers searched multiple databases for studies published between January 1990 through June 2010. They identified 67 relevant studies related to pulmonary TB (48% from low- and middle-income countries) with a total of 5147 participants. In addition they found 25 studies related to extrapulmonary TB (40% from low- and middle-income countries) with a total of 1809 participants.

Many studies were judged to be of poor quality. Estimates of TB serological test sensitivity (0%-100%) and specificity (31%-100% for pulmonary TB; 59%-100% for extrapulmonary TB) were highly variable. The only test with enough studies for a meta-analysis -- the Anda-TB IgG assay -- had a pooled sensitivity of 76% for patients with smear-positive TB and 59% for those with smear-negative TB.

"Despite expansion of the literature since 2006, commercial serological tests continue to produce inconsistent and imprecise estimates of sensitivity and specificity," the researchers concluded. "Quality of evidence remains very low."

"Considerable research is underway on new approaches to the serological diagnosis of TB. These approaches include the use of newly identified selected purified recombinant antigens and antigen combinations," they explained in their discussion. "Recent studies from a number of laboratories have reported several new potential candidate antigens that may be expected to lead to improved antibody detection tests for TB in the future. These conclusions should be reconsidered if, in the future, methodologically adequate research evaluating serological tests becomes available."

These findings were used to inform a recent WHO policy statement against use of serological tests for active TB; the agency is currently reviewing tests for latent TB.

Below is the text of a WHO press release issued in July describing the new recommendations.

WHO Warns Against the Use of Inaccurate Blood Tests for Active Tuberculosis

Geneva -- July 20, 2011 -- The use of currently available commercial blood (serological) tests to diagnose active tuberculosis (TB) often leads to misdiagnosis, mistreatment and potential harm to public health, says WHO in a policy recommendation issued today. WHO is urging countries to ban the inaccurate and unapproved blood tests and instead rely on accurate microbiological or molecular tests, as recommended by WHO.

TB can be wrongly diagnosed

Testing for active TB disease through antibodies or antigens found in the blood is extremely difficult. Patients can have different antibody responses suggesting that they have active TB even when they do not. Antibodies may also develop against other organisms which again could wrongly indicate they have active TB. In addition, different organisms share the same antigens, making tests results unreliable. These factors can result in TB disease not being identified or wrongly diagnosed.

A blood test for diagnosing active TB disease is bad practice

"In the best interests of patients and caregivers in the private and public health sectors, WHO is calling for an end to the use of these serological tests to diagnose tuberculosis," said Dr. Mario Raviglione, Director of WHO Stop TB Department. "A blood test for diagnosing active TB disease is bad practice. Test results are inconsistent, imprecise and put patients' lives in danger."

Today's policy recommendation applies to blood tests for active TB. Blood tests for inactive TB infection (also known as dormant or latent TB) are currently under review by WHO.

New recommendation after 12 months of rigorous analysis

The new recommendation comes after 12 months of rigorous analysis of evidence by WHO and global experts. Ninety-four studies were evaluated -- 67 for pulmonary tuberculosis (TB in the lungs) and 27 for extrapulmonary tuberculosis (TB elsewhere in other organs). Overwhelming evidence showed that the blood tests produced an unacceptable level of wrong results - false-positives or false-negatives -- relative to tests endorsed by WHO.

Problems of misdiagnosis

The research revealed "low sensitivity" in commercial blood tests which leads to an unacceptably high number of patients wrongly being given the "all clear" (i.e. a false-negative when in reality they have active TB). This can result in the transmission of the disease to others or even death from untreated tuberculosis. It also revealed "low specificity", which leads to an unacceptably high number of patients being wrongly diagnosed with TB (i.e. a false-positive when in reality they do not have active TB). Those patients may then undergo unnecessary treatment, while the real cause of their illness remains undiagnosed, which may then also result in premature death.

The inaccurate blood tests are costly

More than a million of these inaccurate blood tests are carried out annually to diagnose active TB, often at great financial cost to patients. Many patients pay up to US$ 30 per test. There are at least 18 of these blood tests available on the market. Most of these tests are manufactured in Europe and North America, even though the blood tests are not approved by any recognized regulatory body.

Selling substandard tests with unreliable results

"Blood tests for TB are often targeted at countries with weak regulatory mechanisms for diagnostics, where questionable marketing incentives can override the welfare of patients," said Dr. Karin Weyer, Coordinator of TB Diagnostics and Laboratory Strengthening for the WHO Stop TB Department. "It's a multi-million dollar business centred on selling substandard tests with unreliable results."

This is the first time WHO has issued an explicit "negative" policy recommendation against a practice that is widely used in tuberculosis care. It underscores the Organization's determination to translate strong evidence into clear policy advice to governments.

Tuberculosis kills 1.7 million people every year, and is the major killer of people living with HIV. Improving the early and effective diagnosis of TB to ensure more lives are saved is a priority action for WHO and the international TB community. TB research is currently underway to bring better and more rapid tests that are easy to administer, effective and accurate.

8/16/11

References

KR Steingart, LL Flores, N Dendukuri, et al. Commercial serological tests for the diagnosis of active pulmonary and extrapulmonary tuberculosis: An updated systematic review and meta-analysis. PLoS Medicine 8(8): e1001062 (full text). August 9, 2011.

DW Dowdy, KR Steingart, and M Pai. Serological testing versus other strategies for diagnosis of active tuberculosis in India: A cost-effectiveness analysis. PLoS Medicine 8(8): e1001074 (full text). August 9, 2011.

Other Source

World Health Organization. WHO Warns Against the Use of Inaccurate Blood Tests for Active Tuberculosis. Press release. July 20, 2011.