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Tuberculosis

Tuberculosis (TB) has been with us for thousands of years, but it declined considerably in developed countries in the first half of the last century, partly due to the MRC’s groundbreaking trial of the first anti-TB drug. It has returned recently for several reasons, including the increasing number of people with HIV/AIDS, who are unable to develop an effective immune response, and increasing antibiotic resistance. Developing countries account for more than 90 per cent of global TB cases, and worldwide the disease kills on average one person every 18 seconds. There are about 7,000 new cases in the UK each year.

TB is a primarily a disease of the lungs. However, the infection can spread via blood from the lungs to all organs in the body. This means that TB may also affect the bones, the urinary tract and sexual organs, the intestines and even the skin. TB can remain dormant for many years. The disease is more common in areas where poverty, malnutrition, poor general health and social disruption are present.

At the end of the nineteenth century, the annual death rate worldwide from TB or ‘consumption’, was estimated to be 7 million people. In 1882, Robert Koch, a German physician and scientist, discovered the bacterium that causes TB – Mycobacterium tuberculosis. This finding formed the basis for the diagnostic skin test for TB, developed 20 years later by a French physician, Charles Mantoux. The test involves the injection of tuberculin, an extract from the TB-causing bacterium, under the skin.

French researchers developed the first TB vaccine in 1921. The Bacille Calmette-Guérin (BCG) vaccine is prepared from a strain of the weakened live bacteria, which has lost its virulence in humans by being specially cultured in an artificial medium for years.

TB and the MRC

The MRC was set up early last century primarily to deal with TB. In 1911, there was a new scheme for health insurance with a provision – paid for, by state contributions, employers and employees, with a penny per working person per year – for sanatorium treatment for cases of TB and for ‘purposes of research’, with the aim of comparing TB in animals and humans. This created a national fund for medical research and amounted to £57,000 a year – equivalent to nearly £4 million today – and was managed by a committee that, by 1919, evolved into the MRC.

The MRC funded a landmark trial of the first anti-TB drug, streptomycin – the first effective non-surgical treatment for the disease – after it was developed in 1944 in the US. Following this, the MRC formed the Tuberculosis Research Unit to conduct randomised controlled trials of the treatment of TB. Subsequently this unit broadened the scope of its activity and became the MRC Tuberculosis and Chest Diseases Unit (TCDU), which continued until the retirement of its Director, Professor Wallace Fox, in 1986. This unit, together with two other MRC TB units, collaborating with many countries, helped to ensure that TB changed from being an untreatable disease to one that could be alleviated in both rich and poor countries1.

Drugs, vaccines and care

Dr Philip D’Arcy-Hart was a pioneer in TB treatment at the MRC’s Tuberculosis Unit, and led the MRC randomised controlled trial on streptomycin2. Dr D’Arcy-Hart also set up facilities for laboratory work on TB at the Mill Hill site of the National Institute for Medical Research (NIMR), where he conducted major investigations into cellular mechanisms of infection, establishing a new era in the understanding of how TB causes disease3.

Before Wallace Fox became Director of the TB Unit, he ran a trial in Madras, India, that compared sanitorium with home treatment. This trial showed that treatment in sanatoria was no better than at home, and thus contributed to the closure of the TB sanitoria by the end of the 1960s, leading to huge financial savings4.

The MRC, in the 1950s, also carried out a large-scale trial of BCG vaccination. This involved over 50,000 schoolchildren, and the results became the basis of a new public health policy of universal vaccination in schools (which has now been replaced with targeted vaccination for individuals at greatest risk). After 20 years of follow-up, the results showed that efficacy of the BCG vaccine was high, averaging nearly 80 per cent5. But the vaccine is much more effective in some areas compared with others, which has encouraged international researchers to find a more specific and uniform vaccine. Results of a recent study indicate that the variation in effectiveness is due to different genetic compositions of the vaccine6.

Developing countries

In the 1960s, the standard treatment for pulmonary TB was the administration of isoniazid and para-aminosalicylic acid (PAS) for between 18 months and two years, along with streptomycin for the first three months. In developing countries, the cheaper drug thiacetazone, instead of PAS, was used. But the two-year course was expensive and there was a problem with patient compliance and supervision. This not only led to poor treatment, but also encouraged the evolution of antibiotic resistance. These problems indicated a need for a shorter course of treatment, especially in developing countries where health services are underdeveloped and HIV/AIDS is a growing problem.

As a result of trials in India and East Africa, a shorter treatment regime emerged. Professor Janet Darbyshire joined the MRC Tuberculosis and Chest Diseases Unit in 1974 and coordinated some MRC clinical trials in Africa. The outcome of these was a six-month course with two drugs – rifampicin and isoniazid – plus pyrazinamide for the first two months7. However, there are problems with people completing even the six-month course. There are several new drugs in the pipeline and currently an aim to reduce the treatment course to four months or less.

Fighting a global pandemic?

Resistance to anti-TB drugs occurs mainly because of poorly managed TB care. Multi-drug resistance TB (MDR-TB) – resistant to at least isoniazid and rifampicin – emerged in the 1990s, and requires the use of other drugs that are less effective, more toxic and more costly. Fifty million people worldwide have multi drug-resistant (MDR) TB, according to the World Health Organization, and 300,000 new patients are infected each year. There is also XDR TB, which is extremely drug resistant. It has emerged in South Africa and is impossible to treat. A study of TB cases worldwide from 2000 to 2004 showed that 20 per cent were MDR and 2 per cent were XDR, raising concerns of a future epidemic8.

MRC researchers are trying to find new drug targets for TB, which could lead to further drug development. At the MRC’s NIMR, scientists have characterised a protein in the TB bacterium, which may be important in the repair of DNA and help the bacterium to persist in the body after infection9. The team is attempting to find a chemical inhibitor for this protein.

Diagnosis is also very important – if left untreated, active TB kills up to half of its victims. Researchers at NIMR have developed a blood test for the disease, which identifies a marker for the disease in blood10. This is an improvement on the current method, which involves the examination of sputum from lungs under a microscope – in rural communities in developing countries, this test is only 40 to 60 per cent accurate.

TB in the UK

Every year around 350 people in England die from TB. The Department of Health in England produced an action plan in 2004 with immediate aims to reduce the risk of new TB infections, provide high quality treatment and care, and to maintain low levels of drug resistance11. Last year, MRC-funded researchers studied a TB strain responsible for a major outbreak of TB in Leicester, and showed that it has a large deletion in its genome which allows persistence in humans12. This strain, however, is responsive to antibiotics.

References

  • 1. Fox et al. (1999). Studies on the treatment of tuberculosis undertaken by the British Medical Research Council Tuberculosis Units 1946–1986, with relevant subsequent publications. Int J Tuberc Lung Dis, 3, S231.
  • 2. Medical Research Council (1948). Streptomycin treatment of pulmonary tuberculosis: A Medical Research Council investigation. BMJ, ii, 7692.
  • 3. Armstrong & Hart (1971). Response of cultured macrophages to Mycobacterium tuberculosis, with observations on fusion of lysosomes with phagosomes. J. Exp Med, 134, 713.
  • 4. Dawson et al. (1966). A 5-year study of patients with pulmonary tuberculosis in a concurrent comparison of home and sanatorium treatment for one year with isoniazid plus PAS. Bulletin of the World Health Organization, 34, 533
  • 5. Hart & Sutherland (1977). BCG and vole bacillus vaccines in the prevention of tuberculosis in adolescents and early life. Final report to the Medical Research Council. BMJ, ii, 293.
  • 6. Brosch R., et al. (2007). PNAS, Published early online, doi:10.1073/pnas.0700869104.
  • 7. Jindani (1976). Short-course (6-month) treatment of pulmonary tuberculosis (Second East African/[British] Medical Research Council Study). Bulletin of the International Union Against Tuberculosis and Lung Disease, 51, 53.
  • 8. Centers for Disease Control and Prevention (CDC). (2006). Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs--worldwide, 2000-2004. MMWR Morb Mortal Wkly Rep, 55, 301
  • 9. Curti et al. (2007). Characterization of the helicase activity and substrate specificity of Mycobacterium tuberculosis UvrD. J. Bacteriol., 189, 1542.
  • 10. Agranoff et al. (2006). Identification of diagnostic markers for tuberculosis by proteomic fingerprinting of serum. Lancet, 368, 1012
  • 11. Donaldson, UK Department of Health (October 2004). Stopping Tuberculosis in England: An action plan from the Chief Medical Officer.
  • 12. Newton et al. (2006). A deletion defining a common Asian lineage of Mycobacterium tuberculosis associates with immune subversion. PNAS, 103, 15594.
  • MRC, April 2007

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