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
SeminarTuberculosis
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
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