Battling the white plague
A brief history of Tuberculosis
June 29, 2011, 2:01 p.m.
Tuberculosis in humans is a very old disease. Recent research shows that the disease probably originated at least several hundred thousand years ago in hominids but perhaps even more than 2 million years ago. The oldest evidence of TB is a half-million year old hominid that was discovered at a stone quarry in Western Turkey. It has lesions on its skull indicating TB infection.
To understand the origins of TB it is important to understand that TB can be caused by several different related bacteria in the genus Mycobacterium. Mycobacterium tuberculosis causes most TB cases in humans. However, Mycobacterium bovis, which causes TB in cows, is also responsible for some TB in humans. Mycobacterium canetti and Mycobacterium africanum also cause TB in humans, while Micobacterium microti, Micobacterium caprae and Mycobacterium pinnipedii cause TB in other animals. Together, these bacterium constitute the Mycobacterium tuberculosis complex. These bacteria share 99.9% of their nucleotides, the building blocks of DNA.
The earliest detected TB --confirmed by genetic analysis-- is from the remains of an extinct bison in North America. The bison had lesions symptomatic of TB. Bruce Rothschild and his colleagues carbon-dated a bone from the bison's foot, calculating that the animal was 18,000 years old. They also analysed bacterial DNA fragments in the bone and it matched the DNA of Mycobacterium tuberculosis complex. Evidence of TB has also been found in mastodons, a relative of the elephant that lived in North America and Asia and became extinct about 11,000 years ago. TB was one of the probable factors responsible for its extinction.
The oldest DNA confirmed evidence of Mycobacterium tuberculosis complex is from an extinct North American bison. Image source: San Diego Zoo.
The earliest confirmed cases of TB in humans were found in the skeletal remains of a mother and her infant who were found in a submerged prehistoric site called Atlit-Yam, a few hundred metres offshore about 10 metres below sea-level, not far from Haifa in Israel. The pair lived about 8 to 9,000 years ago in one of the earliest villages which had both domesticated animals and agriculture. The mother and infant had lesions suggesting TB on their skeletal remains. Using extremely careful techniques, to avoid contaminating their samples, a scientific team extracted bacterial DNA from the ribs, arms and long bones of the mother and infant. It matched DNA fragments of Mycobacterium tuberculosis.
Map of Atlit Yam, where the oldest TB infections in humans confirmed with DNA analysis have been found. Image source: Hershkovitz
The prevailing theory used to be that Mycobacterium tuberculosis descended from Mycobacterium bovis and that TB began infecting humans when we started hunting or herding cattle. However genetic analysis, as well the archaeological record, shows that this is probably not the case. , Mycobacterium tuberculosis has a long history of infecting humans. Mycobacterium bovis probably came later and evolved from an ancient common ancestor with Mycobacterium tuberculosis. Instead of humans originally contracting TB from cows, it seems more likely that cattle helped spread infection "by supporting a larger and denser human population, thus indirectly encouraging the conditions of the long-term maintenance and transmission of Mycobacterium tuberculosis."
Mastodons, an elephant relative, might have been driven to extinction by TB. TB is a serious epidemic in modern elephants. Image source: Elephant Care
TB was a common disease in ancient Egypt. TB DNA has been found in a 5,400 year old skeleton and also in mummies extracted from tombs from as far back as 2050 BC. Besides DNA and bone lesions, TB can also be identified in ancient Egypt from mummies with Pott's disease, a deformation of the spine caused by TB. TB has even been found in Indian elephants from before 2000 BC. Mycobacterium tuberculosis complex was prevalent in the new world too. The oldest discovered cases in South America belong to the Paracas-Caverna culture dating back to about 160 AD and to two mummies recovered from the Andean mountains of about the same time. There is evidence that TB existed in pre-Columbian North America too, but it appears to have become a much bigger cause of death after contact with Europeans.
An article from the International Journal of Tuberculosis and Lung Disease in 2000 explains:
The Americas were peopled by migrants from Asia in two major migrations, one occurring more than 20,000 years ago and the other 12,000 to 11,000 years ago. Tuberculosis reached the Americas with these migrants, persisting at a low level of endemnicity in small, dispersed population groups. Beginning about 1500 years ago, an epidemic of tuberculosis began, probably in the Andean region of South America. It did not reach or subsided in time to leave highly susceptible indigenous American populations at the time of European colonization.
Evidence of TB has also been recovered from an archaelogical site in Korea dating to the first century BC, and from Japan at a similar time. Symptoms of what appear to be TB have been described in 4000-year old Chinese texts, which describe "Lung Fever" and "Lung Cough". DNA analysis has revealed a TB outbreak in a 2000-year-old Chinese population. Human remains recovered from an iron age site in Thailand also show symptoms of TB and its related disease, leprosy (caused by Mycobacterium leprae). On the other hand there is no evidence of TB in Australia prior to 1788, when the first European settlement was established. Yet by the mid-19th century it was probably the leading cause of death in indigenous Australians in areas settled by Europeans.
The current scientific consensus is that Mycobacterium tuberculosis complex has been infecting humans and our predescessors for at least hundreds of thousands of years. TB existed in much of the world before modern European colonisation. Nevertheless, when Europeans spread to the new world they unwittingly created the conditions for TB to flourish and become an even bigger cause of mortality across the globe.
TB has been known through the ages by many names: consumption, psthisis, scrofula, Pott's disease, King of Diseases and the white death (or white plague) are some examples. While the cause of the disease was unknown, its wasting symptoms were familiar enough. Apparently the Code of Hammarubi, a set of Babylonian laws dating to about 1700 B.C., mentions TB. Its symptoms were described in 1500 B.C. in India as "over-fatigue, sorrow, fasting, pregnancy and chest wounds." Brahmins were not allowed to marry into families where it existed. Treatment included life in the mountains, a recommendation that would survive in similar form into western medicine through to the 20th century. The Yajurveda, a Hindu text provides advice for physicians who want to build a good reputation:
Consumption is a disease difficult to stop; it is endowed with great power. A consumptive who is evidently master of himself, who has good digestion, is not emaciated, and is at the beginning of the disease, the physician can cure ... A consumptive who eats little, who is failing, who has diarrhea, tumefaction of the scrotum and of the abdomen, that one, the physician anxious to be a man of renown will abandon ... The physician who wants great fame cures a man attacked by consumption.
TB appears to be mentioned in the Old Testament in two rather fiery passages:
I will even appoint over you terror, consumption, and burning ague that shall consume the eyes and cause sorrow of heart ...
The LORD shall smite thee with a consumption, and with a fever, and with an inflammation, and with an extreme burning, and with the sword, and with blasting, and with mildew; and they shall pursue thee until thou perish.
Hippocrates, who lived in the 5th century BC and is considered the founder of western medicine, said of TB (which was then called phthisis) that it was the most prevalent of the diseases in his time and the only one which killed his patients. Aristotle guessed well when he explained that TB was spread between people by some substance breathed into the air.
The Roman physician Caelius Aurelianus described TB in a very modern way. One of his accomplishments was to translate from Greek to Latin Soranus's On Acute and Chronic Diseases. Image source: Summagallicana
The Greek physician Galen (130-200AD) believed that TB was contagious and incurable. The Roman physician Caelius Aurelianus, who lived in the 5th century AD, wrote on medicine and disease. He gave a detailed description of TB:
The symptoms of the disease are as follows: there is a latent fever, which generally begins toward the end of the day and is relieved by the coming of the new day; this is accompanied by much coughing at the beginning and the end of the night, with the discharge of sanious sputa ... The voice is either hoarse or high pitched, breathing is difficult, cheeks flushed and the rest of the body ashen colored. The eyes have a worn appearance, and the patient is emaciated ... In some cases there is a hissing sound or wheezing in the chest ...
Not all Roman commentators on TB had such a scientific predisposition. Pliny suggested that the cure for TB was to eat wolf's liver boiled in wine. Though his advice was probably more detrimental to wolves than to TB patients. TB was also present in Britain during the Roman period. Skeletons with Pott's disease have been found and dated to about the 3rd to 5th century.
The prevalence of TB in antiquity was high, including in Rome with its dense population, but it is thought that what is commonly known as the dark ages actually provided some relief from this particular disease. Krause (in Waksman, 1965) explains, "The disease was widely prevalent in the cities of the Greek and Roman civilizations. With the disruption of the Western Empire in the fifth and sixth centuries decentralization of population took place in Western Europe, with migration from the cities and the development of separate and widely dispersed agricultural economies."
During the time that corresponds to the European middle-ages, Islamic scholars described symptoms and the pathology of the disease. The Persian physician Avicenna (980-1037AD), also known as Abu-Ali al-Hussain ibn-Abd-Allah ibn-Sina, wrote his Canon of Medicine which was translated to Latin and used in European universities until 1600. He, like Galen, thought that TB might be contagious. On the other hand in Europe, during the rise and consolidation of Christianity, the response to TB was often characterised by superstitious beliefs. There were patron saints for TB who could be summoned to help TB patients. Holy water with a pinch of the ashes of St John's fire, taken every evening, was the presciption for TB in Belgium. So was eating butter milk from cows fed in churchyards, which was no doubt also a good way to make income for the church.
The rise of cities again during the middle ages, coupled with poor living conditions and bad hygiene led to an increase in TB morbidity and mortality. With the onset of the enlightenment in Italy and the beginning of modern science, European society moved to a point where progress against this scourge could be made.
Suffering from TB began taking a somewhat odd and fashionable form in European literature. Alexander Dumas described this. "In 1823 & 1824, it was a fashion to suffer from the lungs; everybody was consumptive, poets especially; it was good form to spit blood after each emotion that was at all sensational and to die before reaching age 30." Keats, Chekhov, Browning and Kafka are some of the more famous writers who died of TB. Chopin also died of TB.
Elizabeth Browning, one of the most popular Victorian poets, probably died of complications due to TB, at the age of 55 in 1861. Image source: Wikipedia.
The Italian physician Girolamo Fracastora wrote a chapter in his book, De Morbis Contagiosis, emphasising that TB (called phthisis by him) was contagious. His writing suggests an understanding that TB is caused by a small infectious agent that lives in the body. Several physicians including Sylvius and Morton (in the 17th century), expanded on this idea. That it was a disease of the lungs was also understood. There were practical steps taken with this knowledge. Salman Waksman explains:
The Republic of Lucca [part of Italy] promulgated a law in 1699 which stated: "In future the health of the human body shall not be harmed or imperiled by objects remaining after death of a person infected with the disease of psthisis."
The names of patients suffering from the disease had to be reported and disinfection measures were required. Autopsies were required, allowing fresh air to flow was considered a duty, patients were encouraged not to eject sputum except into a glass or vessel and the washing of utensils and linen used by people with TB was also enforced by edict.
Girolamo Fracastora, an enlightenment thinker who realised TB was contagious. Image source: Wikipedia.
The invention of the microscope by Zacharias Jansenn in Holland in approximately 1595 was a critical step towards isolating the cause of TB. In 1676 Antony van Leeuwenhoek discovered protozoa under the microscope. So when Benjamin Morton stated in 1720 that TB might be caused by "minute living, creatures" which gained access to the body, it was plausible.
Drawing of one of Van Leeuwenhoek's microscopes. Image source: Berkeley University.
In 1868 Jean Antoine Villemin produced TB in rabbits, by using infected material from people and cattle.
Jean-Antoine Villemin, who proved that TB is contagious. Image source: University of Virginia.
The cause of TB was announced by Robert Koch on 24 March 1882. This is described beautifully on the Nobel Prize website:
Robert Koch, a German physician and scientist, presented his discovery of Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), on the evening of March 24, 1882. He began by reminding the audience of terrifying statistics: "If the importance of a disease for mankind is measured by the number of fatalities it causes, then tuberculosis must be considered much more important than those most feared infectious diseases, plague, cholera and the like. One in seven of all human beings dies from tuberculosis. If one only considers the productive middle-age groups, tuberculosis carries away one-third, and often more."
Koch's lecture, considered by many to be the most important in medical history, was so innovative, inspirational and thorough that it set the stage for the scientific procedures of the twentieth century. He described how he had invented a new staining method and demonstrated it for the audience. Koch brought his entire laboratory to the lecture room: microscopes, test tubes with cultures, glass slides with stained bacteria, dyes, reagents, glass jars with tissue samples, etc. He wanted the audience to check his findings for themselves. Koch showed tissue dissections from guinea pigs which were infected with tuberculous material from the lungs of infected apes, from the brains and lungs of humans who had died from blood-borne tuberculosis, from the cheesy masses in lungs of chronically infected patients and from the abdominal cavities of cattle infected with TB. In all cases, the disease which had developed in the experimentally infected guinea pigs was the same, and the cultures of bacteria taken from the infected guinea pigs were identical. One important scientist in the audience was Paul Ehrlich (Nobel Laureate in Physiology or Medicine in 1908) who later confessed, "I hold that evening to be the most important experience of my scientific life." When Koch ended his lecture there was complete silence. No questions, no congratulations, no applause. The audience was stunned. Slowly people got up and started looking into the microscopes to see the TB bacteria with their own eyes.
Koch's work brought a revolution in medical science. The causes of the great scourges could no longer be assigned to witchcraft, ghosts, God's will or any superstition. Instead they were to be found in germs, microscopic creatures that reproduced in the body and spread from person to person, bringing tragedy with their mindless and exquisite evolution.
Robert Koch, who discovered Mycobacterium tuberculosis the cause of TB. Image source: University of Virginia.
Did I hear from the fireside armchair the bow-wow of the old school defending its drugs? Ah, believe me, Paddy, the world would be healthier if every chemist’s shop in England were demolished. Look at the papers! full of scandalous advertisements of patent medicines! a huge commercial system of quackery and poison. Well, whose fault is it? Ours. I say, ours. We set the example. We spread the superstition. We taught the people to believe in bottles of doctor’s stuff; and now they buy it at the stores instead of consulting a medical man.
—From the Doctor's Dilemna by George Bernard Shaw
When Shaw wrote this play in 1906, his summary of the state of medicine at the time was apt. Medicinal potions were for the most part quackery. But this was set to change. By the 1960s, the rise of scientific medicine had rendered TB curable. Alexander Fleming discovered the anti-bacterial effects of penicillin in 1928. In 1932 Gerhard Domagk discovered the first sulfonamide, Prontosil. He showed that it was active against streptococcal infections. In the 1940s Howard Florey and Ernst Chain turned Fleming's discovery into a medicine. Production of penicillin was scaled up to treat Allied soldiers wounded on D-Day. These events marked the beginning of modern scientific drug discovery. It is often not realised how recently this massively important contribution to increased life-expectancy was made. The "modern" treatment for TB before chemotherapy was to be sent to a sanatorium for fresh air, or to collapse the infected lung.
"A tuberculous mother, on strict bed rest, leaves her room at the sanatorium for a Sunday walk with her family. But she does not leave her bed." Image source: A History of the Fight Against Tuberculosis in Canada.
The morbid reality of the sanatorium is captured beautifully in this poem by Alfred Lichtenstein.
In The Tuberculosis Sanitarium
Many sick people are walking in the garden
Back and forth and lying in the porches.
Those who are the sickest burn with fever
Every wretched day in the hot
Grave of their beds.
Ah, Catholic sisters float
Around wearily in black clothes.
Yesterday someone died. Today another can die.
In the city Fasching is begin celebrated.
I would like to be able to play the difference
On the piano
In 1943 Albert Schatz, a PhD student working in Selman Waksman's department at Rutgers University in New Jersey isolated streptomycin. In 1944 the Swede Jorgen Lehman discovered para-aminosalicylic acid (PAS). Both are still used in TB treatment today (the former for people previously treated for TB and the latter for multi-drug resistant TB). The British Medical Research Council conducted what was arguably the first properly randomised clinical trial in history (previously patients were allocated alternately to the control and intervention groups) when it tested streptomycin. The randomisation technique was developed by Austin Bradford Hill one of the great medical statisticians.
Austin Bradford Hill helped formalise the methodology for clinical trials. Image source: BMJ.
A later trial compared streptomycin and PAS against either drug alone and found that the combination was more effective and reduced the risk of resistance. One of the first streptomycin patients was George Orwell. Near his death he also tried PAS. A beautiful essay by Hilda Bastion explains Orwell's unsuccessful attempts to use these drugs. He died in 1950 of TB.
Eric Arthur Blair, aka George Orwell, was one of the 20th century's greatest writers. He died of TB, despite taking streptomycin and PAS. Image source: James Lind Library.
The anti-TB effect of isonicotinylhydrazine, or simply isoniazid, was discovered in 1952 as a consequence of Domagk's work. When added to the treatment regiment with PAS and streptomycin, it cured over 90% of patients. Nevertheless treatment took up to two years. Ethambutol replaced PAS in the 1960s. It resulted in fewer side effects and an 18 month treatment duration.
Then came the next two drugs, rifampicin and pyrazinamide:
The next advance in therapy was the introduction of rifampicin (RIF). Derived from Streptomyces mediterranei, RIF was studied in early trials by the BMRC in East Africa and Hong Kong, demonstrating that practical combinations of [isoniazid], [streptomycin], [ethambutol] and RIF resulted in predictable cures in 95% of cases in just 8–9 months. The particular activity of RIF that facilitated this compression of treatment was its pronounced capacity of rifamycin to kill mycobacteria undergoing sporadic metabolism, the so-called "sterilising effect". The next step forward was the recognition that the inclusion of pyrazinamide (PZA) allowed a reduction in the duration required to achieve predictable cures. PZA was found to accelerate the time required to achieve culture negativity and to yield 95% cure rates in 6 months when combined with [isoniazid] and RIF. It has been speculated that the singular role of PZA is activity against tubercle bacilli in the acidic debris in pulmonary cavity walls . This is consistent with the observation that PZA exerts all of its beneficial effects in the first 2 months of therapy.
Unfortunately, other than the development of two further rifamycins --rifapenentine and rifabutin-- no new effective TB-specific drugs have been approved, although antibiotics like moxifloxacin are used in second-line treatment. However, the situation is improving. TMC207, developed by Tibotec, looks like a promising new drug candidate. OPC-67683 and PA-824 are two other drugs at an advanced stage of development. Clinical trials of these drugs are however proceeding at a snail's pace.
And so chemotherapy replaced the sanatorium as the standard of TB treatment. Scepticism of the sanatorium began before the success of drugs. Hilda Bastion summarises the demise of the sanatorium:
As critics of the sanatorium had long ago pointed out in France, the common practice of confining 'breadwinners' to bed for months at a time had serious consequences for most people with TB ... Indeed, socialists in France had opposed the focus on sanatoria as an inappropriate response to the problem of tuberculosis. Sanatoria were regarded by them as "a resort scam for the rich and a smokescreen for the working class". There were not enough places in sanatoria for everyone, months without work made people destitute, and the funding of sanatoria meant that there was less investment than there should have been in addressing the social conditions associated with TB ... A decade later, MRC researchers in India published the results of a randomized trial comparing home and sanatorium treatment of TB ... This found that households whose breadwinner hadn’t entered a sanatorium were less likely to suffer reduced income, family breakdown and other serious social problems, without any disadvantages in terms of recovery from the disease.
Salman Waksman, who led the team that discovered streptomycing and played a seminal role in the discovery of TB chemotherapy, wrote a beautiful history of TB in 1964. In it he quotes someone from the International Union Against Tuberculosis saying this in 1962, "If I had tuberculosis ... this idea, formerly terryifying, no longer makes anyone tremble ... antibiotics have appeared, sanatoria have disappeared; as far as the public is concerned the problem is solved; the disease has been conquered."
Waksman himself wrote, "Tuberculosis has not yet been eradicated, and the question is often raised whether it ever can be, but it can be controlled. No one who becomes afflicted by any one of the different forms of this disease need die from it at the present time."
Unfortunately these celebrations were premature. From 1991 to 1992, there was an outbreak of multi-drug-resistant TB (MDR TB) in New York City. 43 of 198 patients diagnosed with TB were resistant to isoniazid and rifampicin (the definition of MDR TB). Enormous resources were used to end the outbreak. But it was the rise of the HIV epidemic that truly put an end to the optimistic view that TB had been almost conquered.
And while there was progress on new drugs, there was little progress on TB diagnostics. Most health facilities across the world still diagnose TB under the microscope using the acid fast stain technique developed by Franz Ziehl and Friedrich Neelsen in the 19th century.
[T]here undoubtedly existed a chance to conquer tuberculosis Worldwide by launching campaigns using optimum chemotherapy. These prospects were greatly enhanced by studies in the Third World where it was shown that even in the slums of Madras, it was possible to treat tuberculosis successfully in the patient’s home and avoid hospitalisation altogether. However, it was not to be; due to doctor errors, lack of financial support by national and international agencies and poor patient compliance, drug and multi-drug resistant strains have become much more prevalent and the final blow has been the advent of AIDS and associated HIV infection, especially in developing regions.
—J. Williamson. Professor Emeritus, University of Edinburgh.
Today TB is the biggest cause of HIV-related death. Over 1.5 million people die annually of TB, making it one of the biggest causes of premature mortality in the developing world. While fatalities from the disease are now uncommon in Europe and North America, it remains one of the biggest scourges of Sub-Saharan Africa with its massive HIV epidemic. Good quality statistics are hard to come by, but a reliable indicator can be found in South Africa. TB is the biggest recorded cause of death in South Africa, with the number of such deaths trebling between 1997 and 2005. Concomitant with the rise of drug-resistant TB this is a major problem for health systems in this part of the world.
Research into TB treatments and diagnostics has increased substantially over the last decade. But it is still inadequate. It is indicative of the problem that most TB funding until recently emanated from a private philanthropic organisation, the Gates Foundation, instead of public funding (this has recently changed). New diagnostics, such as the Gene Xpert which gives a diagnosis with over 90% sensitivity and even higher specificity within 2 hours, will hopefully make a difference to many patients. New drugs should soon get to market. New vaccines are being developed too. But the optimism of the 1960s after the early successes of chemotherapy no longer exists.