Here, we provide commentaries from experts in the field which relate to a number of the topics that have emerged this year, some of which are featured in this update.
The World Health Organisation recommends that, for TB to be controlled effectively, it is necessary to identify both patients with infectious (active) disease so that they can be treated, and those latently infected so that they can be offered prophylaxis to reduce the risk of developing active TB later in life. There are no clinical symptoms and signs in latent TB infection (LTBI); and no gold standard laboratory test is available. LTBI has been traditionally diagnosed by the administration of a tuberculin skin test (TST) such as the Mantoux. This uses an intradermal injection of tuberculin with the result read 48-72 hours later. The technique needs an experienced operator; and assessment is subject to considerable inter- and intra-observer variation. It also requires a second visit for the tested subject. False negatives occur as a result of depressed immunity e.g. sepsis or HIV infection; and false positives are seen due to cross-reactivity with environmental mycobacteria or previous BCG immunisation.
Recently two commercial assays have been developed which utilise the finding that human T cells produce interferon gamma when stimulated with TB antigens if they have previously encountered this infection. By selecting synthetic antigens which do not stimulate BCG-recognising T cells, these blood tests are much-less influenced by prior BCG vaccination than the TST. The potential increase in specificity (only a small number of other mycobacteria contain similar antigens) is matched also by possible improved sensitivity in immunocompromised populations and children.
The interferon gamma release assay (IGRA) blood tests were originally developed to detect latent TB infection. They are currently recommended within NICE Guidance as part of a 2-step process which starts with TST and moves to IGRA if the first test is positive. Studies are underway to determine the cost-benefit of such an approach; and also whether the results of these tests predict the development of active tuberculosis. They have great promise in situations where large numbers of people need to be screened (as part of a public health investigation of an infectious case) or where a simple test is important (eg new entrant screening). Other work is examining their role in the diagnosis of active TB. Here the tests are perhaps harder to interpret as there is no current immunological method to distinguish treated, latent and active TB from each another. Given the high background rates of TB infection in populations who typically have active TB, guidance suggests that the blood tests may have a place in “ruling out” TB, if the test is negative.
The immediate attraction of IGRA is further enhanced by their potential role in the diagnosis of extra-pulmonary TB, where culture (the gold standard of active TB) is often negative. Some data also suggest that treatment response may be mirrored by changes in the measured test values during therapy - thus providing a potential marker of “TB cure”. As yet, the data remain limited; and in field conditions, the tests do not perform quite as well as expected. However they are the first major advance in immune diagnostics since the introduction of the TST over 100 years ago; and will undoubtedly be of value in the control and management of global TB. The HPA has produced guidance for healthcare workers and the general public on IGRA. These are available at http://www.hpa.org.uk/consultations/2007/IGRA.htm and will be updated on a regular basis as more information on this fast-moving and exciting area becomes available.
Tuberculosis (TB) rates in the United Kingdom have been increasing since the mid-1990s after a century of decline. Much of this increase results from immigration from high incidence countries, particularly sub-Saharan Africa. Historically, the bulk of our TB has been fully sensitive to standard therapy, with low rates of resistance to single agents, and even lower multidrug-resistance (7.9% and 1.2% respectively in 2006 1). However, with increasing numbers of cases imported from resistance ‘hot-spots’ around the world, for example the Baltic states, parts of China, and Southern Africa 2, comes the real possibility that rates of drug resistance in the United Kingdom will also increase. Not only will this bring huge additional costs (treating a case of multidrug-resistant TB costs around 10 times as much as a drug-sensitive case), but also major challenges as regards infection control and the management of contacts of these cases.
Over the past year, there has been increasing concern about the global emergence of extensively drug-resistant TB, (XDR-TB) 3. These strains are not only resistant to both rifampicin and isoniazid (i.e. MDR-TB), but also demonstrate extensive resistance to second-line antituberculous drugs 4. XDR-TB has now been reported from over 40 countries worldwide, although the major impact appears to be on resource-limited countries with high HIV prevalence, where alarmingly high and rapid mortality has been reported 5. XDR strains have been reported to cause major nosocomial outbreaks, again a particular issue where infection control facilities and practices may be limited, and where patients are particularly susceptible to primary progressive disease, for example where there is co-infection with HIV.
In recognition of this problem the World Health Organisation has set up a global task force on XDR-TB, and has included data on XDR-TB rates by country in the Global TB Drug Resistance Report published in February 2008 6. Key areas for action include the expansion of laboratory facilities for mycobacterial culture and sensitivity, which will aid both detection/management of individual cases and the collection of epidemiological data; action to strengthen TB control programmes to increase treatment completion rates; increased availability of second-line antituberculous agents; and strategies to reduce transmission, particularly in healthcare settings. Recent advances in the field of TB may in the future provide weapons in our armoury with which to fight XDR strains, for example rapid testing for drug resistance, interferon-gamma release assays for earlier detection of active/latent disease, and strain typing methods to confirm outbreaks at an earlier stage and thus facilitate more rapid control. However, on a global level, these expensive and often technically challenging techniques are unlikely to be available in the areas that need them most for some considerable time.
In the United Kingdom, as yet this degree of resistance is unusual. However, the massive expense and logistical burden of treating such patients, and their contacts, necessitate advanced planning for its arrival. At the level of the individual patient, as always with TB, awareness is key, not only of the possibility of TB as a differential diagnosis in an ill patient, but also of the existence of drug resistance in different parts of the world, and the need to consider resistance as part of the initial assessment of any patient with possible TB 7, with institution of appropriate infection control procedures including isolation in a negative pressure room. Patients with resistance to more than two first line agents are best managed in a specialist unit.
References
International comparisons of epidemiological data, particularly data collected through routine surveillance, are fraught with pitfalls. These pitfalls arise from variations in surveillance systems, different patterns of clinical service provision, and varying availability of diagnostic services. Nonetheless, such comparisons are an essential component of international policy making and priority setting for organisations such as the World Health Organisation and the European Commission. As globalisation increases, so knowledge of differences in international rates and distribution of disease can also inform risk assessments undertaken on a daily basis by public health workers and clinicians providing services to populations and individuals.
This brief update reviews surveillance data on tuberculosis in the WHO European Region, which stretches from Ireland to the East coast of Russia. The focus is particularly on the differences between the East and the West of the Region. The data are largely derived from the EuroTB coordinating unit in Paris, which coordinated the surveillance of tuberculosis (TB) in the 53 countries of the WHO European Region between 1996 and 2007 (this function is now undertaken by the European Centre for Disease Control and Prevention, ECDC, in collaboration with the WHO Euro Office).
There is a clear West to East gradient in reported rates of TB infection, with notification rates in 2005 in the ex-republics of the former Soviet Union running at approximately five times those in the West of the Region (average 110 per 100,000 for the 12 ex-republics compared to 18 per 100,000 in 32 countries of the European Union and ‘Western Europe’). Within the European Union, rates of TB have been below 20 per 100,000 since 2001 in all countries other than the Baltic States (Lithuania, Latvia, and Estonia), Hungary, Poland and Portugal.
Trends in reported rates between 2001 and 2005 in most EU countries have been downwards, the most notable exceptions to this being the UK and Sweden, where much of the rise in cases between 2001 and 2005 has been ascribed to TB in immigrants. In contrast, the trend in the former Soviet Union over that same period was upwards (although the average annual rate of increase in those countries fell from 10% between 1995 and 200, to 4% between 2001 and 2005).
Virtually all of the TB cases reported from the former Soviet Union are indigenous to the reporting country, whereas cases of foreign origin accounted for approximately 30% of cases reported from EU countries.
Co-existent HIV infection appears to be less common among TB cases in the former Soviet Union (1% of cases reported in 2001-2005) than among cases occurring in EU and other ‘Western Europe’ (3%, 2001-2005). Recent rises in the proportion of TB cases with HIV infection have been particularly marked in the UK, Estonia and Latvia.
Multi-drug resistance is a much greater problem in the former Soviet Union than in the Western parts of the European Region. Data on multi-drug resistance, derived from national and regional surveys, indicate that rates as high as 15%-25% are to be found in some of the ex-republics of the former Soviet Union, regardless of prior treatment, and 15%-20% of cases in the Baltic States of the EU, compared to 0%-6% in other countries in the EU. This is consistent with the low proportion of cases reported to have completed treatment successfully and/or reported as failing to resolve their disease, in some of the ex-republics of the former Soviet Union.