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Diagnostics stand up to fight tuberculosis

Paul B Lebeau
TB Group European Diagnostic Manufacturers’ Association
General Manager EMEA
Cellestis Europe

Although the number of tuberculosis (TB) cases is gradually declining in most countries of the  world, except the African region, it remains a prevalent epidemic in some developed and many resource-poor regions. The World Health Organization (WHO) estimates that the largest number of new TB cases in 2004 occurred in WHO’s South-East Asia region, which accounted for 33% of incident cases globally. However, both the highest number of deaths and the highest mortality per capita are in the WHO Africa region. It is estimated that 1.7 million deaths resulted from TB in 2004. According to the recent WHO report “Global TB control: surveillance, planning financing”, the TB epidemic in the European region, which peaked in 2001, is now declining. In particular, 415,172 TB cases were reported in the region in 2004, with 80% in just 16 countries: those in the Commonwealth of Independent States (CIS), the Baltic states and Romania. TB also caused an estimated 69,018 deaths in the region in 2004. In Western Europe, increased emigration from countries with high TB prevalence has resulted in cases in immigrants outnumbering the indigenous cases, and therefore raising the alarm among WHO and EU institutions.

Nonetheless, the emergence of multidrug-resistant TB strains and HIV co-infection provides a new urgency for keeping TB control a major objective of most infection control programmes. The rates of multidrug-resistant TB in the countries of Central and Eastern Europe and the CIS are estimated to be among the highest in the world. Of the 20 countries with the highest rates of multidrug resistance among previously treated cases, 14 are in the WHO European region. The area also reports the highest rate of treatment failure (7%) and the second- highest rate of death as a treatment outcome (6%).

Transmission and detection
The subtle airborne infection route of TB enhances the probability of microbial transmission. The hospital setting provides ample opportunity for such transmission by an insufficiently isolated patient or an infectious caregiver. The disease cycle, which often includes a long period of latency, makes symptom-based recognition and microbiological detection methods poor tools for the identification of infected persons.

Although the detection of latently infected persons has been the object of healthcare worker screening and contact-tracing programmes in hospitals for decades, these have often yielded unsatisfactory results. The blame for this has been placed largely on the lack of a truly effective test for latent TB infection (LTBI).The Tuberculin Skin Test (TST), developed more than 100 years ago, has been the only tool available for detecting LTBI, and the limitations of that procedure are well documented.

Although the TST may be a useful epidemiological tool, its poor specificity and subjective interpretation mean that its Positive Predictive Value is not in keeping with the standards required for medical decisions today. As a consequence of this poor medical return, programmes to detect LTBI, which could include prophylactic treatment of the infection, have often been poorly established, and the control programmes themselves neglected.

New blood tests
The in vitro diagnostic (IVD) industry has been committed in the past years to the development of new blood tests that, unlike the TST, are not confounded by vaccination or infection by nontuberculosis mycobacteria. The goal has been also to eliminate the logistical challenges of skin testing; a simple venipuncture procedure followed by a standard, batchable laboratory procedure is all that is required nowadays to obtain a definitive “Yes” or “No” response to the question of LTBI.

Whereas the TST relies on massive cytokine production at the site of intradermal injection of a poorly defined collection of antigens (tuberculin), new diagnostic tools – already recommended by the National Institute for Clinical Evidence guidelines in the UK, the Swiss Lung League Guidelines and the US Centers for Disease Control and Prevention – measure production of the specific cytokine interferon- gamma in response to in-vitro stimulation of lymphocytes with highly specific TB antigens.

From a practical point of view, the new wave of IVDs allows significant cost savings over TST in the hospital setting. These come from efficiencies in managing the testing programmes, reduced caseloads due to significantly lower rates of positivity and elimination of working time losses for follow-up visits to the occupational health office. In the clinical setting, TB diagnostics progress represents a clear asset for the protection of immunocompromised patients. This group includes, above all, those infected with HIV, those on renal dialysis and those to whom immunosuppressive drugs are being, or are about to be, administered. Such patients are in significant danger for reactivation of LTBI and for fresh TB infection. The IVD manufacturers’ contribution is not limited to the detection of LTBI. Efforts are also focused on the diagnosis of active TB disease. While classic TB detection methods rely on the presence of live bacteria in a sample, new IVDs are intended to provide a strong indicator of the presence of TB from a simple blood sample. Dangerous nonpulmonary TB can therefore be brought into focus and life-threatening TB infection in children can be identified, allowing early treatment initiation and possibly avoiding tragic outcomes.

A problem for today
With headlines being grabbed by “new” threats such as MRSA and H5N1, TB is dismissed by many as “yesterday’s problem”. This view ignores the grim reality that almost two million people die every year from TB worldwide and the widespread prevalence of the infection. With the mobility of the world’s populations ever on the rise, the growth of immigrant populations in low-prevalence areas, and the increased presence of immigrants in patient settings and in healthcare staffs along with ever more immunosuppressive medication, the risks of TB infection in the hospital cannot be ignored.

Beyond the achievement of the development and bringing to market of these new tests, the IVD industry is committed to strengthening its efforts in the research and development of diagnostic tools to fight TB, assisting in this way the international activities aimed at reducing TB prevalence and death rates by 50% in 2015 and eliminating TB as a public health problem (one case per million population) before 2050, as established in the Millennium Development Goals.