The Forgotten Plague:

How the War against Tuberculosis was Won - and Lost

Frank Ryan, 1992

Tuberculosis (TB) has a long history. It was present before the beginning of recorded history and has left its mark on human creativity, music, art, and literature; and has influenced the advance of biomedical sciences and healthcare. Its causative agent, Mycobacterium tuberculosis, may have killed more persons than any other microbial pathogen (Daniel 2006).

It is presumed that the genus Mycobacterium originated more than 150 million years ago (Daniel 2006). An early progenitor of M. tuberculosis was probably contemporaneous and co-evolved with early hominids in East Africa, three million years ago. The modern members of M. tuberculosis complex seem to have originated from a common progenitor about 15,000 - 35,000 years ago (Gutierrez 2005).

TB was documented in Egypt, India, and China as early as 5,000, 3,300, and 2,300 years ago, respectively (Daniel 2006). Typical skeletal abnormalities, including Pott's deformities, were found in Egyptian and Andean mummies (Figure 1-1) and were also depicted in early Egyptian and pre-colombian art (Figure 1-2).

Figure 1-1: Left: Mummy 003, Museo Arqueológico de la Casa del Marqués de San Jorge, Bogota, Colombia. Right: Computerized tomography showing lesions in the vertebral bodies of T10/T11 (reproduced from Sotomayor 2004 with permission).

Figure 1-2: Representation of a woman with pronounced gibbus (Pott's disease?). Momil culture, 200 BC to 100 AD, Sinú River, Colombia (reproduced from Sotomayor 1992, with permission).

Identification of genetic material from M. tuberculosis in ancient tissues has provided a powerful tool for the investigation of the incidence and spread of human TB in historic periods. It also offers potential new insights into the molecular evolution and global distribution of these microbes (see Chapter 2). Research on ancient DNA poses extreme technical difficulties because of the minute amounts of DNA remains, their oxidation/hydrolysis, and the extremely high risk of contamination with modern DNA. For this reason, stringent criteria of authenticity for analysis of ancient DNA were recently proposed, among them: work in physically isolated areas, strict protocols to prevent contamination with modern DNA, the use of negative controls, evaluation of reproducibility in different laboratories, cloning and sequencing, and the study of associated remains (Coper 2002).

Mycobacteria are assumed to be better preserved than other bacteria due to the resistant lipid-rich cell wall and the high proportion of guanine and cytosine in their DNA, which increases its stability. M. tuberculosis are found only in the tissues of an infected host, and the characteristic pathology induced by this strictly mammalian pathogen tends to show residual microbial DNA contained in localized lesions. These bacteria are, therefore, ideal microorganisms for studying ancient DNA and were the first to be pursued. These investigations have answered important questions. They proved that TB is an ancient disease with a wide geographical distribution. The disease was widespread in Egypt and Rome (Zink 2003, Donoghue 2004); it existed in America before Columbus (Salo 1994, Konomi 2002, Sotomayor 2004), and in Borneo before any European contact (Donoghue 2004). The earliest DNA-based documentation of the presence of M. tuberculosis complex organisms was accomplished in a subchondral articular surface from an extinct long-horned Pleistocene bison from Wyoming, USA, which was radiocarbon-dated at 17,870 +/- 230 years before the present (Rothschild 2001).

Another important achievement of the studies on ancient DNA was the confirmation of the TB diagnosis in human remains that showed the typical pathology. Mycobacterial DNA was detected in bone lesions in the spine of a male human skeleton from the Iron Age (400-230 BC), found in Dorset, United Kingdom (Taylor 2005); skin samples from the pelvic region of Andean mummies, carbon-dated from 140 to 1,200 AD (Konomi 2002); and calcified pleura from 1,400 year-old remains, found in a Byzantine basilica in the Negev desert (Donoghue 1998). DNA techniques have also shown the presence of mycobacterial DNA, at a lower frequency, in bones with no pathological changes, suggesting either dissemination of the TB bacilli immediately prior to death or chronic milliary TB (Zink 2003).

Molecular methods other than PCR have also been used to demonstrate the presence of the TB bacillus in ancient remains, including mycolic acid analysis by high performance liquid chromatography (HPLC), which is used for authentication of positive PCR findings in calcified pleura remains (Donoghue 1998). Spoligotyping is a PCR-based technique used for identification and typing of M. tuberculosis complex bacteria (see chapter 9). It is a valuable tool for the study of archeological material, especially when the DNA is highly fragmented, because fragments as small as 55-60 bp long are sufficient to provide a positive result (Donoghue 2004). Spoligotyping was the method used to study the Plesitocene remains of a bison (Rothschild 2001) and was also applied to a subculture of the original tubercle bacillus isolated by Robert Koch, confirming its species identification as M. tuberculosis rather than Mycobacterium bovis (Taylor 2003).

Caelius Aurelianus, 5th century AD (Herzog 1998)

The term phthisis (meaning consumption, to waste away) appeared first in Greek literature. Around 460 BC, Hippocrates identified phthisis as the most widespread disease of the times. It most commonly occurred between 18 and 35 years of age, and was almost always fatal. He even warned physicians against visiting consumptives in advanced stages of the disease, to preserve their reputation! Although Aristotle (384-322 BC) considered the disease to be contagious, most Greek authors believed it to be hereditary, and a result, at least in part, of the individual's mental and moral weaknesses. Clarissimus Galen (131-201 AD), the most eminent Greek physician after Hippocrates, defined phthisis as an ulceration of the lungs, chest or throat, accompanied by coughs, low fever, and wasting away of the body because of pus. He also described it as a disease of malnutrition (Pease 1940).

The initial tentative efforts to cure the disease were based on trial and error, and were uniformly ineffective. Heliotherapy was advocated as early as the 5^th century AD by Caelius Aurelianus. Roman physicians recommended bathing in human urine, eating wolf livers, and drinking elephant blood. In the Middle Ages, it was believed that the touch of the sovereigns of England and France had the power to cure sufferers of the King's Evil or scrofula (scrophula or struma) - the swellings of the lymph nodes of the neck, frequently related to TB. Depending upon the time and country in which they lived, patients were urged to rest or to exercise, to eat or to abstain from food, to travel to the mountains or to live underground.

The life and death of Mr. Badman, presented to the world in
a familiar dialogue between Mr. Wiseman and Mr. Attentive

John Bunyan, 1680

The TB epidemic in Europe, later known as the "Great White Plague", probably started at the beginning of the 17^th century and continued for the next 200 years. Death from TB was considered inevitable and, by 1650, TB was the leading cause of mortality. The high population density and poor sanitary conditions that characterized the enlarging cities of Europe and North America at the time, provided the necessary environment, not met before in world history, for the spread of this airborne pathogen. The epidemic spread slowly overseas by exploration and colonization.

TB existed in America before Columbus' arrival but was rare among the natives. The major outbreaks of TB among the native people of North America began in 1880, after they were settled in reservations or forced to live in barracks in prison camps. Death rates increased rapidly, and by 1886, reached 9,000 per 100,000 people (Bates 1993).

TB was also rare among Africans who lived in small remote villages. When exposed to the disease by contact with Europeans, these populations experienced a high mortality rate. Africans taken as slaves were free from TB on arrival to the Americas. Then, cases of sub-acute fatal TB developed among them. After their liberation from slavery and movement into the cities, TB morbidity and mortality rose quickly, reaching 700 per 100,000 in 1912 (Bates 1993).

There is also evidence of the presence of the disease in pre-historic Asia, but it was only toward the end of the 19^th century that peaks in incidence were observed in India and China.

In the 18^th century, TB was sometimes regarded as vampirism. These folk beliefs originated from two observations: firstly, following the death from consumption of a family member, household contacts would lose their health slowly. This was attributed to the deeds of the recently deceased consumptive, who returned from the dead as a vampire to drain the life from the surviving relatives. Secondly, people who had TB exhibited symptoms similar to what people considered to be vampire traits, such as red, swollen eyes, sensitivity to bright light, pale skin, and a blood-producing cough. They "waste away" and "lose flesh" and at the same time remain active, and conserve a fierce will to live. This dichotomy of lust and "wasting away" was reflected in the vampires' desire for "food", which forced them to feed off living relatives, who, in turn, suffered a similar wasting away (Sledzik 1994).

Precise pathological and anatomical descriptions of the disease began to appear in the 17^th century. Franciscus Sylvius de la Böe of Amsterdam (1614-1672) was the first to identify the presence of actual tubercles as a consistent and characteristic change in the lungs and other areas of consumptive patients. In his Opera Medica, published in 1679, he also described the progression of the lesions from tubercles to ulcers and cavities. The Latin word tuber means all kinds of degenerative protuberances or tubercles.

The English physician Richard Morton (1637-1698) confirmed that tubercles were always present in TB of the lungs. He believed that the disease had three stages: inflammation (tubercle formation), ulceration, and phthisis. Both Sylvius de la Böe and Morton regarded the disease as hereditary, although Morton did not rule out transmission by intimate contact.

Gaspard Laurent Bayle (1774-1816) definitely proved that tubercles were not products, or results, but the very cause of the illness. The name 'tuberculosis' appeared in the medical language at that time in connection with Bayle's theory. More precisely, the name 'tuberculosis' was coined in 1839 by the German professor of Medicine Johann Lukas Schönlein (1793-1864), to describe diseases with tubercles; but he considered scrofula and phthisis to be separate entities. These ideas were also acknowledged by Giovanne Battista Morgagni in Padua (1682-1771) and Rudolf Virchow in Berlin (1821-1902) (Herzog 1998). In contrast, René Théophile Hyacinthe Laënnec (1781-1826) from Paris, inventor of the stethoscope, and the Viennese Karl von Rokitansky (1804-1878) emphasized the unitary nature of both conditions.

The earliest references to the infectious nature of TB appeared in 17^th century Italian medical literature. An edict issued by the Republic of Lucca in 1699 stated that, "… henceforth, human health should no longer be endangered by objects remaining after the death of a consumptive. The names of the deceased should be reported to the authorities and measures undertaken for disinfection" (Herzog 1998).

The Forgotten Plague: How the War against Tuberculosis was Won - and Lost

Frank Ryan, 1992

The book De Morbus Contagiosus, written in 1546 by Girolamo Fracastoro (1478-1553), explained the contagious nature of TB. He pointed out that bed sheets and clothing could contain contagious particles that were able to survive for up to two years. The word "particles" may have alluded to chemicals rather than to any kind of living entity.

In his publication A New Theory of Consumptions, in 1720, the English physician Benjamin Marten (1704-1722) was the first to conjecture that TB could be caused by "minute living creatures", which, once they had gained entry to the body, could generate the lesions and symptoms of phthisis. He further stated, that consumption may be caught by a sound person by lying in the same bed, eating and drinking or by talking together so close to each other as to "draw in part of the breath a consumptive patient emits from the lungs".

In 1865, the French military doctor Jean-Antoine Villemin (1827-1892) demonstrated that consumption could be passed from humans to cattle, and from cattle to rabbits. On the basis of this revolutionary evidence, he postulated that a specific microorganism caused the disease. At this time William Budd (1811-1880) also concluded from his epidemiological studies that TB was spread through society by specific germs.

On the evening of March 24, 1882, in Berlin, before a skeptical audience composed of Germany's most prominent men of science from the Physiological Society, Robert Koch (1843-1910)made his famous presentation Die Aetiologie der Tuberculose. Using solid media made of potato and agar, Koch invented new methods of obtaining pure cultures of bacteria. His colleague Julius Richard Petri (1852-1921) developed special flat dishes (Petri dishes), which are still in common use, to keep the cultures. Koch also developed new methods for staining bacteria, based on methylene blue, a dye developed by Paul Ehrlich (1854-1915), and counterstained with vesuvin. "Under the microscope the structures of the animal tissues, such as the nucleus and its breakdown products are brown, while the tubercle bacteria are a beautiful blue", he wrote in the paper that followed his dramatic presentation that March evening (Koch 1882).

He had brought his entire laboratory with him: his microscopes, test tubes, small flasks with cultures, and slides of human and animal tissues preserved in alcohol. Showing the presence of the bacillus was not enough. He wanted his audience to note that bacteria were always present in TB infections and could be grown on solidified serum slants, first appearing to the naked eye in the second week. Then, he showed that, by inoculating guinea pigs with tuberculous material obtained from lungs, intestines, scrofula or brains of people and cattle that have died from TB, the disease that developed was the same, and cultures obtained from the experimental animals were identical on the serum slopes. Koch continued his speech, proving that whatever the dose and/or route he used, no matter what animal species he inoculated, the results were always the same. The animals subsequently developed the typical features of TB. He concluded saying that "…the bacilli present in tuberculous lesions do not only accompany tuberculosis, but rather cause it. These bacilli are the true agents of tuberculosis" (Kaufmann 2005).

Koch fulfilled the major prerequisites for defining a contagious disease that had, in fact, been proposed by his former mentor Jacob Henle (1809-1885). The reknowned Koch's postulates (or Henle-Koch postulates) were then formulated by Robert Koch and Friedrich Loeffler (1852-1915) in 1884, and finally polished and published by Koch in 1890. The postulates consist of four criteria designed to establish a causal relationship between a causative microbe and a disease:

• The organism must be found in all animals suffering from the disease, but not in healthy animals
• The organism must be isolated from a diseased animal and grown in pure culture
• The cultured organism should cause disease when introduced into a healthy animal
• The organism must be re-isolated from the experimentally infected animal.

In 1890, at the 10^th International Congress of Medicine held in Berlin, Koch announced a compound that inhibited the growth of tubercle bacilli in guinea pigs when given both pre- and post-exposure. It was called 'tuberculin' and was prepared from glycerol extracts of liquid cultures of tubercle bacilli. Clinical trials using tuberculin as a therapeutic vaccine were soon initiated. The results were published in 1891 and revealed that only few persons were cured, at a rate not different from that of untreated patients. But, although results for treatment were disappointing, tuberculin was proven valuable for the diagnosis of TB (Kaufmann 2005).

The Magic Mountain [Der Zauberberg]

Thomas Mann, 1924

Translated from the German by H. T. Lowe-Porter, 1953

Dialogue between Hans Castorp and consul Tienappel

Sanatoria, increasingly found at that time throughout Europe and the US, provided a dual function. Firstly, they protected the general population by isolating the sick persons, who were the source of infection. Secondly, they offered TB patients bed-rest, exercise, fresh-air, and good nutrition, all of which assisted the healing process. Many of them improved and returned to "life in the flatland"; many did not. The TB specialist, the phthisiologist, was responsible for the complete physical and mental care of the patient and the separation of TB care from the practicing clinician became commonplace.

Architectural features were essential to early sanatorium design (Figure 1-3). These included deep verandas, balconies, covered corridors, and garden shelters, furnished with reclining couches for the "Cure", the obligatory two-hour period of rest in the open air that was frequently observed in silence (Figure 1-4). Furniture for TB patients had to be robust, able to be thoroughly cleaned and disinfected, and shaped with a concern for the patient's anthropometric needs.

Figure 1-3: Sanatorio Pineta del Carso, Trieste, Italy.

Figure 1-4: Sanatorio Pineta del Carso. Bed-rest, fresh air and good nutrition were the hallmarks of sanatorium cure.

During the early '60s, many sanatoria started to close. By the middle of that decade only a few beds remained available for patients suffering from TB. Yet, the real end of the TB sanatorium began even earlier, when the depressing era of helplessness in the face of advanced TB was substituted by active therapy.

The Italian physician Carlo Forlanini (1847-1918) discovered that the collapse of the affected lung tended to have a favorable impact on the outcome of the disease. He proposed to reduce the lung volume by artificial pneumothorax and surgery, methods that were applied worldwide after 1913. These and other initial therapies are now considered dangerous and, at least, controversial:

• Artificial pneumothorax - pleural cavities were filled with gas or filtered air, with the result of splinting and collapsing that lung (Sharpe 1931).
• Bilateral pneumothorax - only parts of the lungs were collapsed in such a way that the patient could still live a relatively normal live. The patient suffered from shortness of breath caused by the reduction in the gas exchange surface.
• Thoracoplasty - ribs from one side of the thorax were removed in order to collapse the infected portion of the lung permanently (Samson 1950).
• Gold Therapy - Holger Mollgaard (1885-1973) from Copenhagen introduced the compound sanocrysin in 1925, which is a double thiosulphate of gold and sodium. He tested the compound on animals and considered it safe for human use. However, it was too toxic even in low doses. A controlled trial, completed in the USA in 1934, proved the toxic effects of gold therapy. Within a year, most European countries had ceased to use it (Bedenek 2004).

Nicholas Nickleby

Charles Dickens, 1870

When, in 1820, the poet John Keats (1795-1821) coughed a spot of bright red blood, he told a friend, "It is arterial blood. I cannot be deceived. That drop of blood is my death warrant. I must die". He died within a year, at just 25 years of age. Keats never wrote specifically about phthisis, but his life and his works became a metaphor that helped transform the physical disease "phthisis" into its spiritual offspring, "consumption".

The central metaphor of consumption in the 19^th century was the idea that the phthisic body is consumed from within by its passions. Spes phthisica (spes - hope + phthisis - consumption) was a condition believed to be peculiar to consumptives in which physical wasting led to a sense of well-being and happiness, an euphoric blossoming of passionate and creative aspects of the soul. While the body expired from phthisis, the prosaic human became poetic and the creative soul could be released from the fevered combustion of the body. The paleness and wasting, the haunted appearance, the burning sunken eyes, the perspiring skin - all hallmarks of the disease - came to represent feminine beauty, romantic passion, and fevered sexuality (Morens 2002).

In the 19^th century, it seemed as if everyone was slowly dying of consumption. The disease became to be viewed in popular terms, first as romantic redemption (Figure 1-5), then as a reflection of societal ills (Figure 1-6) (Morens 2002). In Alexandre Dumas' tale "The Lady of the Camellias", the heroine was a courtesan regenerated by love and made unforgettable by progressive consumption. It was adapted to the theatre and the movies and also inspired Giuseppe Verdi's opera "La Traviata". The plot develops around the consequences of the heroine's scandalous past, which prevents her marriage to an honorable youngster whose father objects to the relationship. Redemption is possible only through death, and, in taking her life, consumption also serves as a vehicle for punishment.

Figure 1-5: Romantic view of TB: "The Lady of the Camellias" represented by Brazilian actress Cacilda Becker under Italian director Luciano Salce, in São Paulo, Brazil (1952).

By 1896, the cause of consumption had been discovered, and TB was definitively linked to poverty and industrial disfigurement, child labor, and sweatshops. A contagious disease and shameful indicator of class, it was no longer easily romanticized in conventional artistic terms. Giacomo Puccini's "La bohème" (1896) portrays TB in a new environment, affecting street artists struggling with poverty and disease (Figure 1-6).

At the end of the 19^th century, the association of TB with poor living conditions and hygiene, brought to life the differentiation and societal repulsion of diseased persons, considered to be responsible for a social wickedness. Unlike the previous image (sick people as victims), they began to be viewed as dangerous, because they were capable of spreading the disease to those who did not share their living conditions. TB was changed from a social disease to an individual one and the patient was at the same time offender and victim of this social ailment.

A list of famous people and celebrities who had, or are believed to have had TB is available on Wikipedia at http://en.wikipedia.org/wiki/List_o f_tuberculosis_victims and at http://en.wikipedia.org/wiki/Tuberculosis_in_history_and_art.

Figure 1-6: Social aspect of TB: Second act of "La bohéme", showing Quartier Latin, with a great crowd on the street and sellers praising their wares.

After the establishment, in the '80s, that the disease was contagious, TB was made a notifiable disease. A further significant advance came in 1895, when Wilhelm Konrad von Röntgen (1845-1923) discovered X-rays. After this, the progress and severity of a patient's disease could be accurately documented and reviewed.

Centralized official and/or non-governmental agencies for coordination and communication were organized and called for conferences specifically focused on TB. At the Central Bureau for the Prevention of Tuberculosis, which was formalized in Berlin in 1902, Dr. Gilbert Sersiron suggested that, as the fight against TB was a crusade, it would be appropriate to adopt the emblem of a crusader, the Duke of Lorraine. Godfrey of Bouillon (1060-1100), Duke of Lorraine, was the first Christian ruler of Jerusalem and his banners bearing the double-barred cross signified courage and success to crusaders. Dr. Sersiron's recommendation was adopted and the double-barred cross became the worldwide symbol of the fight against TB (Figure 1-7).

Figure 1-7: double-barred cross, symbol of anti-tuberculosis crusade

Periodic international conferences systematically addressing clinical, research and sociological aspects of TB were held until the outbreak of World War I in 1914. After the war, in 1920, a conference on TB was held in Paris with participation of delegates from 31 countries, among them Australia, Bolivia, Brazil, Chile, China, Colombia, Cuba, Guatemala, Japan, Panama, Paraguay, Iran and Thailand, in addition to those of Europe and North America, thus establishing the International Union Against Tuberculosis and Lung Disease (IUATLD, http://www.iuatld.org/index_en.phtml) in its present form.

With Edward Jenner's (1749-1823) successful invention, showing that infection with cowpox would give immunity against smallpox in humans, many doctors placed their hopes on the use of M. bovis - the agent that causes bovine TB - for the development of a vaccine against human TB. However M. bovis was equally contagious in humans. From 1908 until 1919, Albert Calmette (1863-1933) and Camille Guérin (1872-1961) in France serially passed a pathogenic strain of M. bovis 230 times, resulting in an attenuated strain called Bacille Calmette-Guérin or BCG, which was avirulent in cattle, horses, rabbits, and guinea pigs. BCG was first administered to humans in 1921 and it is still widely applied today (see chapter 10).

Then, in the middle of World War II, came the final breakthrough, the greatest challenge to the bacterium that had threatened humanity for thousands of years - chemotherapy. In 1943, streptomycin, a compound with antibiotic activity, was purified from Streptomyces griseus by Selman A. Waksman (1888-1973) and his graduate student Albert Shatz (1920-2005) (Shatz 1944a). The drug was active against the TB bacillus in vitro (Schatz 1944b) and following infection of guinea pigs (Feldman 1944). It was administered to a human patient at the end of 1944 (Hinshaw 1944). Two pioneering clinical studies were conducted on the treatment of TB patients with streptomycin, one in Europe and the other in the US (Medical Research Council 1948, Pfuetze 1955). A considerable improvement in the disease was observed in patients on streptomycin therapy, but after the first months, some patients began to deteriorate and these pioneering studies properly interpreted such treatment failure as a consequence of development of resistance to the drug.

In 1943, Jörgen Lehmann (1898-1989) wrote a letter to the managers of a pharmaceutical company, Ferrosan, suggesting the manufacture the para-amino salt of aspirin because it would have anti-tuberculous properties (Ryan 1992). The Swedish chemist based his theory on published information, stressing the avidity of tubercle bacilli to metabolize salicylic acid. He realized that by changing the structure of aspirin very slightly, the new molecule would be taken up by the bacteria in just the same way, but would not work like aspirin and would rather block bacterial respiration. Para-aminosalicylic acid (PAS) was produced and first tested as an oral therapy at the end of 1944. The first patient treated with PAS made a dramatic recovery (Lehmann 1964). The drug proved better than streptomycin, which had nerve toxicity and to which M. tuberculosis could easily develop resistance.

In the late '40s, it was demonstrated that combined treatment with streptomycin and PAS was superior to either drug alone (Daniels 1952). Yet, even with the combination of the two drugs, TB was not defeated. Overall, about 80 % of sufferers from pulmonary TB showed elimination of their germs; but 20 % were not cured, especially those with extensive disease and cavitation (Ryan 1992).

Two further findings were very important for TB treatment. Firstly, between 1944 and 1948, the action of nicotinamide on the TB bacillus was discovered by two different groups, but this discovery was not widely appreciated at the time. Secondly, in 1949, reports stated that the Germans had treated some 7,000 tuberculous patients with a new synthetic drug of the thiosemicarbazone series (Conteben), developed by Gerhard Domagk (1895-1964), the discoverer of the first sulphonamide (McDermott 1969). There is a remarkable similarity between the atomic structures of nicotinamide, Conteben, and PAS. Conteben and PAS both contain a chemical ring of six carbon atoms, the benzene ring, while nicotinamide contains the pyridine ring in which an atom of nitrogen replaces one of the carbon atoms (Fox 1953). Thus, by substituting the benzene ring in thiosemicarbazone by this pyridine ring, a new drug, isoniazid, was developed. By mere coincidence, this was accomplished simultaneously in three pharmaceutical companies - one in Germany (Bayer) and two in the USA (Squibb and Hoffman La Roche). Isoniazid was soon submitted for clinical testing and because of the favorable impact of its administration on disease evolution, the lay press headlines already told the story of the "wonder drug" before any scientific paper was published (Ryan 1992). However, none of the three pharmaceutical companies could patent the new drug, because it had already been synthesized back in 1912 by two Prague chemists, Hans Meyer and Joseph Mally, as a requirement for their doctorates in chemistry. Nevertheless, while clinical studies were still underway, six studies showed that M. tuberculosis readily became resistant to isoniazid (Ryan 1992).

In the view of many doctors in those early stages of chemotherapy, the role for drug therapy was to bring the disease under sufficient control to allow surgeons to operate the diseased organs. John Crofton (1912-), working at the University of Edinburgh, developed a protocol that resulted in a breakthrough in TB treatment and control. With his "Edinburgh method" based on meticulous bacteriology and application of the available chemotherapy, a 100 percent cure rate for TB was a reasonable objective. With the success rate obtained by using three drugs together, (streptomycin, PAS, and isoniazid) TB was completely curable, making surgical treatment redundant.

Dr. Crofton believed that the conquest of the disease would also imply other measures, such as pasteurization of milk, tuberculin testing in cattle, BCG vaccination, mass radiography screening for early diagnosis of disease, isolation of infectious cases, and general population measures, including reduction of overcrowding and general improvement of the standard of living.

The "Madras Experiment" was carried out in India in 1956 to test a totally different concept of therapy, by comparing the results of treatment in a sanatorium with treatment at home with daily PAS and isoniazid for a year. After a 5-year period of follow up, the proportion of persons clear of disease in the two groups was similar and approached 90 %.

The spirit of optimism that followed was encouraged by the discovery of a series of new anti-tuberculosis drugs. The drug company Lepetit discovered that the mold Streptomyces mediterranei produced a new antibiotic, Rifamycin B. Chemical manipulation of this compound by CIBA resulted in the production of rifampicin, which has a remarkable potency against M. tuberculosis. Other compounds with anti-tuberculosis activity were discovered: pyrazinamide, ethambutol, cycloserine, and ethionamide.

At the end of the '70s, the primary care of TB patients moved from specialized institutions to general hospitals and ambulatory care services. At that time, many hospitals were reluctant to assume such responsibility for fear of spreading the disease to other patients and to hospital personnel. To overcome their apprehension, rational safety measures were introduced for the provision of primary care to TB patients in those settings. Earlier studies on TB transmission performed by Wells and Riley provided an insight into the characteristics of TB transmission and set the basis for its containment (Gunnels 1977, see chapter 11). By applying the experimental design of his mentor William Firth Wells, Richard Riley pioneered the study that first documented the role of the droplet nuclei in the transmission of TB (Riley 1962). The experiments were carried out using guinea pigs lodged in chambers above wards where TB patients were hospitalized. Only particles small enough to be carried by the air reached the animals, which, as a result of the inhalation of these particles, became infected with the same strains as those infecting the patients. This could be confirmed by comparison of drug susceptibility patterns.

Indeed, the conclusions of those investigations still stand strong. During coughing, sneezing, talking or singing, sputum smear-positive TB patients can eliminate large or small droplets of moisture containing viable bacilli. Large droplets tend to settle quickly onto the floor and, if inhaled, are trapped in the upper airways and destroyed by local mucocilliary defenses. Smaller droplets (1-10 µm) remain suspended in the air for prolonged periods of time. Evaporation of moisture leaves a residue - the droplet nucleus. This frequently contains only one or a few bacteria, which are the infectious units of TB. It was thus established that the risk of TB transmission is proportional to the concentration of droplet nuclei in the environment.

Infectivity was also found to be associated with environmental conditions and the characteristics of the disease in each individual case, such as the bacillary content of sputum, the presence of cavitation, the frequency of cough, and the presence of laringeal TB (see chapter 11). Therapy with anti-tuberculosis drugs was identified as the most effective measure for controlling patient's production of infectious particles and thus readily reversing infectivity (Gunnels 1977). Therefore, patients should only require isolation while they were sputum positive and before initiation of specific therapy. Hospitalization was either abolished or reduced to a few weeks for most patients (Kaplan 1977). Once a patient's diagnosis and treatment program had been defined, physicians who had no particular expertise in chest medicine could maintain a quality treatment program in most instances. That was the end of the phthisiologist's era.

Fact sheet N°104

Revised March 2006

TB programmes had become loose in industrialized countries because the disease was considered close to elimination. A study performed in 1991 showed that 89 % of 224 patients discharged on TB treatment were lost to follow-up and failed to complete therapy. More than a quarter were back in hospital within a year, still suffering from TB (Brudney 1991). This study reflected the occurrence of inconsistent or partial treatment, which was going on everywhere (Clancy 1990). Patients cease to take all their medicines regularly for the required period for different reasons: they start to feel better, doctors and health workers prescribe the wrong treatment regimens, or the drug supply is unreliable. Uncompliance frequently results in the emergence of bacteria resistant to drugs and ultimately in the emergence of a "superbug", resistant to all effective drugs (Iseman 1985). Multidrug-resistant TB, or MDR-TB, refers to M. tuberculosis isolates that are resistant to at least both isoniazid and rifampicin, the two most powerful anti-tuberculosis drugs. MDR-TB takes longer to treat with second-line drugs, which are more expensive and have more side-effects (see chapters 18 and 19).

In the early '90s, an extensive outbreak of highly resistant TB affected more than 350 patients in New York City. The strain was resistant to all first-line anti-tuberculosis drugs and almost all patients had HIV/AIDS. The hospital environment was the setting where more than two thirds of the patients acquired and transmitted the infection. As a consequence, this outbreak affected mainly HIV-infected patients and health care workers (Frieden 1996). At that time, New York City became the epicenter of drug-resistant TB, where one in three new cases were found resistant to one drug and one in five to more than one drug. Important HIV/AIDS related hospital outbreaks of MDR-TB similar to the one occurred in New York were described also in non-industrialized countries like Argentina (Ritacco 1997).

Indeed, the HIV/AIDS epidemic has produced a devastating effect on TB control worldwide. While one out of ten immunocompetent people infected with M. tuberculosis will fall sick in their lifetimes, among those with HIV infection, one in ten per year will develop active TB. In developing countries, the impact of HIV infection on the TB situation, especially in the 20-35 age group, is overwhelming.

While wealthy industrialized countries with good public health care systems can be expected to keep TB under control, in much of the developing world a catastrophe awaits. In poorly developed countries, TB remains a significant threat to public health, as incidences remain high, even after the introduction of vaccination and drug treatment (Murray 1990). The registered number of new cases of TB worldwide roughly correlates with economic conditions: highest incidences are seen in the countries of Africa, Asia, and Latin America with the lowest gross national products (see chapter 7).

Supervised treatment, including sometimes direct observation of therapy (DOT), was proposed as a means of helping patients to take their drugs regularly and complete treatment, thus achieving cure and preventing the development of drug resistance. The Directly-Observed Treatment, Short-course (DOTS, http://www.who.int/tb/dots/whatisdots/en/index.html) strategy was promoted as the official policy of the WHO in 1991 (see chapter 7).

The World Health Organization estimates that eight million people get TB every year, of which 95% live in developing countries. An estimated two million people die yearly from TB. World Health Organization (http://www.who.int/tb/en) declared TB a global health emergency in 1993 (World Health Organization 2006).

In 1998, the IUATLD joined with the WHO and other international partners to form the Stop TB Initiative, a defining moment in the re-structuring of global efforts to control TB. The original Stop TB Initiative has evolved into a broad Global Partnership, Stop TB Partnership (http://www.stoptb.org), with partners gathered in Working Groups to accelerate progress in seven specific areas: DOTS Expansion, TB/HIV, MDR-TB, New TB Drugs, New TB Vaccines, New TB Diagnostics, and Advocacy, Communications and Social Mobilization.

The World Health Assembly of 2000 endorsed the establishment of a Global Partnership to Stop TB and the following targets:

• By 2005: 70% of people with infectious TB will be diagnosed and 85% of them cured.
• By 2015: the global burden of TB disease (deaths and prevalence) will be reduced by 50% relative to 1990 levels.
• By 2050: The global incidence of TB disease will be less than one per million population (elimination of TB as a global public health problem)

In spite of these global efforts, TB continues to pose a dreadful threat. A notorious example is the sudden emergence in 2005, in a rural hospital located in Kwa-Zulu-Natal, a South African province, of a deadly form of TB associated with HIV/AIDS. This outbreak illustrates the devastating potential of what came to be called extensively drug resistant TB (XDR-TB) (Gandhi 2006). XDR-TB was defined as MDR-TB with further resistance to second-line drugs (see chapter 19). XDR-TB can develop when these second-line drugs are also misused or mismanaged and, therefore, also become ineffective (Raviglione 2007). The menace of XDR-TB is not restricted to that remote African setting. A recent survey, performed by 14 supra-national laboratories, on drug susceptibility testing results from 48 countries confirmed this. From 19.9 % of identified MDR-TB isolates, 9.9 % met the criteria for XDR-TB. These isolates originated from six continents, confirming the emergence of XDR-TB as a serious worldwide public health threat (Shah 2007).

Nowadays, treating TB is feasible and effective, even in low income countries, if based on reliable public health practice, including good laboratory infrastructure, appropriate treatment regimens, proper management of drug side-effects and resources to maintain adherence and prevent spread. The emergence of XDR-TB should stimulate the improvement of these basic control measures.

It is also crucially important to intensify research on developing effective TB vaccines, as well as shortening the time required to ascertain drug sensitivity, improving the diagnosis of TB, and creating new, highly effective anti-tuberculous medications. Without supporting such efforts, we still run the risk of losing the battle against TB.

1. Bates JH, Stead WW. The history of tuberculosis as a global epidemic. Med Clin North Am 1993; 77: 1205-17.
2. Benedek TG. The history of gold therapy for tuberculosis. J Hist Med Allied Sci 2004; 59: 50-89.
3. Brudney K, Dobkin J. Resurgent tuberculosis in New York City. Human immunodeficiency virus, homelessness, and the decline of tuberculosis control programs. Am Rev Respir Dis 1991; 144: 745-9.
4. Campbell M. What tuberculosis did for modernism: the influence of a curative environment on modernist design and architecture. Med Hist 2005; 49: 463-88.
5. Clancy L. Infectiousness of tuberculosis. Bull Int Union Tuberc Lung Dis 1990; 65: 70.
6. Cooper A, Poinar HN. Ancient DNA: do it right or not at all. Science 2000; 289: 1139.
7. Daniel TM. The history of tuberculosis. Respir Med 2006; 100: 1862-70.
8. Daniels M, Hill AB. Chemotherapy of pulmonary tuberculosis in young adults; an analysis of the combined results of three Medical Research Council trials. Br Med J 1952; 1: 1162-8.
9. Donoghue HD, Spigelman M, Greenblatt CL, et al. Tuberculosis: from prehistory to Robert Koch, as revealed by ancient DNA. Lancet Infect Dis 2004; 4: 584-92.
10. Donoghue HD, Spigelman M, Zias J, Gernaey-Child AM, Minnikin DE. Mycobacterium tuberculosis complex DNA in calcified pleura from remains 1400 years old. Lett Appl Microbiol 1998; 27: 265-9.
11. Feldman WH Hinshaw HC Effects of streptomycin on experimental tuberculosis in guinea pigs: a preliminary study. Proc Staff Meet Mayo Clin 1944; 19: 593-9.
12. Fox HH. Newer synthetic structures of interest as tuberculostatic drugs. Science 1953; 118: 497-505.
13. Frieden TR, Sherman LF, Maw KL, et al. A multi-institutional outbreak of highly drug-resistant tuberculosis: epidemiology and clinical outcomes. JAMA 1996; 276: 1229-35.
14. Gandhi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006; 368: 1575-80.
15. Gunnels JJ, Bates JH. Shifting tuberculosis care to the general hospital. Hospitals 1977; 51: 133-4, 136, 138.
16. Gutierrez MC, Brisse S, Brosch R, et al. Ancient origin and gene mosaicism of the progenitor of Mycobacterium tuberculosis. PLoS Pathog 2005; 1(1):e5.
17. Herzog H. History of tuberculosis. Respiration 1998; 65: 5-15.
18. Hinshaw HC, Feldman WH Evaluation of therapeutic agents in clinical tuberculosis. Am. Rev. Tuberculosis 1944; 50:202-13.
19. Iseman MD. Tailoring a time-bomb. Inadvertent genetic engineering. Am Rev Respir Dis 1985; 132: 735-6.
20. Kaplan AI. Tuberculosis treatment in Massachusetts in 1977. N Engl J Med 1977; 297: 616-7.
21. Kaufmann SH, Schaible UE. 100th anniversary of Robert Koch's Nobel Prize for the discovery of the tubercle bacillus. Trends Microbiol 2005; 13: 469-75.
22. Koch R. Classics in infectious diseases. The etiology of tuberculosis: Robert Koch. Berlin, Germany 1882. Rev Infect Dis 1982; 4: 1270-4.
23. Koch R. Weitere Mittheilungen über das Tuberkulin. Dt. Med. Wochenschr. 1891; 17: 1189-92.
24. Konomi N, Lebwohl E, Mowbray K, Tattersall I, Zhang D. Detection of mycobacterial DNA in Andean mummies. J Clin Microbiol 2002; 40: 4738-40.
25. Lehmann J. Twenty years afterward historical notes on the discovery of the antituberculosis effect of paraminosalicylic acid (PAS) and the first clinical trials. Am Rev Respir Dis 1964; 90: 953-6.
26. McCarthy OR. The key to the sanatoria. J R Soc Med 2001; 94: 413-7.
27. McDermott W. The story of INH. J Infect Dis 1969; 119: 678-83.
28. Medical Research Council. Streptomycin treatment of pulmonary tuberculosis. BMJ 1948; 2:769-82.
29. Morens DM. At the deathbed of consumptive art. Emerg Infect Dis 2002; 8: 1353-8.
30. Murray CJ, Styblo K, Rouillon A. Tuberculosis in developing countries: burden, intervention and cost. Bull Int Union Tuberc Lung Dis 1990; 65: 6-24.
31. Pease AS. Some remarks on the diagnosis and treatment of tuberculosis in antiquity. Isis 1940; 31: 380-93.
32. Pfuetze KH, Pyle MM, Hinshaw HC, Feldman WH. The first clinical trial of streptomycin in human tuberculosis. Am Rev Tuberc 1955; 71: 752-4.
33. Raviglione MC, Smith IM. XDR tuberculosis--implications for global public health. N Engl J Med 2007; 356: 656-9.
34. Riley R, Mills C, O'Grady F, et al. Infectiousness of air from a tuberculosis ward - ultraviolet irradiation of infected air: comparative infectiousness of different patients. Am Rev Respir Dis 1962; 84: 511-25.
35. Ritacco V, Di Lonardo M, Reniero A, et al. Nosocomial spread of human immunodeficiency virus-related multidrug-resistant tuberculosis in Buenos Aires. J Infect Dis 1997; 176: 637-42.
36. Rothschild BM, Martin LD, Lev G, et al. Mycobacterium tuberculosis complex DNA from an extinct bison dated 17,000 years before the present. Clin Infect Dis 2001; 33: 305-11.
37. Ryan F. The forgotten plague: how the battle against tuberculosis was won - and lost. 1^st Ed. Little, Brown and Company, New York, 1992.
38. Salo WL, Aufderheide AC, Buikstra J, Holcomb TA. Identification of Mycobacterium tuberculosis DNA in a pre-Columbian Peruvian mummy. Proc Natl Acad Sci U S A 1994; 91: 2091-4.
39. Samson PC, Dugan DJ, Harper HP. Upper lobe lobectomy and concomitant thoracoplasty in pulmonary tuberculosis. A preliminary report. Calif Med 1950; 73: 547-9.
40. Schatz A, Bugie E, Waksman S. Streptomycin, a substance exhibiting antibiotic activity against Gram-positive and Gram-negative bacteria. Proc Soc Expt Biol and Med 1944a; 55: 66-9.
41. Schatz A, Waksman S. Effect of streptomycin and other antibiotic substances upon Mycobacterium tuberculosis and related organisms. Proc Soc Expt Biol and Med 1944b; 57:244-8.
42. Shah NS, Wright A, Bai G-H, et al. Worldwide energence of extensively drug-resistant tuberculosis Emerg Infect Dis [serial on the Internet]. 2007 Mar [date cited]. Available from http://www.cdc.gov/EID/content/13/3/380.htm.
43. Sharpe WC. Artificial pneumothorax in pulmonary tuberculosis. Can Med Assoc J 1931; 25: 54-7.
44. Sledzik PS, Bellantoni N. Brief communication: bioarcheological and biocultural evidence for the New England vampire folk belief. Am J Phys Anthropol 1994; 94: 269-74.
45. Sotomayor H. Arqueomedicina de Colombia Prehispánica. Editorial de Cafam. Bogotá DC, 1992.
46. Sotomayor H, Burgos J, Arango M. [Demonstration of tuberculosis by DNA ribotyping of Mycobacterium tuberculosis in a Colombian prehispanic mummy] Biomedica 2004; 24: 18-26.
47. Taylor GM, Murphy E, Hopkins R, Rutland P, Chistov Y. First report of Mycobacterium bovis DNA in human remains from the Iron Age. Microbiology 2007; 153: 1243-9.
48. Taylor GM, Stewart GR, Cooke M, et al. Koch's bacillus - a look at the first isolate of Mycobacterium tuberculosis from a modern perspective. Microbiology 2003; 149: 3213-20.
49. Taylor GM, Young DB, Mays SA. Genotypic analysis of the earliest known prehistoric case of tuberculosis in Britain. J Clin Microbiol 2005; 43: 2236-40.
50. World Health Organization (WHO). Frequently asked questions about TB and HIV. Retrieved 6 October 2006.
51. Zink AR, Grabner W, Reischl U, Wolf H, Nerlich AG. Molecular study on human tuberculosis in three geographically distinct and time delineated populations from ancient Egypt. Epidemiol Infect 2003; 130: 239-49.