Book Review

In the Shadow of Tuberculosis

Clinical Tuberculosis

Tuberculosis: Current concepts and treatment

Tuberculosis: Pathogenesis, protection, and control

N Engl J Med 1995; 332:1106-1109April 20, 1995

Article

Clinical Tuberculosis
Edited by P.D.O. Davies. 426 pp., illustrated. New York, Chapman & Hall, 1994. $99.95. ISBN: 0-412-48630-X

Tuberculosis: Current concepts and treatment
Edited by Lloyd N. Friedman. 366 pp., illustrated. Boca Raton, Fla., CRC Press, 1994. $179.95. ISBN: 0-8493-4825-0

Tuberculosis: Pathogenesis, protection, and control
Edited by Barry R. Bloom. 637 pp., illustrated. Washington, D.C., ASM Press, 1994. $72. ISBN: 1-55581-072-1

Imagine a global emergency in the form of a reemerging disease that is infectious; often fatal; increasingly resistant to antimicrobial agents; associated with drug use, AIDS, and alcohol abuse; common among immigrants and inner-city homeless people; and acquired merely by breathing in the deadly airborne pathogen. These are the ingredients of an epic saga with sensationalist elements in which the public responds with panic, discrimination, prejudice, and stigmatization to those with disease. The disease that fits this description is tuberculosis, declared a global emergency by the World Health Organization (WHO) in 1993.

Acid-fast bacilli have been found in a Peruvian mummy from about a.d. 700, and there is evidence of the disease in the spines of figurines from the predynastic era (before 3000 b.c.) in Egypt, but tuberculosis was probably sporadic until the increases in population density in relatively recent times. At its peak incidence in Europe in the 16th through 19th centuries, tuberculosis accounted for a quarter of all deaths; in India and sub-Saharan Africa, however, the disease was seldom recognized by 19th-century medical observers. In Papua New Guinea tuberculosis was not recognized in the highlands as late as 1950, when Western travelers first explored the area.

Once the tubercle bacillus spread to susceptible populations, the rate of disease increased dramatically, notably in North American Indians, among whom the death rate from tuberculosis reached 9000 per 100,000 population in 1886, a time when mortality due to the disease in Boston and New York was about 400 per 100,000. In England, the rate of death from tuberculosis has been steadily decreasing since 1800, probably largely because of improvements in housing conditions. Less crowding and better ventilation remain the goals of public health efforts to control tuberculosis.

Many famous names embellish the history of tuberculosis research. Robert Koch described the bacillus in 1882. Albert Calmette and Camille Guérin developed the attenuated mycobacterial strain used in the bacille Calmette–Guérin (BCG) vaccine that has been administered to more than 4 billion people worldwide. Max Lurie used a rabbit model to demonstrate inherited resistance to tuberculosis. An effective cure began with Selman Waksman's discovery of streptomycin in 1944 and culminated in the comprehensive clinical trials conducted under the auspices of the British Medical Research Council by Wallace Fox and Denis Mitchison, which established that six-month multiple-drug regimens eradicated infection and prevented the emergence of resistant strains. By 1970 it was widely believed that the disease had been beaten and all that had to be done was to identify the few remaining infectious cases and treat them. A whole generation of physicians in the United States and Europe were trained without any experience in recognizing or treating patients with tuberculosis. Tuberculosis sanitariums closed, tuberculosis-control programs lapsed, and research on tuberculosis declined.

The reemergence of tuberculosis, best documented in the United States since the early 1980s, coincided with the AIDS epidemic and shattered this sense of security. Suddenly the public-health infrastructure for tuberculosis control was inadequate, containment facilities were lacking, inner-city homelessness and poverty were highlighted, and drug-resistant organisms caused epidemics in prisons, hospitals, and overcrowded shelters for the homeless. The lack of trained personnel was recognized and public expenditure increased. The press has helped produce this increased awareness in high-income countries, yet the chief problem is not in affluent countries but in the low-income countries of the world.

Enlightened self-interest should arouse our concern about tuberculosis at a time when international travel has transformed the world increasingly into a “global village.” WHO estimates of the incidence of tuberculosis show that the disease is increasing alarmingly not only in sub-Saharan Africa but also in the large cities of India and Southeast Asia, where projections of a 16-fold increase in cases by the year 2000 — in association with the human immunodeficiency virus (HIV) epidemic — should set off alarms. Already tuberculosis is thought to cause a quarter of the preventable deaths among adults in the developing world.

Simple diagnostic tests and effective multiple-drug treatments are available to control this epidemic. But resources are still needed to strengthen national tuberculosis-control programs, develop diagnostic facilities, purchase the necessary drugs and provide them where they are needed, ensure patients' adherence to treatment until therapy is complete, increase public education about the disease, and maintain tuberculosis-control programs long after the initial enthusiasm has waned.

The epidemic in the United States has provoked a fresh wave of interest in and research on tuberculosis. Established dogma is being questioned, and the embarrassing lack of answers to fairly basic questions provides a fertile field for research. Molecular biology can detect the DNA fingerprints of individual strains of Mycobacterium tuberculosis; such techniques are being used to track the epidemiology of the disease and determine whether cases are caused by the reactivation of dormant organisms or by fresh infection. The polymerase chain reaction (PCR) may reduce the length of time required to make a diagnosis and lessen the tedium of looking at stained sputum smears and preparing cultures — still the benchmark diagnostic tests worldwide. Already the problem of laboratory contamination of the PCR has demonstrated that even in the best laboratories, quality control will be vital and that these new molecular methods will have to be simplified and standardized before they are ready for use in the developing world.

Perhaps the nature of protective immunity is the most remarkable gap in our knowledge of tuberculosis. There has been an assumption that the results of the tuberculin skin test correlate with exposure to mycobacteria, including immunization by the BCG vaccine, and therefore reflect immunity. However, there is no correlation between skin-test conversion after vaccination with BCG and protection from subsequent tuberculosis. The animal models of tuberculosis do not closely resemble human disease, and the human homologue of a recently defined resistance gene in the mouse, NRAMP (natural resistance-associated macrophage protein), does not appear to code for protection in humans, suggesting that the control of susceptibility to tuberculosis is polygenic. A major effort is being made to establish the nucleotide sequence of the entire genome of M. tuberculosis; this information will challenge us to identify the function of the many encoded proteins, using reverse genetics.

New drugs against tuberculosis and a new vaccine are sorely needed. The authors of a recent meta-analysis of BCG-vaccine trials concluded that the vaccine had 50 percent protective efficacy against subsequent disease but efficacy of more than 70 percent in preventing deaths and disseminated disease and 64 percent in preventing meningitis. In countries where tuberculosis is endemic, most experts would favor continuing immunization with the BCG vaccine, despite the risk of disseminated BCG disease in severely immunocompromised recipients and the disappointing results of the largest trial of the vaccine in southern India. The search is on for alternative attenuated or even environmental mycobacteria that might stimulate protective immunity against tuberculosis. However, the cost and amount of time required for vaccine trials make it even more urgent to find surrogate markers of protective immunity; these might be identified by skin tests or simple in vitro tests that can be performed easily in the field.

For those charged with controlling the tuberculosis epidemic, promises of new drugs and a more effective vaccine are frustrating diversions from the primary task of diagnosing open tuberculosis (sputum-smear–positive cases) and maintaining therapy for six months in patients whose compliance is often poor. Intermittent but directly observed therapy, the ideal solution, is possible only if novel ways of ensuring adherence to the chemotherapy regimen can be implemented in different geographic areas, ethnic groups, and social situations. A regimen of twice-weekly therapy given under direct observation and lasting for six months has been found effective not only in Denver but also in Zululand, where the distribution of tablets is delegated to primary health care workers or even shopkeepers.

Now is the time to invest in research, while public awareness is at a high level and the need to control the epidemic is urgent. However, the mass media tire of subjects quickly, and we cannot allow the inevitable decline in public interest to limit our responsibility to help countries with too few resources to control tuberculosis. Case finding and treatment require the sustained support of national tuberculosis-control programs, many of which are already staggering under the burden of an escalating epidemic, with predictions of 5-to-20-fold increases in cases by the year 2000. The World Development Report states that the control of tuberculosis is among the most cost-effective health interventions available, costing only $10 per discounted year of healthy life gained. WHO and the International Union against Tuberculosis and Lung Disease have demonstrated that well-organized control programs can contain tuberculosis, but they, too, are operating on meager budgets. The World Bank is currently targeting China and India for tuberculosis control. Surely there should now be a consensus to support an international collaborative effort to control the disease worldwide.

In the current era of HIV disease, the textbooks on tuberculosis need to be rewritten. Not only does clinical tuberculosis now differ from classic tuberculosis, but diagnosis is problematic in HIV-positive patients. Treatment regimens and their duration need to be reviewed; side effects of drug treatments are more common; relapse and reinfection after treatment are more frequent; multidrug-resistant tuberculosis has arisen as a rapidly fatal condition, particularly in HIV-positive people; and mortality among HIV-positive patients with tuberculosis is high. Eliminating tuberculosis as a serious health problem is no longer a realistic goal for the present, and in many countries controlling tuberculosis appears an unattainable goal as incidence continues to rise. Under these circumstances, it is not surprising that several new books on tuberculosis have been published in the past three years. The three reviewed here are quite different in their orientation and their target readerships.

Clinical Tuberculosis, edited by Peter Davies, has been written largely by British and European authors, with several contributions from people working in the tropics. It is intended to be a reference work for clinicians and for public health workers on the diagnosis and management of tuberculosis and on current issues in tuberculosis control. It succeeds in achieving this goal, though its handsome presentation in hardcover will make it unaffordable in the developing world. Furthermore, it has a more academic orientation than the paperback of the same title by John Crofton, N. Horne, and F. Miller (London: Macmillan, 1992), which was clearly written to meet the needs of workers in the developing world. In his preface, Davies points out the tragic irony of the untimely closure, just as the AIDS epidemic was about to erupt, of the British Medical Research Council units that demonstrated the efficacy of short-course chemotherapy for tuberculosis. Although obviously viewed as shortsighted now, with the benefit of hindsight, at the time these decisions must have seemed reasonable as a way to switch research support away from clinical trials. The content of Davies's Clinical Tuberculosis reinforces the important conclusion that both basic and clinical science are needed to combat this reemergent disease.

The book has engaging chapters on historical and epidemiologic aspects of tuberculosis and brief discussions of microbiology, pathology, and immunology, followed by more detailed descriptions of the clinical aspects of pulmonary and extrapulmonary disease, tuberculosis in children, and HIV-associated disease. Therapeutic and preventive interventions are well described by renowned authors, and there are useful and practical chapters on control programs in countries with low and high prevalence. The authors have not attempted to place this book at the forefront of molecular science, except as it relates to the practical aspects of diagnostic tests and DNA fingerprinting. Rather, the book is intended as a useful, practical guide to health professionals working in the field of tuberculosis prevention and treatment.

Tuberculosis: Current Concepts and Treatment, edited by Lloyd Friedman, summarizes the current situation in the United States with little attention to the experience in the rest of the world. The book is clinically oriented, with excellent chapters on such important topics as transmission and safety issues, extrapulmonary disease, tuberculosis in childhood and pregnancy, nontuberculous mycobacteria, chemotherapeutic agents, and the problems of drug resistance. Chemoprophylaxis is tackled in the U.S. context, with useful analysis of the value of tuberculin skin testing with the purified protein derivative (PPD) and treatment in groups at high risk for tuberculosis. The controversial topic of the efficacy of the BCG vaccine is dealt with in a well-reasoned chapter, which highlights the importance of finding better surrogate markers of protective immunity than the PPD skin-test results, and a better animal mode for use in testing the next generation of vaccines. The chapter on the control of tuberculosis makes interesting reading when one considers that as recently as 1989, there was a strategic plan for the national elimination of tuberculosis (defined as the occurrence of less than one case per million population) by the year 2010. Although predictably doomed to failure, the plan at least focused attention on the need for basic and applied research to develop and evaluate new forms of technology for the treatment, diagnosis, and prevention of tuberculosis.

Tuberculosis: pathogenesis, Protection, and Control, edited by Barry Bloom, is a beautifully produced book that is pleasing to read, printed on good-quality paper, with many illustrations and tables. Even the references are a model of clarity, presenting a complete list of authors in bold type, a full title, and then the location of the reference in italic type. The list of authors serves as an international Who's Who in the field, with a particularly welcome twist: some chapters have been written by at least two authors from different institutions, which makes for a balanced approach but allows for diversity of opinion. The book is a worthy tribute to the select group of scientists and physicians to whom it is dedicated, who are described as keeping “the spirit of inquiry and research on tuberculosis and leprosy alive.”

The book includes an excellent overview of the current world situation with regard to tuberculosis, interesting vignettes from the rich history of the disease, and succinct chapters on clinical aspects and laboratory methods, with a valuable focus on issues of biologic safety. Unlike the other books reviewed here, Bloom's contains an excellent review of animal models used for the study of tuberculosis. The book is particularly strong on the basic-science aspects of M. tuberculosis, with superb articles covering the recent advances in molecular genetics, the intermediary metabolism and physiology of the organism, and the current understanding of immune mechanisms of protection and disease pathogenesis.

Topics authoritatively reviewed include the BCG vaccine and future vaccines, the molecular epidemiology of the disease, and new approaches to diagnosis and drug development. The final chapter on operational research makes the case for a more realistic approach to tuberculosis control worldwide and clarifies the need for more research in this area. This is a superb book, which summarizes current progress in the field and will be required reading for all those engaged in research on tuberculosis.

Each of these three new books on tuberculosis has different strengths. Bloom's book is at the forefront of research; although it will therefore become dated more quickly than the others, it is a superb collection of authoritative statements about the disease. Friedman's book also contains excellent chapters, with a strong emphasis on U.S. practice. Davies's is a more user-friendly reference work for health professionals in medicine and public health who want a guide to recent developments and current practice.

Keith P.W.J. McAdam, M.D., B.Chir.
London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom

Citing Articles (1)

Citing Articles

1. 1

   Imelda Bates, Caroline Fenton, Janet Gruber, David Lalloo, Antonieta Medina Lara, S Bertel Squire, Sally Theobald, Rachael Thomson, Rachel Tolhurst. (2004) Vulnerability to malaria, tuberculosis, and HIV/AIDS infection and disease. Part 1: determinants operating at individual and household level. The Lancet Infectious Diseases 4:5, 267-277
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