Elsevier

The Lancet

Volume 378, Issue 9785, 2–8 July 2011, Pages 57-72
The Lancet

Seminar
Tuberculosis

https://doi.org/10.1016/S0140-6736(10)62173-3Get rights and content

Summary

Tuberculosis results in an estimated 1·7 million deaths each year and the worldwide number of new cases (more than 9 million) is higher than at any other time in history. 22 low-income and middle-income countries account for more than 80% of the active cases in the world. Due to the devastating effect of HIV on susceptibility to tuberculosis, sub-Saharan Africa has been disproportionately affected and accounts for four of every five cases of HIV-associated tuberculosis. In many regions highly endemic for tuberculosis, diagnosis continues to rely on century-old sputum microscopy; there is no vaccine with adequate effectiveness and tuberculosis treatment regimens are protracted and have a risk of toxic effects. Increasing rates of drug-resistant tuberculosis in eastern Europe, Asia, and sub-Saharan Africa now threaten to undermine the gains made by worldwide tuberculosis control programmes. Moreover, our fundamental understanding of the pathogenesis of this disease is inadequate. However, increased investment has allowed basic science and translational and applied research to produce new data, leading to promising progress in the development of improved tuberculosis diagnostics, biomarkers of disease activity, drugs, and vaccines. The growing scientific momentum must be accompanied by much greater investment and political commitment to meet this huge persisting challenge to public health. Our Seminar presents current perspectives on the scale of the epidemic, the pathogen and the host response, present and emerging methods for disease control (including diagnostics, drugs, biomarkers, and vaccines), and the ongoing challenge of tuberculosis control in adults in the 21st century.

Introduction

Tuberculosis has plagued humankind worldwide for thousands of years. John Bunyan (Nov 28, 1628–Aug 31, 1688), an English Christian writer and preacher, described tuberculosis as “The Captain among these men of death” at a time when tuberculosis case rates in London had reached 1000 per 100 000 population per year.1 Tuberculosis continued to cause many deaths in London during the 19th century and accounted for up to 25% of deaths in Europe. The death toll from tuberculosis began to fall as living standards (housing, nutrition, and income) improved early in the 20th century, well before the advent of antituberculosis drugs. Despite the first antituberculosis drugs being discovered more than 60 years ago, tuberculosis today still kills an estimated 1·7 million people each year.2 Progress in the scaling up of tuberculosis diagnostic, treatment, and control efforts worldwide over the past decade has been associated with improvements in tuberculosis control in many parts of the world, but progress has been substantially undermined by the HIV-1 epidemic, the growing challenge of drug resistance, and other increasingly important epidemiological factors that continue to fuel the tuberculosis epidemic.3 Greater investment in new technologies, basic science, and translational and applied research has led to progress in the development of improved tuberculosis diagnostics, drugs, treatment regimens, biomarkers of disease activity, and vaccines; new perspectives in the pathogenesis of tuberculosis are also emerging. Our Seminar focuses on tuberculosis in adults and presents current perspectives on the scale of the epidemic, the pathogen and host response, current and emerging methods for disease control (including diagnostics, drugs, biomarkers, and vaccines), and the ongoing challenge of tuberculosis control in the 21st century.

Section snippets

Epidemiology

The estimated total number of incident cases of tuberculosis worldwide rose to 9·4 million in 2009—more than at any other time in history.4 The worldwide tuberculosis incidence rates are estimated to have peaked in 2004 and to have decreased at a rate of less than 1% per year since that time. However, the overall worldwide burden continues to rise as a result of the rapid growth of the world population. Most cases are in Asia and Africa, with smaller proportions of cases in the eastern

Microbiology of Mycobacterium tuberculosis

M tuberculosis was first identified by the German scientist Robert Koch (figure 3), who announced the discovery on March 24, 1882. The M tuberculosis complex of organisms, which can cause human disease, consists of M tuberculosis, Mycobacterium africanum, Mycobacterium bovis, Mycobacterium microti, and Mycobacterium canetti. M bovis was responsible for about 6% of all human tuberculosis deaths in Europe before the introduction of milk pasteurisation; subsequent attenuation of a laboratory

Host–pathogen interactions

The yearly probability of developing active clinical tuberculosis after inhalation of an M tuberculosis aerosol from an infectious patient with active tuberculosis is very small, with an estimated lifetime risk of about 10%.27 The risk of transmission is highest within the first few years after infection, but decreases substantially thereafter. Most immunocompetent individuals (over 90% of those infected) either eliminate M tuberculosis or contain it in a latent state. So-called latent

Biomarkers

High on the tuberculosis research agenda is the discovery of host and pathogen biomarkers of active tuberculosis for diagnosis, monitoring treatment, and assessing outcomes (including cure and relapse). A biomarker is defined as a characteristic that is objectively measured and assessed as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention. Biomarkers thus provide information about current health status, future health

Diagnostics

The estimated worldwide detection rate for new sputum smear-positive cases of tuberculosis of 62% in 2008 fell substantially short of the 2005 target detection rate of 70%,2 and the lack of accurate and rapid diagnostics remains a major obstacle to progress in this regard. Over 90% of the worldwide burden of tuberculosis is in low-income and middle-income countries where the diagnosis of tuberculosis still relies heavily on sputum smear microscopy and chest radiology. These techniques are often

Clinical presentation

Although tuberculosis predominantly affects the lung, it can cause disease in any organ (figure 6) and must be included within the differential diagnosis of a vast range of clinical presentations. Symptoms and signs include those associated with the specific disease site as well as non-specific constitutional symptoms such as fever, weight loss, and night sweats. However, in the early stages of disease, symptoms might be absent as shown by community-based active case finding studies in Asia101

Treatment

The WHO revised international guidelines for the treatment of tuberculosis in 2010,107 specifically responding to the growing evidence base108, 109, 110, 111 and escalating problem of drug-resistant disease worldwide.32 Earlier guidelines emphasised the use of two main standardised treatment regimens, one for new (previously untreated) cases and one for patients with sputum smear-positive disease who had previously received treatment (retreatment regimen). The drug combinations used in these

Vaccines for tuberculosis

There is a dire need for a universally effective vaccine for the control of tuberculosis.137, 138 The only licensed vaccine, BCG, was first given to a human infant in 1921. The vaccine has been given to 4 billion people so far and to more than 90% of the children in the world today, making it the most widely used vaccine in the world. However, it has done little to contain the current tuberculosis pandemic. Despite evidence of confirmed efficacy against childhood tuberculous meningitis and

Tuberculosis control

After the declaration in 1993 that tuberculosis was a global emergency, WHO launched the directly observed treatment, short-course (DOTS) strategy, which was successfully expanded as the principal tuberculosis control strategy, focusing primarily on detection and effective treatment of infectious cases. Between 1995 and 2008, 43 million people were treated under DOTS, 36 million were cured, case-fatality rates decreased from 8% to 4%, and an estimated 6 million deaths were potentially averted.2

Conclusions

Tuberculosis remains a major cause of death and morbidity worldwide, and control efforts so far have not adequately controlled the epidemic in many parts of the world, especially in the countries of sub-Saharan Africa and parts of eastern Europe. Absence of a cheap point of care diagnostic test, the long duration of treatment, lack of an effective vaccine, emergence of drug-resistant tuberculosis, and weak health systems in resource-poor developing countries are all factors that continue to

Search strategy and selection criteria

Our Seminar is focused on tuberculosis in adults. Readers are referred to recent reviews on tuberculosis in children. Our search strategy included a 7-year review of PubMed (2004–11), the Cochrane library (2004–10), WHO and WHO-STOP TB publications (2000–10), and Embase (2004–10), and three recent comprehensive tuberculosis textbooks (Tuberculosis: a comprehensive clinical reference [Philadelphia, PA: Saunders, 2009]; Tuberculosis: the essentials, 4th edn [London: Informa, 2009]; Handbook of

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