Clinical review

Tuberculosis

Alimuddin Zumla, reader in infectious diseases, ^a John Grange, reader in clinical microbiology. ^b

^a Centre for Infectious Diseases, University College London Medical School, London W1P 6DB, ^b Imperial College School of Medicine, National Heart and Lung Institute, London SW3 6LY

Correspondence to: Dr Zumla a.zumla{at}ucl.ac.uk

Tuberculosis is the leading infectious cause of death worldwide, being responsible for 3 million deaths annually. Among those aged over 5 years, tuberculosis kills more people than AIDS, malaria, diarrhoea, leprosy, and all other tropical diseases combined. The tragedy of this situation is that treating tuberculosis is one of the most effective and cost effective of all health interventions. The World Health Organisation has calculated that, unless urgent action is taken, the annual number of deaths could rise from 3 million to 4 million by the year 2004.¹ We urgently need improvements in the implementation of existing strategies for tuberculosis control, with particular emphasis on early diagnosis and delivery of effective treatments. In addition, basic research is needed for the development of simple and rapid diagnostic tests, more effective vaccines, and new drugs. This article focuses on new scientific approaches to tuberculosis control that could soon be incorporated into routine practice. However, the impact of new approaches will be negligible if the wealthy Western nations fail to address the gross global inequities in healthcare provision,² which account for the fact that 98% of deaths from tuberculosis occur in the poorer developing countries (fig 1).

So serious is the global threat of tuberculosis that, in 1993, the WHO took the unprecedented step of declaring this disease a global emergency.¹ The problem is fuelled by the pandemic of HIV infection and AIDS and the emergence of drug and multidrug resistance. HIV infection renders a person infected by Mycobacterium tuberculosis much more likely to develop overt tuberculosis, and the evolution of the disease is considerably accelerated. At present, about 8-10% of all cases of tuberculosis worldwide are related to HIV infection, but the association is much more common in many African countries, often 20% or more.⁴

Drug resistance is ubiquitous, although the incidence varies greatly from region to region. Globally, about 10% of cases of tuberculosis are resistant to one drug, and, although primary multidrug resistance is uncommon (about 0.2%), it occurs in a median of 4.4% of previously treated patients.⁵ These figures may be an underestimate, as countries with good facilities for testing for drug resistance also have good tuberculosis control programmes.

	Priorities for research

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The dilemma facing tuberculosis researchers and funding agencies is whether to give priority to operations research to determine the most effective ways of using the available control measures or to focus on basic research into new diagnostic tests, vaccines, and treatment regimens. Despite inadequate funding resources, much effort is being devoted to both approaches, involving a multidisciplinary approach from diverse disciplines such as molecular biology, social anthropology, and health economics.

Diagnostic tests
The traditional diagnostic tools, apart from a thorough clinical examination, are chest radiology, which is sensitive but non-specific, and sputum microscopy, which is specific but of limited sensitivity. Microscopy has two advantages: it detects open, infectious cases, and it does so rapidly. Culture is more sensitive, but several weeks elapse before the diagnosis is made and there is an even longer wait for the results of drug susceptibility tests. Automated systems for more rapidly detecting growth of M tuberculosis are available, but their cost and complexity restrict their use to major centres.

View larger version (20K): [in this window] [in a new window]   Fig 1.   Estimated incidence and prevalence of, and number of deaths due to, tuberculosis in 1997 (data from World Health Organisation3)

Vaccines and vaccination strategies
The BCG vaccine has been used extensively since 1921, but its contribution to disease control has been limited for two reasons. Firstly, its protective efficacy varies considerably, from 0% to about 80%, in different regions.¹⁰ Secondly, when it is effective it affords a high degree of protection against the serious but usually non-infectious forms of primary tuberculosis but gives little or no protection against the post-primary forms of the disease, due to endogenous reactivation or exogenous reinfection, which are responsible for transmission of the disease.

The immune response
In the absence of HIV infection or other cause of immunosuppression only about 10% of people infected by M tuberculosis develop overt tuberculosis, indicating that the immune response to this pathogen is usually good. There is evidence that the immune response in those who do develop tuberculosis is not weak but dysregulated. It is now known that helper T lymphocytes mature along two pathways, resulting in so called Th1 and Th2 cells that are distinguishable by the chemical messengers (cytokines) that they release. Regulation of these Th1-Th2 type responses may be influenced by glucocorticoids and dehydroepiandrosterone.¹³ The protective immune response in tuberculosis is mediated by Th1 cells, but a Th2 or a mixed Th1-Th2 response renders cells very sensitive to killing by the cytokine tumour necrosis factor (TNF), thereby inducing the gross tissue destruction characteristic of progressive tuberculosis (fig 2).¹⁴

View larger version (22K): [in this window] [in a new window]   Fig 2.   Effect of maturation of T helper lymphocytes into Th1 and Th2 types on immune response in tuberculosis. Immunity requires a Th1 response, and tumour necrosis factor (TNF) is needed as an additional, macrophage activating factor. With a mixed Th1-Th2 cytokine response, TNF becomes toxic and mediates the gross tissue destruction characteristic of active, progressive tuberculosis. Stress and corticosteroids tend to drive newly recruited T cells towards Th2 responses

The factors determining the pattern of T cell maturation are not fully understood, but it seems that the immune system may be programmed to respond in a certain way by past experience, including exposure to the antigens of mycobacteria present in the environment. In addition, stress and glucocorticoids tend to drive newly recruited T cells towards Th2,¹³ while these steroids also directly inhibit the ability of macrophages to limit the growth of M tuberculosis.¹⁵ Vaccinating a person whose immune response is inappropriately programmed may therefore not lead to protection, and this may explain why BCG fails to afford protection in some regions and may even predispose people to the disease.¹⁰ Accordingly, the vaccine of the future may be one that contains not only specific antigens but also adjuvants able to modulate the immune response.¹⁶

Treatments
Modern short course treatment regimens based on rifampicin and isoniazid are highly effective. However, if resistance to these drugs develops, prolonged treatment with less effective, and often more toxic and expensive, drugs is required and the mortality is high, especially in patients infected with HIV. There are two main approaches towards developing new drugs: firstly, to screen many products randomly against M tuberculosis or a related rapidly growing mycobacterium or, secondly, to study metabolic pathways unique to this bacillus in the hope of producing "designer drugs." The success of either strategy cannot be predicted, so it is important to prevent the emergence and transmission of drug resistance by effective use of available drug treatment and appropriate control measures.

	Effective use of available control measures

Top Priorities for research Effective use of available References

The paradox of the global emergency of tuberculosis despite the availability of highly effective treatment reveals gross deficiencies in its deployment.² The principal cause of failed disease control is "non-compliance," for which the patient is usually blamed but which is usually the fault of the healthcare provider. The WHO has advocated the directly observed therapy short course (DOTS) strategy,¹⁷ a strategy that will work only if attention is given to the many social, cultural, and ethnic factors that affect the use of tuberculosis services by the community.¹⁷

The conquest of this disease will not be achieved by medical advances alone. As the powerful tools for treatment and control that are currently available have made little impact, we cannot expect any new ones to do so unless there is global political willingness to address the gross inequities of wealth and healthcare provision in society.² While tuberculosis can affect anyone, the greatest burden of disease falls on the poor. In November 1997 the UK Department for International Development published its white paper Eliminating World Poverty: A Challenge for the 21st Century.¹⁸ This paper champions the cause of the world's poor and sets precedence to the Western nations to target their aid packages for developing countries towards achieving reductions in world poverty. If this is successful, a parallel reduction in the incidence of tuberculosis can be anticipated. Indeed, the director of the WHO global tuberculosis programme has stated: "The growing tuberculosis epidemic is no longer an emergency only for those who care about health, but for those who care about justice."¹

	References

Top Priorities for research Effective use of available References

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