Challenges

Challenges - History tells the story of things past. The future of TB must concern all of us now. Whatever the past may have taught us, we face a future challenged by rising TB incidence in much of the world. That HIV infection fosters the spread of TB and that multidrugresistant disease is an increasing problem add to the challenges and call for new initiatives. New drugs and a better vaccine are needed. The spread of TB is now being approached with new tools made possible by genetic typing of mycobacteria. What we learned by contact tracing has been augmented with new knowledge, for now it is possible to connect sources and targets of air-borne tubercle bacilli with great certainty. The contacts are not always obvious, and often are buried in the forgotten past. 

CFP-10 ESAT-6

ESAT-6 CFP-10

New approaches to the diagnosis of TB are being made possible by new knowledge of the antigens of mycobacteria. There is a vast panoply of these proteins; some are limited to specific species or trains, while others are widespread among members of the genus. ESAT-6, for example, is an antigen that has been lost from BCG, so it is possible to use the presence or absence of immune recognition of it to distinguish BCG infections from true tuberculous infection. Immunization has served since the time of Edward Jenner as a major weapon in the battle against infectious diseases. However, BCG has fallen short of initial hopes for controlling TB. As more is learned about the immunopathogenesis of TB, it is becoming more possible to target candidate vaccines against specific components of the tubercle bacillus, perhaps increasing protective efficacy. New vaccines are currently in development; field trials to assess their efficacy will pose large challenges.

Drug discovery efforts have long neglected TB, but this has changed in recent years. New agents targeting new microbial receptors are being produced by pharmacologists now alerted to the challenges of multidrug-resistant TB. Research workers – immunologists, epidemiologists, microbiologists, pharmacologists, molecular biologists, experimental pathologists – are attacking these challenges. One can hope that expanding knowledge emanating from their laboratories will produce new and unanticipated tools for control of the ‘Captain among these Men of Death’.

Prevention and Control

Prevention and Control - Without dismissing the importance of their efforts at case finding and treatment, public health workers interested in TB sought measures that might prevent this disease. With knowledge of Edward Jenner’s vaccinia prevention of smallpox and Louis Pasteur’s immunization treatment of rabies, Albert Calmette decided to turn his efforts at the Pasteur Institute in Lille, France, to developing a vaccine against TB. 

Prevention anda Control Tuberculosis

Together with his colleague, Camille Gue´rin, he began efforts to attenuate M. bovis by serial passage in 1902.15,38 During the devastating German siege of Lille in 1914 and the subsequent German occupation, they managed to maintain their cultures. In 1921 Calmette, now in Paris, was ready to try the vaccine known as Bacillus Calmette-Gue´rin (BCG) in a human subject. He approached Drs. Benjamin Weill-Halle´ and Raymond Turpin at the Hoˆ pital Charite´, and, on 18 July 1921, the new vaccine was administered to a 3-day-old infant whose mother had just died of TB and who would be raised by its tuberculous grandmother. 

The infant lived and thrived. During the next 4 years more than 100,000 doses of BCG were administered, and the TB death rate in vaccinated children was thought to be reduced by 10-fold. BCG came into widespread use in Europe following the Second World War, and in December 1973 the World Health Organization Expert Committee on Tuberculosis issued its NinthReport, in which it recommended that BCG should be used as widely as possible. Many trials of BCG efficacy have been conducted, some more rigorous than others. There is a striking disparity of results.39 This disparity is illustrated in Fig. 1.6, 

which is taken from a review by Paul Fine. Ultimately, an expert consensus emerged that BCG is useful in the prevention of miliary and meningeal TB in young children but has no epidemiological impact and no utility in prevention-oriented TB control programmes. Epidemiologists of the US Public Health Service never embraced BCG. Rather, they focused on prophylactic treatment of latent TB with isoniazid, an approach first suggested by Edith Lincoln.40 Large randomized control studies demonstrated the efficacy of this preventative measure in a variety of populations.41 Other countries have been slow to follow the American lead, however, and current control strategies in most nations emphasize treatment under direct observation using optimal.

Origins

Origins - The genus Mycobacterium has a slow rate of mutation, and this fact has enabled the development of hypotheses concerning the origins and evolution of Mycobacterium tuberculosis. There is some inferential reasonto suspect that the genus, as represented by Mycobacterium ulcerans, may have existed 150 million years ago in the Jurassic period.1 Gutierrez and her colleagues2 at the Pasteur Institute have concluded that the progenitor of M. tuberculosis emerged from an array of mycobacterial species about 3 million years ago, presumably infecting early hominids and other primates in prehistoric times.

It seems likely that all modern members of the M. tuberculosis complex evolved from a common ancestor 15,000–20,000 years ago.3,4 Mycobaterium bovis and other species in the complex split off from the central line at later times. Figure 1.1 presents the phylogenetic tree developed by Gutierrez and her colleagues. The hypothesized genome of the common progenitor more closely resembles M. tuberculosis than other mycobacterial species. Thus it is presented as a straight line from the hypothesized progenitor in Fig. 1.1. 

Genus Mycobacterium

Mycobacterium Tuberculosis

The positionin time of the common progenitor implies that whatever diversity had occurred during preceding millennia became severely constricted before giving rise to modern species. Present-day TB is caused by six or seven clades – strains with common ancestors – of M. tuberculosis, which have separate geographic origins.5–7 Dating methods applied to members of two of these strains suggest that they emerged in their present form between 250 and 1,000 years ago.6 The earliest archaeological evidence of human TB comes from Egyptian art and mummies; there is ample evidence of spinal TB (Pott’s disease) as early as 5,500 years ago.8–10 While early workers attributed these infections to M. bovis, there is now good evidencefrom studies of amplified DNA recovered from mummies that M. tuberculosis was the cause of disease in ancient Egyptians.11,12

There are unequivocal references to TB in the Old Testament books of Deuteronomy and Leviticus at the time when Jews were in exile in Egypt.13 In fact, although the archaeological record issparse or non-existent, there is reason to believe that TB was widespread, if not uniformly distributed, in Africa long before Arabians and Europeans entered the continent.14 There is general agreement that TB first appeared as a human disease in East Central Africa and that it travelled with early peoples as they migrated into Asia Minor and across the globe. There are imprecise prehistoric references to TB from India and China, but no archaeological evidence.15 Migrating early peoples reached the Americas across the land bridge connecting Siberia and Alaska and along its coast, perhaps in several waves, reaching as far south as Chile by 15,000 years ago. Tuberculosis was common in a number of western hemisphere locations before the arrival of Columbus and the Spanish conquistadores.16 As in Egypt, Andean mummies have yielded mycobacterial DNA. In both Africa and the Americas the TB epidemic wave seems to have crested and receded at early times, leaving naive populations susceptible to the reintroduction of TB by European colonizers.