Immunology

The immune system's role in the development of tuberculosis is complicated, and part of that role still remains obscure. The complexity of the role has made it difficult to determine the extent to which antibodies protect the body against active disease and to what extent they cause it. Individual resistance to tuberculosis undergoes marked fluctuations: Quiescent infections often flare up under conditions that depress resistance, only to be suppressed when resistance is recovered. Acquired resistance to the tubercle bacillus confers no stable and durable protection as it does in diseases such as measles and smallpox, and can, to the contrary, make the development of active disease even more likely.

The efficacy of immunization against tuberculosis is still debated. Antituberculosis vaccination usually consists of administering the famous strain BCG (bacillus Calmette-Guerin), an attenuated form of the bovine bacillus first isolated in 1921 by the French bacteriologists A. Calmette and C. Guerin after years of laboratory cultivation. Clinical tests and epidemiological evidence indicate that it offers some degree of immunity when the recipient has not been infected before.

History Antiquity

Archaeological evidence indicates that tuberculosis afflicted prehistoric men and women in Eurasia and Africa at least from the Neolithic period. Stone Age skeletons with lesions apparently caused by tuberculosis of the spine have been unearthed in Britain and

Germany, and spinal tuberculosis has been found in numerous Egyptian mummies dating from the third millennium before Christ. In China, a woman's mummified body dating from the early Han dynasty (206 B.C. - A.D. 7) clearly displays tuberculosis scars on her lungs. Trade and migration patterns ensured the dissemination of China's chronic diseases throughout East Asia during the first three centuries of the present era. Skeletal evidence strongly suggests that native Americans suffered from the disease as early as 800 B.C., and pulmonary lesions that contain acid-fast bacilli dating from A.D. 290 have been discovered in Chilean mummies.

This physical evidence suggests two important points concerning the prehistory of tuberculosis. First, the disease quite possibly evolved together with humans from the earliest of times. Some specialists have presented the view that tuberculosis was originally limited to animals and first affected humans only after people started to domesticate cattle and other beasts. Others have contested this view, asserting that in the case of such a chronic disease, no animal intermediary is necessary to maintain viable bacilli even in relatively small populations. The second point is that tuberculosis afflicted most people worldwide from prehistoric times, save for small numbers of peoples, such as the Maori, who lived in isolation for centuries. Because of this, most epidemics of the disease resulted not from the introduction of foreign pathogens into virgin populations but from changes in the host population and its environment.

Textual sources support these conclusions, although not always with complete clarity because of marked differences in the ways people in different times and cultures have perceived the symptoms and course of tubercular disease. Until the present concept of tuberculosis - as a single disease caused by the tubercle bacillus - emerged during the last decades of the nineteenth century, its various forms were often known by separate names and thought of as different diseases. For example, the pulmonary forms were commonly called phthisis or pulmonary consumption; infections of the lymph glands surrounding the neck were termed scrofula; and those of the skin referred to as lupus vulgaris. This nosological confusion makes identification of the disease from historical texts difficult, and consequently conclusions concerning tuberculosis based on most written sources up to the mid-nineteenth century necessarily engender some skepticism.

Nevertheless, classical Hindu, Babylonian, Assyrian, Chinese, Greek, and Roman sources all describe the signs and symptoms of tuberculosis. Hindu texts dating from 1200 B.C. and perhaps earlier, along with Mesopotamian texts from the seventh century B.C., had established procedures for treating pulmonary tuberculosis and scrofula. The first description of the disease in Chinese may date back to 2700 B.C., and texts from around 400 B.C. clearly describe the symptoms of tuberculosis. The first Greek mention of what probably was tuberculosis is that of Homer, about 800 B.C. Hippocratic writings from approximately 400 B.C. discuss phthisis, the Greek term for consumption, which they attributed to the effects of evil airs. Phthisis then became the standard European term that signified a cluster of symptoms akin to and including those of pulmonary tuberculosis. Other Greek and Roman writers of both medical and nonmedical texts use the term extensively, including Galen, who during the second century of the Christian era recommended a change of climate as therapy for consumption. René and Jean Dubos, in their classic study of tuberculosis, The White Plague (1952), note that the ancient cultures that described the signs and symptoms of the disease were primarily urban, whereas pastoral cultures make scarce mention of the disease. Biblical literature, for example, makes scant reference to it.

Medieval Period

Medieval Europeans suffered considerably from tuberculosis, although contemporary documents mention it more often in its glandular form rather than its pulmonary form - that is, as scrofula or tuberculosis. This was because of the custom of the "king's touch," in which kings of France and England were believed to have the power to cure scrofula simply by touching its victims. The custom originated in the twelfth century and continued through the eighteenth to its demise along with the divine right of kings at the end of that century.

Chinese medical texts that provide the most detailed treatments of the disease were written during the Sui (581-617) and Tang (618-907) dynasties. Japanese physicians appropriated the Chinese texts, and with their aid clearly described the symptoms of tubercular diseases in their own country. By the twelfth century, Chinese Taoist priests had attributed phthisis both to infection by evil airs (qi) and to animalculae, which attacked a physically or mentally exhausted individual. The disease was said to pass through six stages in which these animalculae underwent a series of metamorphoses and in the last stage became highly infectious. In positing this systematic germ theory of tuberculosis, the Chinese anticipated Western medical theorizing by two centuries. In the first half of the sixteenth century, Girolamo Fracastoro, better know as Fracastorius, became the first Western physician to propose such a theory. Unlike the Chinese theory, however, Fra-castorius's was not limited to phthisis, which he believed was only one of many diseases caused by the spread of animalculae.

Sixteenth Through Eighteenth Century

During the sixteenth century, mortality from tuberculosis increased noticeably in countries with growing urban populations. In England, for example, it caused about 20 percent of all deaths at midcentury, with the greatest concentrations of the disease found in London. A similar phenomenon occurred in Japan at nearly the same time: Contemporary observers remarked that phthisis had become widespread in the rapidly growing administrative capital of Edo at the beginning of the seventeenth century. It was during the eighteenth century, however, that the world's great epidemics of tuberculosis began, and they were well underway by the beginning of the following century. The nations that suffered most severely from tuberculosis at this time also were experiencing intense urbanization and industrialization. Thus physicians and other writers reported that phthisis was common in the cities of England, the United States, Italy, and France.

Autopsies showed that close to 100 percent of some urban populations, such as those of London, Paris, and other major industrial cities, had at some point in their lives developed the disease, although they had died of some other cause. Rates of mortality from tuberculosis in most major American cities during the early nineteenth century ranged from 400 to 500 per 100,000 of population, and in Philadelphia (1811-20) they reached 618. Women workers in textile industries generally led other groups in tuberculosis mortality in every country where modern textile factories were appearing. When statistics for tuberculosis mortality became available for most industrial countries of western Europe and the United States after 1860, they showed that its epidemics were declining. In the developing countries of the time, however, including most eastern European nations and Japan, tuberculosis epidemics were just starting at the end of the nineteenth century.

Increasing attention was given to tuberculosis by European physicians beginning with the seventeenth century, in part because of major changes in medical theory and in part because of growing mortality from phthisis and scrofula. In 1685 Richard

Morton became the first Western physician to publish a single text on phthisis, a term which he used to embrace a number of wasting diseases, including pulmonary consumption and scrofula. Morton depended on traditional humoral theory to describe the etiology of phthisis. By the eighteenth century, however, physicians were redefining their concepts of diseases, and searching for new explanations for their causes. As a result, the nineteenth century became a period of intense research into and speculation about tubercular diseases. In Europe and especially in the United States, physicians and laypersons alike looked for elements in both life-style and environment that made a person "susceptible" to it. Among those "elements" were dissolute and immoral living, alcohol and tobacco consumption, along with various developmental crises in the host's physical well-being such as puberty or childbirth. In addition, damp soil and filth in general could make an individual susceptible to consumption. Others, however, believed that pulmonary consumption was a hereditary affliction - a belief that became a powerful social stigma in much of the world. Indeed, throughout much of the nineteenth century, popular (and some medical) concepts of tuberculosis resonated with the notion that the disease expressed a person's inherent nature as opposed to just being something that one had. In fact, those considered susceptible to tuberculosis were said to have a phthisical diathesis.

Nineteenth Through Twentieth Century

Theories of Etiology. A major break with previous theories of tubercular diseases occurred at the beginning of the nineteenth century, which initiated a process that had transformed their classification by the 1880s, especially among European medical scientists. From the early 1800s, the French clinical school analyzed pathological phenomena by comparing the course of disease observed at the bedside with autopsy observations. René Théophile Hyacinthe Laennec, a leading physician of this school, postulated the theory that all tubercular phenomena, including phthisis, scrofula, and miliary tubercles, in fact constituted a single disease.

German physicians of the "physiological" school, who opposed the "ontological" view of diseases, which posits clearly definable entities for which distinct species can be established, vigorously attacked Laennec's theory of tuberculosis. A leading theoretician of German "physiological medicine," Karl Wunderlich, asserted that it was impossible to draw a distinct line between, for example, dysentery and enteric diarrhea. Wunderlich thought of disease names only as conveniences, not as linguistic symbols for specific entities. In his views of tuberculosis, Wunderlich echoed the ideas of his contemporary, Rudolph Virchow. Virchow, in many respects one of the greatest medical theoreticians of the nineteenth century, also repudiated the ontological theory of diseases, including Laennec's idea that all tubercular phenomena manifested a single, specific disease. Rather, he divided tubercular manifestations into the two separate categories of inflammatory and neoplastic phenomena, and thought that some forms fundamentally resembled cancer. Virchow considered the important difference between diseases not to be one of cause but of pathological processes within individual cells.

Despite Virchow's views, however, the tradition of combining clinical and pathological investigations continued in France, most notably in the work of Jean-Antoine Villemin, who followed Laennec in saying that tuberculosis was a specific disease caused by a specific agent, but went one step beyond him by demonstrating in practice what Laennec had postulated in theory. In 1865 Villemin caused tuberculosis in rabbits by injecting them with matter from human tubercles. Although this work had a negligible impact on German ideas concerning tuberculosis, the notion that it was a specific disease was provided an unshakable scientific foundation in the work of the Prussian bacteriologist Robert Koch.

Using the clearly defined bacteriologic methods he had developed, Koch proved in 1882 that it was possible to give animals tuberculosis by inoculating them with bacteria - and not simply tubercular matter - that he had isolated from human tubercles. Although a number of problems in the identification of tuberculosis remained (such as the identity of scrofula, which some still maintained was a separate disease), the discovery of the tubercle bacillus finally established tuberculosis as a single disease clearly distinguishable by a single cause. It is true that for several more years, some circles, particularly the group led by Virchow, disputed Koch's methods and conclusions. Nonetheless his discovery of the tubercle bacillus changed the way not only members of the medical profession thought about tuberculosis but also how most people viewed the disease: No longer was it the result of an inherent susceptibility but, rather, something that one "had."

Early Attempts at Prevention. Koch's discovery had little effect on attempts to treat tuberculosis, but it had important implications for prophylaxis. Observers attempting to establish the most important routes of infection concluded that dry tubercle bacilli in dried sputum presented the greatest threat. To prevent the disease, they recommended the general removal of dust from all public and private places, restrictions on spitting and the use of spittoons in all places, and the disinfection or destruction of the belongings and surroundings of tuberculosis victims. In some places, such procedures were already "on the books," because many national and local governments had passed laws specifying some or all of them. It was not until the 1930s that researchers demonstrated that, in most cases, infection was the result of airborne infection and that dried sputum or other forms of contact with the bacillus played little role in the transmission of the disease.

Early Treatment. The primary interest of most practicing physicians at this time, however, was not in ascertaining the etiology of tuberculosis but, rather, in treating the disease. The many hundreds of thousands of tuberculosis victims worldwide were desperate to be cured, and created an unbounded demand for remedies, making equally large opportunities for both physicians and quacks - although by today's standards it is often difficult to separate the two. Some of the most popular cures for tuberculosis that physicians advocated during the nineteenth century included creosote, carbolic acid solutions, gold, iodoform, arsenic, and menthol oil; at various times all were administered orally, inhaled, or injected directly into the lungs. More unusual treatments ranged from drinking papaya juice to enemas of sulfur gases. Starting during the late nineteenth century and continuing well into the twentieth, physicians practiced surgical therapies, including pneumothorax, or collapsed-lung treatments, and the surgical removal of ribs with the objective of reducing the size of the thoracic cavity.

Advances in Diagnosis. It was the search for a remedy, rather than his discovery of the tubercle bacillus, that brought Koch international fame. In 1890, at the strong urging of Kaiser Wilhelm II's government, he announced that he had discovered a cure for tuberculosis, which attracted hundreds of scientists and thousands of the afflicted to his laboratory in Berlin. Within a year, however, many were questioning the efficacy of "Koch's lymph" (a glycerol-based extract from the tubercle bacillus). As a cure it was not effective; in fact, it proved harmful in advanced cases. On the other hand, it soon became the extremely impor tant diagnostic tool better known as tuberculin and the primary means of determining infection by the tubercle bacillus.

Along with the discoveries of the tubercle bacillus and tuberculin, the X-ray, discovered in 1895, helped change the way in which both physicians and laypersons thought about tuberculosis. It made visible to the eye lesions in the lungs and other parts of the body caused by the disease long before its symptoms became noticeable, allowing physicians to start treatment at a much earlier stage in the disease. Although they did not become a dependable diagnostic tool until the end of the second decade of the twentieth century, X-ray photographs together with tuberculin became the basic tools of the mass screening programs that governments and antituberculosis associations implemented from the 1920s to the 1950s.

Later Therapies and Prevention. As diagnostic techniques improved but medicinal cures remained ineffective, therapies based on climate and regimen became increasingly popular. Hippocrates had first recommended a change of climate as a treatment for phthisis, and from the seventeenth century onward physicians in both the West and the East continued to recommend healthful climates and life-styles as consumption cures. From the mid-nineteenth century, open-air and rest therapies became increasingly popular throughout Europe and the United States, and as an extension of rest therapy, pneumothorax, or the collapsing of a heavily diseased lung so that it could "rest," became popular in the late 1800s and remained common in many countries until the 1940s. The systematic integration of these therapies with other forms of treatment culminated in the sanitorium. From the 1880s, luxury sanitoria for the wealthy, like the one in Davos, Switzerland (immortalized in Thomas Mann's The Magic Mountain), drew patients from around the world. And about 1900, state-sponsored sanitoria began to appear throughout western Europe, North America, and Japan.

Where sanitoria were not feasible, such as in inner cities, public health bureaucrats and physicians developed alternatives that offered open-air treatment for the diseased as well as preventive regimens for those who seemed susceptible.

Many sanitoria and prevention programs were sponsored or managed by private or semiprivate antituberculosis organizations. These had been established in most of western Europe and North America from the 1890s, and in much of the rest of the world during the first two decades of the twenti eth century. Such organizations also supported educational programs, which became a mainstay of tuberculosis control movements. Their purpose was to inform the public of the ways in which the disease was transmitted and developed, and to encourage people to secure frequent checkups and early treatment if they were infected. The most commonly afflicted groups, however - factory laborers, other industrial workers, and the urban poor - rarely had the necessary resources to secure treatment for the disease even if they received an early diagnosis.

Mortality and Incidence. Understandably, medical scientists, public health bureaucrats, and workers in such prevention movements where rates of mortality from tuberculosis declined dramatically from the late nineteenth century onward concluded that the decline was the direct result of their efforts. This was especially the case in Great Britain, Germany, and the United States. Yet the experience of others contradicted such claims. During the first four decades of the twentieth century, the Japanese, for example, implemented almost all the tuberculosis control measures that Western countries had developed, including extensive legislation aimed at the control of tuberculosis, state-sponsored sanitoria in the major urban centers, intensive education programs, and government-administered mass screenings and BCG immunizations. Throughout the first three decades of this period, however, Japan's rates of mortality from tuberculosis hovered at around 200 per 100,000, and then actually increased from the early 1930s. It was not until the late 1940s that the rates of tuberculosis mortality began a sustained fall. In the case of Japan, the prevention movement was much less important than later improvements in living standards and working conditions and even later government intervention with nationwide treatment programs using streptomycin, PAS, and, after 1952, isoniazid.

Since the 1950s, the countries with the highest tuberculosis mortality rates have been those with low standards of living, poor working conditions, and inadequate treatment programs. Medicine has learned that the mere availability of specifics against tuberculosis is not enough to stem the disease; their administration must be coordinated with reforms that raise living standards and improve working conditions, or the incidence of the disease will remain inordinately high. During the early 1970s, over 20 nations worldwide - all of them developing countries - had new case rates for tuberculosis of over 150 per 100,000 per year; Macau (in 1973),

Swaziland (in 1970), and Bolivia (in 1972) all had incidence rates of over 400.

Thus although the leaders of antituberculosis movements long spoke of eradicating the disease, it remains a major health problem in many countries, and serves as an index of social conditions worldwide. Even in developed, industrial countries, when social conditions deteriorate, the incidence of tuberculosis rises quickly. Clearly, the disease remains far from eradicated in the developing world. But even in the developed world, tuberculosis retains the potential of becoming a significant health problem during times of economic depression, war, and social unrest.

William D. Johnston

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