Introduction and Historical Perspektive

Introduction and Historical Perspektive - Considering the centuries during which TB has been afflicting humanity, awareness that the disease is the result of a transmissible airborne infection is surprisingly recent. Although scientists such as Aristotle and his contemporaries believed that TB was contagious, they had no understanding of what caused it or exactly how it was spread. During the Middle Ages through to the seventeenth century, clinical practice and societal laws in Europe attested to the fact that the contagiousness of TB was suspected, if imperfectly understood.

Tuberculosis

M. Tuberculosis

In Italy and Spain, cases of TB had to be reported to city authorities, and, when a patient with TB died, his personal belongings were burned in order to eradicate any traces of the disease that might spread to others. Moreover, physicians of the time, such as Valsalva and Morgagni, refused to perform autopsies on victims of TB, concerned that the procedure would spread the disease, as indeed

it does.1 In the seventeenth century, however, a contrary view began to emerge. Eminent scientists and clinicians in Europe started to question whether TB was really transmissible. As proof, they offered observations that many healthcare workers who came into contact with TB patients did not themselves acquire the disease. Under situations ideal for transmission, they reasoned, how could TB possibly be considered a transmissible disease? Instead, noting the clustering of cases within families, they concluded that infection with TB was probably a hereditary phenomenon.1 Given the long latency periods that routinely occur between exposure and disease development, firm conclusions about transmissibility were understandably elusive. By 1910, decades after Koch discovered the tubercle bacillus, Chapin, in his influential book The Sources and Modes of Infection argued against the airborne mode of transmission of any organism:

Bacteriology teaches that former ideas in regard to the manner in which diseases may be airborne are entirely erroneous; that most diseases are not likely to be dust-borne, and they are spray-borne for only 2 or 3 feet, a phenomenon which after all resembles contact infection more than it does aerial infection as ordinarily understood Chapin did concede that, if any infection was airborne, it would likely be TB. But, in Thomas Mann’s 1927 novel The Magic Mountain, visitors to the fictitious alpine sanatorium lived with patients for weeks at a time with no apparent fear of contagion.3 As recently as 1932, Fishberg wrote that it was not risky for ‘healthy adults to be coughed at by patients suffering from pulmonary or laryngeal tuberculosis’.4 The partial immunity acquired by infection early in life undoubtedly contributed to the misleading observation thatmany of those exposed did not develop disease. By 1947, the American Public Health Association (APHA) stated that ‘conclusive evidence is not available at present that the airborne mode of transmission is predominant for any particular disease’.5 Instead, it was postulated that TB might be spread by direct contact with infected sputum. Public health campaigns to discourage spitting were a logical consequence. 

The prevailing perception through the early 1900s, therefore, was that the airborne spread of TB beyond the immediate proximity of the source was unlikely. Yet even as many in the medical, public health, and scientific communities accepted Chapin’s view on airborne transmission, other researchers were working to better understand the propagation of infections, including TB. It was not until the late 1950s, however, a full decade after the APHA’s conclusion, cited above, that the tide of

scientific opinion once again turned on this matter. Among the landmark investigations in this areawere those ofWilliam FirthWells,who while working as a sanitary engineer at Harvard University first conceptualized how certain infectious agents such as measles and TB might become airborne and travel from person to person.

In his seminal 1934 paper entitled ‘On air-borne infections. II. Droplets and droplet nuclei’, Wells introduced the notion that transmissible infections fell into two major categories: those spread by local, direct, person-to-person contact and those spread more widely without direct contact by the airborne route.6 In 1931 Wells had developed an air centrifuge, a device that allowed him to concentrate airborne microorganisms from air samples. He had been commissioned by the Massachusetts Department of Health to investigate the aetiology of respiratory infections among textile mill workers. He speculated that the source of these infections was bacteria from contaminated standing water that had been aerosolized to keep dust down in the mill. Using his air sampler, he identified the same organisms in the air and in the standing water.7

The next intellectual leap was to theorize that aerosols produced by coughing and sneezing could also be responsible for person-to-person airborne transmission. He was assisted in this investigation by then Harvard medical student Richard Riley, with whom he shared credit for making the distinction between ordinary large respiratory droplets and so-called droplet nuclei – the dried residua of larger respiratory droplets. He ultimately published a comprehensive exposition of his theories and observations in his now classic 1955 text ‘Airborne contagion and air hygiene’, much of which remains valid to this day.8 Riley later updated and summarized this work in his 1961 monograph Airborne Infection and Control.

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.