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ISSN: Print -2349-0977, Online - 2349-4387


 
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CHRONICLES OF MEDICINE
Year : 2017  |  Volume : 4  |  Issue : 1  |  Page : 7-26

The tuberculosis timeline: Of white plague, a birthday present, and vignettes of myriad hues


Departments of Radiodiagnosis, Orthopedic Surgery, Medicine and Nuclear Medicine, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India

Date of Web Publication6-Nov-2017

Correspondence Address:
Yatish Agarwal
Department of Radiodiagnosis, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2349-0977.217662

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  Abstract 


Researchers have been digging hard to unearth the hoary past of tuberculosis. Unbelievable as it may seem, growing evidence exists that the first ancestors of Mycobacterium tuberculosis inhabited earth more than 2.6 million years ago. Eons before the hominoids set their feet on this godly planet, and Adam and Eve and their children came into being! Some ancient skeletal and mummified fossils belonging to diverse species, including dinosaurs, Pleistocene bison, and other bovines like goats and cows, have been found stamped with classic tubercular lesions and bearing the irrefutable molecular genetics inscription of mycobacteria. Of the human tuberculosis, the most ancient evidence has been found in the remains of half a million year old hominid. Old medical texts emanating from different parts of the world – in ancient lands of India, China, Egypt, Babylonia, and Greece – portray the disease through its umpteen names and nuances. Known by such grisly appellations as “the Robber of Youth”, “the Graveyard Cough”, “the White Plague”, tuberculosis burnt a deadly trail claiming millions of lives down the ages. The first major breakthrough against it came in 1882, when the German physician Robert Koch isolated the culprit organism. By mid 20th century, a chain of therapeutic molecules had been found to thwart the malevolent bacteria. Still, “the Captain of the Men of Death” carried on its death-game, finding staunch allies in hunger, malnutrition and poverty. Came the 1980s, it found new vigor by teaming with a new half-brother, the human immunodeficiency virus. Epidemics returned to lands where the disease had stood previously diminished; pushing for the discovery of newer treatments and novel therapies. The wicked dance of tuberculosis, however, continues to rage. Current estimates indicate that nearly a third of the world's population is infected with the bacillus, 10.4 million people carry active disease, and more than 2 million perish of the disease each year. The global community has declared a war on the disease and given the clarion call of “End TB strategy”. Yet, only time shall tell who will score the last hurrah: the bacillus or man!

Keywords: Captain of the men of death, discovery of mycobacterium tuberculosis, drug development, history, molecular diagnostics, oldest leptomeningitis tuberculosa, phthisis, tuberculosis in hominoids


How to cite this article:
Agarwal Y, Chopra RK, Gupta DK, Sethi RS. The tuberculosis timeline: Of white plague, a birthday present, and vignettes of myriad hues. Astrocyte 2017;4:7-26

How to cite this URL:
Agarwal Y, Chopra RK, Gupta DK, Sethi RS. The tuberculosis timeline: Of white plague, a birthday present, and vignettes of myriad hues. Astrocyte [serial online] 2017 [cited 2017 Nov 22];4:7-26. Available from: http://www.astrocyte.in/text.asp?2017/4/1/7/217662






  The Origin Top


2.6 – 2.8 Ma

With the birth of modern techniques in molecular genetics and indisputable sequencing of inscribed genome — or footprints of ancient pathogens — on fossilized tissues and skeletal remains of a number of mammals and other animals, understanding about the evolutionary history of several major diseases has taken a new shape. Ancient skeletal and mummified fossils belonging to diverse species, including dinosaurs, Pleistocene bison, and other bovines like goats and cows, have been found stamped with classic tubercular lesions and bearing the irrefutable molecular genetics inscription of mycobacteria. Current ancient DNA research pertaining to the earliest tuberculosis bacilli indicates that the oldest progenitor species of Mycobacterium tuberculosis originated some 2.6 to 2.8 million years ago in East Africa.[1] This implies that, in all likelihood, Mycobacterium tuberculosis [Figure 1] would have afflicted the earliest of our hominid ancestors.
Figure 1: Photomicrograph of Mycobacterium tuberculosis.

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  The first Specimens Top


~500,000BC

Till date, the most ancient evidence of tuberculosis in hominid tissue has been found in a 500,000 year old fossilized hominid specimen. Isolated from a solid block of travertine stone unearthed at a stone quarry located north of the village of Kocabas in Western Turkey, the Homo erectus skeletal tissue fossil bear the classic lesions of leptomeningitis tuberculosa on the endocranial surface of a well-preserved frontal bone [Figure 2].[2]
Figure 2: View of the inside of a plaster cast of the skull of the newly discovered young male Homo erectus from western Turkey. The stylus points to tiny lesions 1-2 mm in size found along the rim of bone just behind the right eye orbit. The lesions were formed by a type of tuberculosis that infects the brain and, at 500,000 years in age, represents the most ancient case of tuberculosis known in humans.

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  Birth of a Tribe Top


35,000 – 15,000BC

Researchers have found corroborative evidence to establish that modern members of the M. tuberculosis complex, including Mycobacterium tuberculosis and its African variants —  Mycobacterium africanum Scientific Name Search ycobacterium canettii — as well as Mycobacterium bovis, were born of a common ancestor bacillus some 35,000 years ago. The modern strains of M. tuberculosis may have originated a little later, taking shape 20,000–15,000 years ago [Figure 3].[3]
Figure 3: With modern techniques and sequencing of the genome through molecular genetics, researchers have tried to map out how the Mycobacterium tribe might have grown.

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  Narrative of the Mummies Top


9,000BC

Some authors believe and perhaps, quite aptly, that tuberculosis may have been the first disease to have become known to human race. In 2008, evidences of tuberculosis infection were discovered in human remains from the Neolithic era dating from 9,000 years ago, in Atlit Yam, a settlement in the eastern Mediterranean. This finding was confirmed by morphological and molecular methods; and to date this is the oldest evidence of tuberculosis infection in humans.[4] Similar evidence of tuberculosis infection in humans was also found in a cemetery near Heidelberg, in the Neolithic bone remains that show evidence of the type of angulations often seen with spinal tuberculosis.[5]

Archeological evidence of tuberculosis has been documented in different parts of the world since 8,000BC. Typical skeletal abnormalities of tuberculosis, including characteristic Pott's deformities, have been found in Egyptian mummies and are clearly depicted in early Egyptian art [Figure 4].[6] More recently, M. tuberculosis DNA has been amplified from tissues of Egyptian mummies proving the hand of tuberculosis in early skeletal disease.
Figure 4: An ancient Egyptian painting depicting a man afflicted with Pott's disease of the vertebral spine.

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Definitive evidence of osseous tuberculosis, including Pott's disease and multisystem tuberculosis, has also been well demonstrated in mummies discovered in Peru in South America [Figure 5]a and [Figure 5]b. As in Egypt, M. tuberculosis DNA has been recovered also from mummified tissues in Peru. While the earliest evidence of pre-Columbian tuberculosis in America comes from the Andean Region, there is abundant archeological evidence that the disease occurred throughout the hemisphere prior to the arrival of the first European explorers.[7]
Figure 5: (a) MRI images in a pre-Columbian Peruvian mummy depicting multisystemic tuberculosis. (b) Peruvian mummy, preserved at Lima Museum, was found to be afflicted with multisystem tuberculosis.

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  The first Written Records Top


2700BC – Biblical Times

The first written account of tuberculosis is found in the Vedas. The most ancient of them all, Rig Veda, 1500BC calls the disease yaksma.[8] The Atharvaveda calls it balasa. It is in the Atharvaveda that the first description of scrofula is given.[8] The Yajurveda advises sufferers of the disease to move to higher altitudes [Figure 6] away from the village. This may, in effect, construe that the traditional doctors (vaidyas) in ancient India believed the disease to be infectious in nature. The Sushruta Samahita, written around 600 BC, recommends that the disease be treated with cow milk, various meats, and rest.
Figure 6: The Vedas, works of ancient thought in India, hold perhaps the first written account of tuberculosis in the world.

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Records of the disease are found in ancient works across a number of old civilizations. The disease finds a distinct reference in the legal text written in cuneiform on a stone pillar by Hammurabi, a Babylonian king, as a chronic lung disease in the 2nd millennium BCE [Figure 7]. It is described as a “wasting disease” in the celebrated Chinese medical work, the Huang Ti Nei-Ching [Figure 8] dating back to third millennium BCE.
Figure 7: The Hammurabi's inscription in Babylonia writes of tuberculosis as a chronic lung disease.

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Figure 8: The ancient Chinese work Huang Ti Nei-Ching describes tuberculosis as a wasting disease.

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Tuberculosis the disease was also known in classical Greece. Homer's epic poem Odyssey from the 8th century BC refers to “grievous consumption which took the soul from the body and caused a person to “lie in sickness. a long time wasting away” [Figure 9].[9] The ancient Greeks called the disease “phthisis”. Hippocrates of Cos had a profound understanding of the clinical presentation of the disease. In Book 1, Of the Epidemics (410–400BC) he portrayed a disease of “weakness of the lung” with fever and cough which he referred to as phthisis (Gr. phthiein = to waste away) [Figure 10]. Phthisis was described as the commonest disease of the period and usually ended being fatal.[9]
Figure 9: Homer's epic poem Odyssey penned in 8th century BC refers to tuberculosis as a grievous consumption which took the soul from the body.

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Figure 10: The Greek physician, Hippocrates, recognized tuberculosis and understood its clinical presentation. In Book 1, Of the Epidemics, he refers to it as phthisis.

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“Early in the beginning of spring, and through the summer, and towards winter, many of those who had been long gradually declining, took to bed with symptoms of phthisis;. Many, and, in fact, most of them died, and of those confined to bed, I do not know of a single individual survived for any considerable time., Consumption was the most considerable of the diseases which then prevailed, and the only one which proved fatal to many persons. Most of them were affected by these diseases in the following manner; fevers accompanied with rigors., constant sweats., extremities very cold, and warmed with difficulty; bowels disordered, with bilious, scanty, unmixed, thin, pungent, and frequent dejections. The urine was thin, colorless, unconcocted, or thick, with a deficient sediment. Sputa small, dense, concocted, but brought up rarely and with difficulty; and in those who encountered the most violent symptoms there was no concoction at all, but they continued throughout spitting crude matters.”

The Greek physician, Clarissimus Galen, who became the physician to Roman Emperor Marcus Aurelius in 174 AD, wrote of tuberculosis and recommended fresh air, milk, and sea voyages as its treatment.

Records of tuberculosis are also found in the Biblical books of Deuteronomy and Leviticus, which use the ancient Hebrew word schachepheth for the disease [Figure 11].[10]
Figure 11: The Biblical books of Deuteronomy and Leviticus have used the ancient Hebrew word schachepheth for tuberculosis.

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  The Royal Healing Touch Top


487AD – 17th century

Since the very early days, tuberculosis of lymph glands of the neck was given the name scrofula. The disease was first described, in all probability, by Aristotle (384–322 BCE) and Cassius Felix (447 CE), and was known to eventually produce ulceration and suppuration.[11]

In the olden times, scrofula was also known as the King's Evil since it was believed it could be cured by the King's touch. The faith had its origins with Clovis of France (487–511), and later other European monarchs such as Robert the Pious (972–1031), Edward the Confessor (1003–1066) and Philip I of France (1052–1108) reinforced this belief. The practice was common after the 13th century and carried forward by the English and French monarchs. The Dutch naval surgeon and later a surgeon to King Charles II army, Richard Wiseman, wrote on the theme of King's evil and its cure by the King in 1672 in his Treatise of the King's Evil in the fourth book of his Chirurgical Treatises. The British monarch touched 92,102 subjects during his 25 year reign [Figure 12].[12]
Figure 12: Charles II (29 May 1630–6 February 1685), King of England, Scotland and Ireland, lays his hands on a subject to cure him. He touched 92,102 subjects with cervical lymph nodal tuberculosis during his 25 year reign.

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Shakespeare in Macbeth, Act IV, Scene 3, refers to King Edward curing a “wretched crew of souls” of scrofula:

“… strangely-visited people,

All swoln and ulcerous, pitiful to the eye,

The mere despair of surgery, he cures;

Hanging a golden stamp about their necks,

Put on with holy prayers.; and 'tis spoken,

To the succeeding royalty he leaves.

The healing benediction … “

It was not known then however that scrofula was related to phthisis or consumption. Sylvius de la Boë, Richard Morton and René Laennec all recognised that scrofula often occurred in association with pulmonary phthisis, however the fact the two diseases had the one cause was not known until the 19th century.[9]


  The Birth of the Term “tubercles” Top


1679AD

In 1679, Franciscus Sylvius, an Amsterdam physician [Figure 13], pioneered the use of the term “tubercles” to describe the lesions of phthisis of the lung.[9] He described them by the name of tubercula glandulosa (glandulous tubercles) in his work Opera Medica and described their progression to abscesses, ulcers, and empyema.[9] In addition, Sylvius also described the association between phthisis and a disease of the lymph glands of the neck called scrofula.[9]
Figure 13: Franciscus Sylvius, born Franz de le Boë, was a Dutch physician. He was born on 15 March 1614 in Hanau, Germany, and died on 19 November 1672 in Leiden, Netherlands. He coined the term tubercles and described the course of their natural progression.

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  Tuberculosis in Times of Poetic Prose Top


17th century

English physician Richard Morton [Figure 14], who was also the physician to King James II, described the pathology of pulmonary and other forms of phthisis, tubercles of the lung, and scrofula in his work Phthisiologia published in1689.[9] He considered the disease was transmissible by intimate contact. Morton described the severity of the disease in young people, “the Consumption of Young Men, that are in the Flower of their Age”.
Figure 14: English physician Richard Morton gave the hypothesis that tuberculosis was transmissible by intimate contact with a patient of tuberculosis.

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John Bunyan, the celebrated British author of Pilgrim's Progress, in his 1690 work, “The Life and Death of Mr. Badman” referred to consumption as the Captain of all these men of Death:[13]

“He parts from his wife – diseases attack him under captain consumption, he rots away, and dies in sinful security. Yet the captain of all these men of death that came against him to take him away, was the consumption, for it was that that brought him down to the grave.”


  The Edict Top


1699AD

The earliest European reference to the infectious nature of the disease is found in the 17th century Italian medical literature. An edict issued by the Republic of Lucca in 1699 states 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.”[14]


  Identification of Tuberculous Meningitis Top


1768AD

Scottish physician Robert Whytt [Figure 15] gave the first clinical description of tuberculous meningitis. He is remembered most for his book on diseases of the nervous system. His work gave a robust insight into a number of areas in neurology, which incorporated unconscious reflexes, tubercular meningitis and hysteria. Whytt also served the Royal College of Physicians of Edinburgh as its President.[15]
Figure 15: Scottish physician Robert Whytt (1714–1766) gave the first clinical description of tuberculous meningitis.

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  Pott's Disease Top


1799AD

British surgeon Sir Percival Pott [Figure 16] gave the first description of tuberculous vertebral lesions in 1779. He was the first to record that the condition could produce vertebral collapse and be associated with serious spinal cord symptoms. He captured his excellent clinical description in his Remarks on that Kind of Palsy of the Lower Limbs.[16] The disease has since then been popularly known in medical circles as Pott's disease in recognition of his seminal work.
Figure 16: Sir Percival Pott (6 Jan 1714–22 Dec 1788) was an English surgeon, and one of the founders of orthopedics. He gave the first scientific account of spinal tuberculosis.

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  Laennec's Great Legacy Top


1816AD–1826AD

French physician Rene Theophile Hyacinthe Laennec, working at the Necker-Enfants Malades Hospital, devised the stethoscope in 1816. The stethoscope proved to be a major step in the redefinition of disease from being a bundle of symptoms. With a keen auscultation of the chests of tuberculous patients, and correlating his findings with his observations during autopsy dissection, Laennec identified the characteristic findings of consolidation, pleurisy, and pulmonary cavitation. He explained pulmonary and extra-pulmonary tubercles in detail and showed that they were the first phase of phthisis. Laennec gave a detailed description about how tubercles first appeared in the lung in their “miliary” (millet seed-like) form, progressing to larger tubercles containing “cheese-like” (caseous) material, their breakdown into pus, and eventually forming cavities and empyema [Figure 17]. He also described extra-pulmonary phthitic tubercles in the intestines, liver, meninges and other organs, and tuberculous infection in vertebrae which caused vertebral collapse and spinal cord paralysis.17 Laennec's work is considered to have clearly elucidated the pathogenesis of tuberculosis and unified the concept of the disease, whether pulmonary or extra pulmonary. In Laennec's time, tuberculosis had become epidemic in Europe and its annual mortality rates aggregated to a high of 800-1,000 per 100,000 population per year. Laennec himself fell to tuberculosis in 1826.[17]
Figure 17: French physician Rene Laennec (17 Feb 1781–13 Aug 1826), who devised the stethoscope, made a major contribution to the understanding of tuberculosis by describing the auscultatory and autopsy findings in pulmonary and extra pulmonary tuberculosis.

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  The Baptism Top


1834AD

German physician Johann Lukas Schonlein [Figure 18] coined the term tuber-culosis in 1834 to give the disease its present name. The basis of him naming the disease thus were the pathognomic tubercles found in the disease.[16] The term tuberculosis of the lungs was first employed by Hermann Brehmer, a medical graduate of the University of Berlin, in 1853. He used the term in his doctoral thesis, “De legibus ad initium atque progressum tuberculosis pulmonum spectantibus, translated as “On the Laws concerning the Beginning and Progress of Tuberculosis of the Lungs”.[18] He also referred to tuberculosis being curable in its early stages.
Figure 18: German physician Johann Lukas Schonlein (30 Nov 1793–23 Jan 1864) gave tuberculosis its present name.

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It appears that after this time the term tuberculosis supplanted phthisis, although consumption still remained as the lay term for the disease. Jean Antoine Villemin used the term tuberculose in 1865 and in 1882 Robert Koch used the term tuberkulose, translated to English as tuberculosis, describing his discovery of the bacterium he called Tubercle bacillus, after which the disease was known as either tuberculosis or TB.[9]


  A Fashionable Romantic Malady Top


19th century

Tuberculosis was considered a fashionable disease in the European creative circles during the early 19th century. It was poignantly dubbed the White Plague, mal de vivre, and mal du siècle and was seen as a “romantic disease”. Suffering from tuberculosis was thought to bestow upon the sufferer a heightened sensitivity. The slow progress of the disease allowed for a “good death” as sufferers could arrange their affairs. The disease began to represent spiritual purity, even holiness, and temporal wealth, leading many young, upper-class women to purposefully pale their skin to achieve the consumptive appearance [Figure 19]. Consumptive patients took on the appearance of a thin, pale, melancholy, almost delicate spirit. The wan and pallid facies of the victim was thought to be attractive and it gave women a “terrible beauty”.
Figure 19: A Golden Day Dream by Emily Mary Osborn. Oil on canvas. In the 19th century Europe, tuberculosis began to represent spiritual purity, even holiness, and temporal wealth, leading many young, upper-class women to purposefully pale their skin to achieve the consumptive appearance.

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Essentially, the disease was called “white” because of the extreme anemic pallor of those affected. The term white plague was used by Oliver Wendall Holmes, an American physician and writer, in 1861 in comparing the enormity of the epidemic to other severe plagues of the time.

The disease was romanti-cized in society by such celebrated poets as George Lord Byron [Figure 20], John Keats [Figure 21], and PB Shelley, and writers such as Edgar Allan Poe [Figure 22], Robert Louis Stevenson, Anton Chekov, and Emily Bronte [Figure 23], many of whom themselves died from the disease. The romantic poetry of Keats and Shelley sought to find beauty in the horror and melancholy of consumption. Such poetry of the time was sometimes called “the graveyard poetry”.
Figure 20: English poet George Lord Byron (22 Jan 1788–19 Apr 1824) is known to have said “should like, I think, to die of consumption.”

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Figure 21: John Keats (31 Oct 1795–23 Feb 1821), one of the all time great romantic poets, died of tuberculosis aged only 26 years. Of tuberculosis, he wrote, “Youth grows pale, and spectre thin, and dies.”

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Figure 22: American writer Edgar Allan Poe (19 Jan 1809–7 Oct 1849) with his young wife, Virginia. She had tuberculosis and Poe described her as being ‘delicately, morbidly angelic’. Virginia later succumbed to tuberculosis.

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Figure 23: The three Brontë sisters, in an 1834 painting by their brother Branwell Brontë. From left to right: Anne, Emily and Charlotte. Emily Brontë, her four sisters, and her brother Branwell died in young adulthood from tuberculosis, and their mother also died of tuberculosis.

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George Lord Byron once remarked to his friend, Lord Sligo, “should like, I think, to die of consumption.” When Lord Sligo asked why, Byron replied, “Because then all the women would say 'See that poor Byron – how interesting he looks in dying.'

Considered by many literary critics to be one of the greatest English poets of all times, John Keats began his career as a surgeon's apprentice, but gave up medicine for literary pursuits in 1814. He published his first collection in 1817, and his productive years between 1818 and 1820 yielded some of his best-known poems, including “Endymion”, “Ode to a Nightingale”, “Lamia,” “The Eve of St. Agnes” and “Ode on a Grecian Urn.” On a winter evening in 1818 when Keats was returning to his home in Hampstead Heath from London, he felt ill and immediately went to bed. He suddenly coughed blood onto his pillow and said to his friend John Arbuthnot Brown, “ I know the colour of that blood. It is arterial blood, I cannot be deceived by its colour. It is my death warrant. I must die.” He had tuberculosis. Painting a sketch of the disease, he wrote, “Youth grows pale, and spectre thin, and dies.” In 1821 he left England and went to Italy for health reasons, but died a few months later of tuberculosis, aged only 26 years, leaving his epic poem “Hyperion” unfinished.

American writer, poet, critic and editor Edgar Allan Poe, best known for his evocative short stories and poems, captured the imagination and interest of readers around the world with his imaginative storytelling and tales of mystery and horror which gave birth to the modern detective story. He portrayed his young wife, Virginia, who had tuberculosis as being 'delicately, morbidly angelic'. In 1842 as they were having dinner, Virginia had a sudden coughing fit and hemoptysis and Poe remarked:

“Suddenly she stopped, clutched her throat and a wave of crimson blood ran down her breast. It rendered her even more ethereal.”

Born in Yorkshire, England as a member of the famed Brontë writing clan — which included her sisters Charlotte (author of Jane Eyre) and Anne (author of Agnes Grey) — Emily Brontë, the author of the legendary novel Wuthering Heights, died at the young age of 30, of tuberculosis. Emily began writing Wuthering Heights in 1845 and it was published late in 1847. The book's troubled lovers, the beautiful Catherine Earnshaw and the stormy, troubled Heathcliff, have become famous figures in literature. Emily Bronte described the tuberculous heroine in Wuthering Heights as “rather thin, but young and fresh complexioned and her eyes sparkled like diamonds”.

Polish French composer and pianist of the Romantic period, best known for his solo pieces for piano and his piano concerti, Frédéric Chopin (1 Mar 1810–17 Oct 1849), also died of tuberculosis while still very young. George Sand doted on her phthisic lover, calling Frédéric Chopin, her “poor melancholy angel”.

In France, at least five novels were published expressing the ideals of tuberculosis: Dumas's La Dame aux camélias, Murger's Scènes de la vie de Bohème, Hugo's Les Misérables, the Goncourt brothers' Madame Gervaisais and Germinie Lacerteux, and Rostand's L'Aiglon. The portrayals by Dumas and Murger in turn inspired operatic depictions of consumption in Verdi's La traviata and Puccini's La bohème.

Even after medical knowledge of the disease had accumulated, the redemptive-spiritual perspective of the disease has remained popular. The 2001 film Moulin Rouge based in part on La traviata and the musical adaptations of Les Misérables is a staunch reflection of this tenacious hold of tuberculosis on human creativity.


  Of Poverty, Malnutrition, and Overcrowding Top


18th and 19th century Europe

During the 18th and 19th centuries, tuberculosis raged as an epidemic over most parts of Europe. It was deeply associated with the existing social conditions linked to the industrial revolution — poverty, malnutrition, and overcrowding [Figure 24]. Conditions for the working classes were extremely poor. In mid 18th century London and Hamburg carried high mortality rates of 1,000 per 100,000 people per year. In 1838 and 1839 in England between a quarter and a third of tradesmen and laborers died from tuberculosis compared to a sixth of “gentlemen”.[19]
Figure 24: Venezuelan painter Cristóbal Rojas Poleo's famous work La miseria (the misery), which the artist painted in 1886. The oil on canvas depicts a desolate scene of a young husband sitting next to his supine wife who has just died in an impoverished setting of tuberculosis.

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“The disease picked out and killed a few Princes

and it carried off more than one

bejeweled, tender-hearted courtesan;

but it slaughtered the poor by the million.”[12]

Between 1851 and 1910 in England and Wales four million died from tuberculosis, and more than one third of those aged 15 to 34 and half of those aged 20 to 24 died. Wealthy tuberculosis sufferers could afford to travel in search of sunny and mild climates or seek refuge in mountain sanatoria, whereas poorer people had to look after their own ill consumptive family in dark, unventilated, closed rooms, sealing their own fate to die of the same disease a few years later.


  The Big Riddle Top


19th century

Until the great maestro Robert Koch's momentous discovery of the tubercle bacillus in 1882, the pathology and transmission of phthisis was a piece of profound intrigue for the 19th century physicians. At that time, a big debate centered on two important questions: firstly, whether the disease was infectious, hereditary, or a form of cancer; and secondly, whether scrofula, tubercles, and phthisis were separate disease entities or manifestations of the one disease.

The most prominent proponents of a single entity were Rene Laennec and the Viennese pathologist Carl von Rokitansky. In contrast, Giovanna Battista Morgagni of Padua, and German physicians Rudolf Virchow and Johann Lukas Schonlein believed the diseases were separate entities.[9]

By the 18th century many Italian physicians had come to believe that phthisis was infectious, and avoided doing autopsies on patients who had died from phthisis to protect themselves and their students. Many British and American physicians however still thought phthisis to be hereditary or due to constitutional weakness. A fourth school of thought was that phthisis was related to zymes, chemicals that themselves did not cause diseases but acted as catalysts in causing decay within the body and could cause zymotic fevers.[20]

The 19th century saw several big breakthroughs in tuberculosis research that elucidated the infectious nature of the disease. In 1843 Philipp Friedrich Hermann Klencke, a German physician, successfully inoculated rabbits with material from a tubercle although he believed the disease to be cancer. In 1844, Friedrich Gustav Jakob Henle, a German pathologist, postulated that phthisis was infectious.[9]

The first major break-through however occurred in 1865. French military surgeon Jean Antoine Villemin [Figure 25], working at the Army Medical School, Val-de Grace, observed that soldiers stationed for long times in barracks were more likely to have phthisis than soldiers in the field, and healthy army recruits from the country often became consumptive within a year or two of taking up their posts. He showed by controlled experiments that phthisis from humans, or tuberculosis as he also called it in his work Cause et nature de la tuberculose: son inoculation de l'homme au lapin, could be transmitted to rabbits demonstrating that the disease was infectious. Villemin thought that phthisis was similar to glanders, an infectious disease in horses. Villemin's experiments confirmed the contagious nature of the disease and forced the medical community to accept that tuberculosis was indeed an infectious disease, transmitted by some etiological agent of unknown origin.[9]
Figure 25: French military surgeon Jean Antoine Villemin confirmed the contagious nature of tuberculosis in 1865AD.

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  The Great Discovery Top


24th March 1882

German physician Robert Koch, one of the founding fathers of bacteriology, discovered the bacillus that caused tuberculosis in 1882. Son of a mining engineer, Koch went to the University of Göttingen to study medicine, taking his MD degree in 1866. He started his career as a doctor in small German provincial towns. He was in practice in Wollstein (later Wolsztyn in Poland) when his wife gave him a microscope for his thirtieth birthday. He had no other scientific equipment and was cut off entirely from libraries and contact with other scientific workers. Still, he curtained off a part of his consulting room to create a small laboratory for himself in the 4-roomed flat that was his home, and using the microscope and a home-made incubator went on to study and establish the cause of anthrax in spite of the demands made on him by his busy practice [Figure 26]. As a result, in 1880 he was appointed to a post at the Imperial Health Office in Berlin, where he turned his attention to tuberculosis.[21]
Figure 26: German physician Robert Koch isolated the tuberculosis bacillus in 1882AD. His wife's gift of a microscope on his birthday and his great probing mind led him to make a number of seminal bacteriological discoveries.

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Koch used material from cases of pulmonary, extra-pulmonary and meningeal tubercular disease as well as cases of scrofula. For staining Koch used methylene blue in a solution of caustic potash. Culture of the bacteria was difficult, and he eventually used a medium of coagulated bovine serum developed by John Tyndall, a British microbiologist. Koch successfully inoculated the bacteria from the culture to infect laboratory animals. He thus fulfilled the postulates of infectious disease developed by his mentor from Gottingen, Friedrich Gustav Jakob Henle, and which he and Henle later modified to become the Henle-Koch postulates.[21]

Koch used his technique to demonstrate the presence of the bacillus in all forms of human and animal tuberculosis. He thus proved unequivocally that not only the bacillus was the cause, but the many different forms of tuberculosis were manifestations of the one disease entity.[21]

Koch delivered his findings in a lecture to the Berlin Physiological Society on 24th March 1882 at the Charite Hospital in Berlin under the title Die čtiologie der Tuberkulose (The Aetiology of Tuberculosis). The audience of Koch's lecture listened in rapt silence and awe and admiration to what must have been an extraordinarily enlightening presentation. Afterwards the audience rose to look at Koch's cultures and microscope slides of the bacillus. Paul Ehrlich, then assistant bacteriologist to Professor Friedrich von Frerichs at the Charite Hospital, Berlin, and who later discovered Salvarsan and became the founder of immunology and chemotherapeutics, was present at the lecture and remarked, “I hold that evening to be the most important experience of my scientific life.”22

On 10 April 1882 Koch published his lecture in the Berliner Medicinische Wochenschrift, and sent a copy to John Tyndall who in turn published Koch's essential findings in a letter to The Times on 22 April 1882. The letter was subsequently reprinted in the New York Times, the New York Tribune and other newspapers around the world, and within a short time Koch had gained fame in discovering the cause of a scourge that had affected humankind since recorded history.

In his acceptance of his Nobel Prize in 1905 Koch he alluded to the work of his colleague and a fellow bacteriologist, Carl Flugge, that bacilli in droplets from a cough could possibly transmit infection. However it wasn't until the mid-20th century that it was conclusively shown that tuberculosis was transmitted by the inhalation of contaminated air droplets.


  Founding of the Sanatoriums Top


1850s and beyond

The story of the founding of the sanatoriums is closely interwoven with the lives and works of three physicians, Hermann Brehmer, Peter Dettweiler, and Edward Trudeau. Until the first half of the 19th century, though hospitals specializing in the care of consumption had taken shape, these only provided a place for the poor to die rather than to be cured; and for physicians to study the disease. In general, medical leaders presumed that there was no hope of cure for tuberculosis and no medications could help except for bringing a symptom relief.

The founder of the sanatorium movement was the German physician, naturalist and astronomer Hermann Brehmer [Figure 27]. Brehmer graduated in medicine in 1853 with the thesis Tuberculosis primis in stadiis semper curibalibus. In this work, he gave the heretic notion that tuberculosis could be cured. The basis of his thesis was the pathological studies of Rokitansky who showed that healed tubercles could be seen at autopsy and that the heart was atrophic in fatal tuberculosis. Brehmer reasoned that a weak heart reduced the circulation to the lungs and that this predisposed those with the hereditable tendency to develop tuberculosis. Brehmer's work described how appropriate exercise with good nutrition would strengthen the heart, improve the circulation and heal the lungs. Determined to put this idea into practice, Brehmer established a sanatorium in the village of Görbersdorf in Silesia [Figure 28] naming it the Heilanstalt (the healing place).[18],[23] In 1854 he began to treat patients and billeted them in the village. Brehmer's treatment included walks on mountain trails to a waterfall where the patient stood underneath a cold mountain stream, the 'forest douche' or Walddusche, which he supervised personally to counter any objections to the icy water that his patients might give. In the sanatorium his patients were given nutritious food and milk, Hungarian wine with dinner, and French cognac at bedtime. Brehmer published the details of his treatment in 1857 in his work Die Chronische Lungenschwindsucht und Tuberkulose der Lunge: Ihre Ursache und ihr Heilung, “The Laws and Healing of Chronic Tuberculosis of the Lung”.[18],[23]
Figure 27: German physician Hermann Brehmer (14 Aug 1826–28 Dec 1889). He founded the sanatorium movement.

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Figure 28: Heilanstalt (the healing place): sanatorium established in the village of Görbersdorf in Silesia in 1854 by Hermann Brehmer.

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The second leader of the sanatorium movement was Peter Dettweiler who contracted consumption while serving as a surgeon in the military. He recovered at Görbersdorf, served again in the 1870 French war, but the disease relapsed and he returned. With improvement he became Brehmer's assistant. In 1875 he founded his own sanatorium at Falkenstein in the hills close to Frankfurt. He mainly focused on rest as the chosen treatment, and did not think mountains played any major role in healing.[23]

Edward Trudeau introduced sanatoria to North America. As a young physician, he had become a victim of tuberculosis and in 1873 to spend his last days he chose the Adirondack Mountains of New York, where he could pursue his pleasures of hunting and shooting. However his disease remitted, and as his health improved, he returned to medicine and began to read journals. He described how he read in 1882 of an account of Brehmer's sanatorium in Anstie's English The Practitioner. Inspired by this he resolved to develop a similar institution in Saranac. In 1885 his first accommodation, “The Little Red Cottage” for consumptives opened. He determined to work for free and provide care “for working men and women who came here with short purses.”[23]

Towards the end of the 19th century sanatoria were also built for the poorer classes. They were much less salubrious with plainer food, and the patients had to work and do their own housekeeping. Rooms in sanatoria were sometimes ventilated with stringent airs – creosote, turpentine and eucalyptus. Tuberculosis sanatoria became an important treatment in many countries well into the 20th century and many urban hospitals had open air wards as sanatoria. Sanatoria treatment was often beneficial for patients with minimal disease, but many with severe infection still died.[23]


  The first Sanatoriums in India Top


The early 1900s

A sanatorium for “consumptive girls” was opened at Tilaunia between Ajmer and Phalera by the American Methodist Episcopal Church in 1907. It was particularly meant for girls from the boarding schools and orphanages in Northern India that were connected with the mission. Cases of advanced consumption were said to be welcomed, and then segregated, rather than being turned away. A second smaller sanatorium, also established under mission auspices was started at Almora in 1908 [Figure 29].[24]
Figure 29: London Missionary Society Buildings, Almora, India, which began operations as a sanatorium in 1908.

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The first sanatorium to be established under Indian management was opened in 1909 at Dharmpur near Kasauli, and the first government run sanatorium was the King Edward VII sanatorium started at Bhowali near Nainital which opened in 1912.[24]

A variety of other institutions were set up around this time for the open air treatment of tuberculosis, but in general only those people who could pay for their stay were admitted, and by around 1920 there were less than 500 beds available in all these institutions. A number of special wards were also set up in civil hospitals, but they could do little more than provide segregation and “open air treatment”. The numbers that could be accommodated though was tiny compared with the need.[24]


  Of Pneumothorax and Other Surgical Treatments Top


Late 1880s …

From the late 1880s, sanatoria treatment was supplemented by surgical treatment and collapse therapy, or pneumothorax therapy. The benefit of lung collapse was first suggested in 1771 by Edmond Claude Bourru of Faculte de Medicine in Paris. In 1885 Edouard Bernard de Cerenville, a Swiss surgeon, and in 1890 Max Schede, a German surgeon, performed thoracoplasty, unilateral partial rib resection to reduce thoracic cavity volume and collapse tuberculous cavities, the principle being to allow them to heal and prevent spread of infection.[12],[21]

In 1888 Carlo Forlanini, an Italian physician of Pavia, Lombardy, created the first artificial pneumothorax by collapsing the lung and filling the pleural cavity with nitrogen [Figure 30]. Other forms of surgical treatment were used such as lobectomy and segmentectomy, but were commonly complicated by the spread of the infection, fistulas and empyema. In the 1940s the space created by surgical pneumothorax was filled with oil ('oleothorax').[12],[21]
Figure 30: Creating an artificial pneumothorax to treat tuberculosis of the lung.

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Subsequent to the introduction of streptomycin in 1945 and other anti-tuberculous drugs, all forms of surgical treatment were largely abandoned in favor of drug treatment, though they still come in useful in patients with a drug-resistant disease.


  Just Two Minutes Top


1900s …

The big discovery of X-rays in 1895 by the German physicist Wilhelm Konrad von Rontgen proved to be a major boon in the diagnosis and control of tuberculosis. The X-rays could show tuberculosis in the lung in its various stages, especially the Ghon focus and the apical cavitation and calcification.

X-ray screening was introduced for military recruits during World War I and then for the general population through to World War II [Figure 31] where it was again used to screen military recruits.[21] Its efficacy in population screening, however, was found to be rather low and the mass miniature radiography was brought to a stop in the 1950s. However, chest radiography still continues to be a cheap means of individual diagnostic screening.
Figure 31: Mass chest radiography became a screening mantra for detecting early pulmonary tuberculosis. Its low yield rate however led to its abandonment in the 1950s.

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  The Mantoux Test Top


1907AD

French physician Charles Mantoux [Figure 32] introduced a serological skin test to determine whether a person is infected with tuberculosis.[21] The test which employs intradermal instillation of purified protein derivative of tuberculosis bacteria is best known as the Mantoux test, but it is also called as the tuberculin sensitivity test, Pirquet test, or PPD test. The test works on the simple principle that a person who has previously been exposed to the tuberculosis bacteria would demonstrate an immune response towards the bacterial proteins and this would produce a skin reaction. A positive result indicates TB exposure.
Figure 32: The Mantoux skin test consists of an intradermal injection of one-tenth of a millilitre (ml) of PPD tuberculin.

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  The Bcg Vaccine Top


1921AD

In 1900 two French bacteriologists and Pastoriens, Albert Calmette and Camille Guerin, began their research for an antituberculosis vaccine at the Pasteur Institute in Lille. By 1908, by successive sub culturing a virulent strain of Mycobacterium bovis on a medium containing ox bile, they were able to produce a non-virulent strain which they formulated into a live attenuated vaccine. By 1919 Calmette and Guerin [Figure 33] showed the effectiveness of their vaccine in animals and called their vaccine Bacille Calmette-Guerin or BCG. In 1921 the first human administration of BCG was performed by two French physicians, Benjamin Weille-Halle and Raymond Turpin, at the Charite Hospital, Paris.
Figure 33: French scientists, Camille Guerin (left) and Albert Calmette (right), developed the Bacillus Calmette-Guerin vaccine.

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The vaccine was given to an infant born of a mother who died from tuberculosis shortly after giving birth, the child survived and did not contract the disease. The vaccine soon became popular throughout Europe and over the next seven years over one hundred thousand children were immunized.[20],[21]

In 1930 popular confidence in the vaccine was greatly affected when in Lubeck in Germany 250 children were given a BCG vaccine that had been accidently contaminated by virulent tubercle bacilli, 73 of the children died in the first year from tuberculosis infection and a further 135 were infected but recovered.[9]

World War II was followed by a resurgence of tuberculosis throughout Europe and Asia and in 1948 UNICEF undertook a tuberculosis control program of tuberculin testing and BCG vaccination in children and many countries followed suit.

Routine BCG vaccination was discontinued in most parts of the world in the 1970s. However, it is still given in many countries with a high prevalence of tuberculosis, including India, to prevent childhood tuberculous meningitis and miliary disease, and for health care and military personnel and other people at high risk of exposure to tuberculosis.


  Birth of Antituberculous Drugs Top


1940s and beyond

Just before his demise in 1916, American physician Edward Trudeau, had penned a communication to the British Journal of Tuberculosis which was later published posthumously. It stated:

“My faith in the possibilities of chemotherapy for tuberculosis is based simply on what Ehrlich has demonstrated as possible in syphilis – namely, that a chemical compound could be discovered which killed the germ without injuring the cell. I see no reason why what has been accomplished in the treatment of syphilis should not be attained in tuberculosis.”

Edward Trudeau's prophesy came true in the 1940s. Working at Rutgers University with funding from a drug company Merck and Co., Ukrainian born American microbiologist Selman Waksman and his colleagues Albert Schatz and Elizabeth Bugie isolated streptomycin from the fungi Streptomyces griseus [Figure 34].[9] Streptomycin was found to be highly effective against tuberculosis and the human body could tolerate it well.[9] The year was 1944. Round about the same time, in 1943-44, Jörgen Lehmann, a Swedish physician, developed 4-para-aminosalicylic acid (PAS) and in 1945 Gerhard Domagk, a German bacteriologist, developed thiosemicarbazone. Both the finds were successful against the bacillus.[9]
Figure 34: Microbiologists Selman Waksman, Albert Schatz and Elizabeth Bugie isolated streptomycin from the fungi Streptomyces griseus in 1944.

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Waksman received the Nobel Prize in 1952 for his historic discovery, but by then, the tubercular bacillus had been bested, nay vanquished. In 1948, researchers at Britain's Medical Research Council had established the efficacy of a combined treatment with streptomycin and 4-aminosalicylic acid against tuberculosis, proving that the combination was superior to the use of any single drug. Just four years later, in 1952, Isoniazid came to the fore revolutionizing the treatment of tuberculosis. The same year, amino acid derivative cycloserine was isolated. Cycloserine was also found to be effective against mycobacterium tuberculosis. In 1962, the bacteriostatic drug ethambutol was developed. Nine years later, in 1971, antibiotic Rifampicin broke ground. The therapeutic machine against tuberculosis was willy-nilly complete, although more was to follow, in the terms of second line of drugs used in drug resistant infections.


  The Chingleput (Madras) Trial Top


1956–1961AD

The first randomized control trial, often referred to as the Madras Classic, was a comparison of domiciliary chemotherapy with treatment in sanatorium, and comm-enced in September 1956 in the district of Chingleput. The results of this trial, the first of its kind, demonstrated that domiciliary chemotherapy was by no means inferior to institutional treatment in terms of therapeutic efficacy during drug intake, relapse during a 4-year follow-up period, and incidence of tuberculosis over 5 years in close family tuberculosis [Figure 35]. These startling findings peremptorily dismissed several time-honoured beliefs, and laid the foundation for India's policy of mass domiciliary chemotherapy in the treatment of tuberculosis.
Figure 35: The Chingleput trial was the first randomized control trial to establish that domiciliary chemotherapy was by no means inferior to institutional treatment in terms of therapeutic efficacy.

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  The Comeback Top


1980s and 1990s

Came the 1980s and 1990s, and just as the human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) raised their ugly head producing a severe impairment of human immune system, the tuberculosis bacillus staged a major comeback. Coupling with its newfound half-brother HIV, it surged globally as a major opportunistic infection. The risk of developing tuberculosis was found to be between 12-20 times greater in people living with HIV than those without HIV infection [Figure 36].[25]
Figure 36: In the 1980s and 1990s, as the HIV-AIDS epidemic hit the world, tuberculosis found a new half-brother in it to emerge as a major opportunistic infection.

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WHO estimates that in 2012 there were 8.6 million new cases of tuberculosis, of which 1.1 million had HIV co-infection, and 1.3 million died from tuberculosis. The largest number of new cases of tuberculosis occurred in Asia, accounting for 60% of new cases. Sub-Saharan Africa had the highest rate per population with over 260 new cases per 100,000. Worldwide 15% of patients with tuberculosis have HIV co-infection, and up to 50-80% have HIV co-infection in parts of sub-Saharan Africa.[25]

Tuberculosis continues to be the leading cause of death in people with HIV infection and AIDS, 1 in 3 people with AIDS die from tuberculosis. The incidence of HIV-related tuberculosis has declined in developed countries due to effective anti-TB and anti-HIV treatment, but it still remains a significant health problem in many developing countries.


  Launch of Dots Program Top


1995AD

The World Health Organization launched the Directly Observed Treatment, Short-Course (DOTS) program as a control strategy for tuberculosis. The DOTS program focused on an intermittent, supervised system of drug intake by patient, which eliminated drug default [Figure 37]. It was described by the WHO as “the most important public health breakthrough of the decade in terms of lives saved”.[26]
Figure 37: Launched in 1995, the DOTS program focused on an intermittent, supervised system of drug intake by patient, which eliminated drug default.

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  Developments in Genomics Top


1998AD onwards

In 1998, the mycobacterium tuberculosis (H37Rv strain) genome was sequenced [Figure 38], such that scientists could develop better therapies, ranging from drug treatments for tuberculosis to preventive vaccines against the disease.[27] Two years later, in 2000, the Mycobacterium tuberculosis Structural Genomics Consortium was formed as a worldwide consortium of scientists with the goal of providing a structural basis for the development of therapeutics for tuberculosis.
Figure 38: Deciphering the biology of mycobacterium tuberculosis: the mycobacterium tuberculosis (H37Rv strain) genome.

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The consortium has five core facilities (located at Lawrence Livermore National Laboratory, Los Alamos National Lab, Lawrence Berkeley National Laboratory, University of California, Los Angeles and Texas A and M University) that carry out an increasing fraction of routine tasks such as protein production, crystallization and X-ray data collection.


  Formation of Tb Alliance Top


2000AD

The Global Alliance for TB Drug Development (TB Alliance) got established in Cape Town, South Africa as a non-profit organization dedicated to the discovery and development of new, faster-acting and affordable tuberculosis drugs.


  Stop Tb Partnership Top


2001AD

The Stop TB Partnership took shape in Geneva, Switzerland with the purpose of eliminating tuberculosis as a public health problem. It has 1000 partner organizations, including international, nongovernmental and governmental organizations and patient groups [Figure 39].
Figure 39: Set up in 2001, the Stop TB Partnership program focused on eliminating tuberculosis as a public health problem.

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  The Devil's Own Game Top


1990s and till date

In recent decades multidrug resistant tuberculosis (MDR-TB), tuberculosis which does not respond to at least Isoniazid and Rifampicin, has emerged as a major threat and is present in most countries [Figure 40]. In 2012, the WHO estimated 450,000 cases of MDR-TB worldwide, most of which were in India, China and the Russian Federation. Of them, 10% had extensively drug resistant tuberculosis (XDR-TB).[28],[29]
Figure 40: Since the 1990s, multidrug resistant tuberculosis has emerged as a big challenge at the global community. The tubercular bacillus has kicked in its primeval self survival instinct and has taken quick steps to change its genomic colors.

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MDR-TB is on the rise in many countries, but an international initiative financed by UNITAID is currently making progress in improving the access in participating countries towards diagnostic services for tuberculosis and HIV, and especially in the diagnosis of MDR-TB.


  Bedaquiline Wins Approval Top


2012AD

United States FDA approved bedaquiline for treating multi-drug-resistant tuberculosis. It is the first new drug for tuberculosis in more than forty years.


  The End Tb Strategy Top


2014AD

The World Health Organization and partners launched the first-ever targeted roadmap with key steps and costs to scale up the response to tuberculosis and end tuberculosis-related deaths [Figure 41]. The vision is a world free of tuberculosis, zero deaths, disease and suffering due to tuberculosis; the goal is to end the global tuberculosis epidemic, and the journey is to be punctuated by landmark indicators, including a 95% reduction by 2035 in number of TB deaths compared with 2015; 90% reduction by 2035 in TB incidence rate compared with 2015; and zero TB-affected families facing catastrophic costs due to TB by 2035.[30]
Figure 41: Launched in 2014, the End TB Strategy focuses on achieving a world free of tuberculosis. Whether the strategy shall succeed, only time shall be thy witness.

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Currently, this may appear to be a faraway dream, particularly as the tubercular bacillus has kicked in its primeval self survival instinct to stave off the challenges posed by the antituberculous drugs and has taken quick steps to change its genomic colors, which can confront the boldest and most efficient of treatment programs. Only time shall tell who will score the last hurrah: the bacillus or man!



 
  References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16], [Figure 17], [Figure 18], [Figure 19], [Figure 20], [Figure 21], [Figure 22], [Figure 23], [Figure 24], [Figure 25], [Figure 26], [Figure 27], [Figure 28], [Figure 29], [Figure 30], [Figure 31], [Figure 32], [Figure 33], [Figure 34], [Figure 35], [Figure 36], [Figure 37], [Figure 38], [Figure 39], [Figure 40], [Figure 41]



 

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  In this article
Abstract
The Origin
The first Specimens
Birth of a Tribe
Narrative of the...
The first Writte...
The Royal Healin...
The Birth of the...
Tuberculosis in ...
The Edict
Identification o...
Pott's Disease
Laennec's Gr...
The Baptism
A Fashionable Ro...
Of Poverty, Maln...
The Big Riddle
The Great Discovery
Founding of the ...
The first Sanato...
Of Pneumothorax ...
Just Two Minutes
The Mantoux Test
The Bcg Vaccine
Birth of Antitub...
The Chingleput (...
The Comeback
Launch of Dots P...
Developments in ...
Formation of Tb ...
Stop Tb Partnership
The Devil's ...
Bedaquiline Wins...
The End Tb Strategy
References
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