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S.P. Tripathy1, Kanchan Srivastava2, Surya Kant3 and Rohit Sarin4* 1Director-in-charge, National Institute forResearch in Tuberculosis, Chennai 2Research Scientist, 3 Prof and Head, Department of Respiratory Medicine, King George's Medical University, UP, Lucknow, India 4 Director, The National Institute of Tuberculosis and Respiratory Diseases (NITRD), New Delhi *Email: [email protected] ABSTRACT The culprit, tuberculosis is for sure the most successful conqueror of the human lives as it infects one in three people worldwide every year on a global scale. Thought to be one of the oldest human diseases, over the years not only the medical implications but also the social and economic impact of tuberculosis has been enormous. To make matter worse, the TB bug is infamous for turning resistant to common drugs and invading almost every tissue in the human body, poses a challenge to" Masters of Medicine" with its baffling unsolved problems. Alexander the Great has been indisputably, the greatest of conquerors mankind has witnessed since the dawn of human civilization. But unimaginably, the strength and valor of this all time hero appears stumpy when viewed against the triumphs of the single celled bug that unleashes, across the globe, spelled out as tuberculosis, the captain of all the men of death". KEY WORDS: , Mycobacterium tuberculosis, Romantic Disease, Sanatorium

INTRODUCTION Tuberculosis (TB) and humans have had a long relationship with each other. The relationship has not been a friendly one. For centuries, TB has been a major killer of humans. TB was very common among U.S. in 1940. The devastation wreaked by TB stimulated research that led to several medical breakthroughs during the 19th and 20th centuries. The control of infectious disease, including TB, is regarded as one of the 10 great public health achievements in the 20th century. Indeed, after 1945, our success in treating infectious diseases, including TB, was remarkable. That was "time to close the book on infectious diseases". In 1959, the following words appeared in a report from a conference organized by the Public Health Service (PHS) and the National Tuberculosis Association (now the American Lung Association): "Tuberculosis can be extinguished as a public health problem...If the opportunity to end tuberculosis is not seized now, it may be lost indefinitely" [1, 2, 3]. However, with the important exception of , we have not closed the book on infectious diseases. Although, a victims of TB occur all over the globe, this disease posses a tough challenge in the developing countries, which accounts for about 95% of all TB cases. The resurgence of TB in between 1985 and 1992 was a reminder that while TB is an ancient malady, it is very much a contemporary problem as well- even in industrialized societies and even though we know its cause, how to prevent it, how to treat it, and how to cure it [4]. More than 50 years ago, the microbiologist René Dubos said this about TB; "Tuberculosis is a social disease, and presents problems that transcend the conventional medical approach...Its understanding demands that the impact of social and economic factors on the individual be considered as much as the mechanism by which tubercle bacilli cause damage to the human body."

18 Thought to be one of the oldest human diseases, over the years not only the medical implications but also the social and economic impact of TB has been enormous. To make matter worse, the TB bug is infamous for turning resistant to common drugs and invading almost every tissue in the human body, poses a challenge to" Masters of Medicine" with its baffling unsolved problems. There is a silver line regarding the elimination of TB, our honorable Prime Minister launched a campaign to eradicate TB from India by 2025, five years ahead of a globally-set deadline during inauguration of the Delhi End-TB Summit. He also launched the TB-free India Campaign to take the activities under the National Strategic Plan for TB Elimination forward in a mission mode for ending the by 2025. Affecting the poorest people in society who live in overcrowded areas and maintained poor hygiene, TB is an airborne communicable disease plaguing human populations since antiquity. Sign of tubercular decay have been found in bone fragments of 40000-year old Egyptian mummies. The word "tuberculosis" is a derivative of the Latin world 'tubercula' which means of 'A small lump'. Several names have been used to refer TB. Pulmonary TB has been referred to as "tabes pumonali," Cutaneous TB has been called "lupus vulgaris", Abdominal TB has been called as "tabes Mesenterica,"Acute progressive TB has called "galloping TB"[ 2, 5, 6]. The Stigma of being a victim of TB was so much in total isolation until death. The first reference to TB in early Asian civilization and in The East Ancient India is found in the . In Sanskrit, the disease has been called "Rajayakshma", "Ksayah" and "Sosa". In Yajurveda Samhita, there is a reference to how "Soma" (moon) had been affected by Yakshma. Since Soma was "King and Ruler" was affected by "Yakshma". It came to be known a Rajayakshma". The Yajurveda advises sufferers to move to higher altitudes. The oldest of them (Rigveda, 1500 B.C.) calls the disease yaksma (Book 10, hymn 161).The Atharvaveda calls it another name: balasa. It is in the Atharvaveda that the first description of scrofula is given. The , written around 600 B.C., recommends that the disease be treated with breast milk, various meats, alcohol and rest. The Manu Smriti, written around 1500 B.C., states that sufferers of yaksma are impure and prohibits Brahmans from marrying any women that has a family history of the disease. Apasmaara-Kusstta-Kssaya-Arshah Prameha_ Jvaro[a-U]nmaada-Gulma-Adi-Rogaa Mahaantah | Pishaacaash-Ca Sarve Bhavat-Patra-Bhuutim Vilokya Kssannaat-Taaraka-Are Dravante ||25|| (25.1… Apasmara (Epilepsy), Kussttha (), Kssaya (Consumption), Arsha (Piles), Prameha (Urinary diseases like Diabetes)… 25.2: … Jwara (Fever), Unmada (Madness, Insanity), Gulma (Enlargement of Spleen or other glands in the abdomen) and other formidable Diseases … 25.3: … as also all types of Pisachas (Evil Spirits) … (when) in Your Bibhuti (Sacred Ash) contained in a Leaf … 25.4: … sees You, Who is the Enemy of the formidable Taraka (i.e demon Tarakasura), they hasten to Run away immediately). "The Father of Medicine", identified the illness as the most common cause of illness in his time. Phthisis, Means "to consume" "to spit", and "to waste away" first appeared in Greek literature around 460 BCE. (460 -377 B.C.) Although, Aristotle believed that the disease might be contagious and to be hereditary. , the most eminent Greek physician after Hippocrates, defined phthisis as the "ulceration of the lungs, thorax or throat, accompanied by a cough, fever, and consumption of the body by pus. Ibn Sina/

19 (980-1037 A.D.), a renowned Arabic physician, known as "Arab Galen" described TB in words, "diqq and sulz" in his book," Al-Quanoon-Fit-Tibb," also called "Canon of Avicenna" praised as "Medical Bible". TB was epidemic in and the US in 1600s, probably started in the 17th century and lasted two- hundred years, was known as the "Great White Plague". In Pre-Columbian America/ South America, the first evidence of the disease is found in the Arawak culture around 1050 BCE. Although the most significant finding belongs to the mummy of an 8 to 10-year-old Nascan child from Hacienda Agua Sala, dated to 700 CE. The first evidence of the in humans was found in a cemetery near Heidelberg, in the bone remains that show evidence of the type of angulations often seen with spinal TB. Typical Pott's disease in the body of mummy. Some authors call TB, the first disease known to mankind [7, 8, 9]. The 12th century contained a very extend explanation of the illnesses' cause. With the spread of Christianity, monarchs were seen as religious figures with magical or curative powers. It was believed that , the touch of the sovereign of or France, could cure diseases due to the divine right of sovereigns. This practice was so common in France, that scrofula became known as the "mal du roi" or the "King's Evil". The first mention of TB in Chinese literature in a medical text written by Emperor Shennong of China (2700 BC). Girolamo Fracastoro became the first person to propose, in his work De contagione, that phthisis was transmitted by an invisible virus, usually transmitted through direct contact or the discharged fluids of the infected, what he called fomes [5, 10]. In Seventeenth and eighteenth centuries, Franciscus Sylvius began differentiating between the various forms of TB (pulmonary, ganglion). He was the first person to recognize that the skin ulcers caused by scrofula resembled tubercles seen in phthisis noting that "phthisis" is the scrofula of the lung" in his book Opera Medica published posthumously in 1679. Benjamin Marten (1720) proposed in A New Theory of Consumptions more Especially of Phthisis or Consumption of the Lungs that the cause of TB was some type of Animacula. The theory was rejected and it took another 162 years before Robert Koch demonstrated, it to be true. , (1761) an Austrian physician, developed the percussion method of diagnosing TB, a method rediscovered some years later by John Nicholas of France. Robert Whytt (1768) gave the first clinical description of TB meningitis. Percivall Pott, (1779) an English surgeon, described the vertebral lesions that carry his name. In Systematik de speziellen Pathologie und Therapie, J. L. Schönlein, Professor of Medicine in Zurich, proposed that the word "tuberculosis" be used to describe the affliction of tubercles. Bayle (1774-1816) introduced the term" Tuberculosis" for the first time. The incidence of TB grew progressively during the middle Ages, peaking between the 18th and 19th century [6, 11]. In Nineteenth century it was seen as a "romantic disease." The slow progress of the disease allowed for a "good death" as sufferers could arrange their affairs. The disease began to represent spiritual purity and expanded their wings in Arts and Literature too. There have been references to TB in several works of fiction. Such as the "consumptive lover" of Much Ado About Nothing in William Shakespeare's plays and "Scrofula" in Macbeth. Thomas Mann's The Magic Mountain contains one of the most well known descriptions of TB Sanatorium. TB does not respect anybody. Several important personalities, Statesmen and stateswomen (Mrs. Kamla Nehru, Mohammed Ali Jinnah, Nelson Mandela) Writers and poets (John Keats, Percy Bysshe Shelly Robert Louis Stevenson, Munshi Prem Chand), Mathematician Srinivasa Ramanujan were wiped out by TB [12, 13]. Keats says "I know the colour of that blood. Its arterial blood…That blood is my death warrant, I must die. (Dr. John discovers a drop of blood on the sheet while examining him) and Youth grows pale, and spectre thin, and die"

20 We have known the cause of TB since 1882, when Dr. Robert Koch announced to the world the results of experiments that had led him and his colleagues to identify Mycobacterium tuberculosis (Mtb) as the culprit. He reported his results in an evening lecture to the Physiological Society of Berlin on March 24 of that year. (March 24 is observed each year as World TB Day) and awarded a Noble Prize in Physiology & Medicine in 1905." In 1882, Robert Koch, utilized a new staining method and applied it to the sputum of TB patients, revealing for the first time the causal agent of the disease: Mtb or Koch's bacillus. Villemin's experiments had confirmed the contagious nature of the disease and had forced the medical community to accept that TB was indeed an infectious disease, transmitted by some etiological agent of unknown origin. In the preceding years, Koch and his colleagues had developed methods for growing the tubercle bacillus and had refined a method for staining the bacillus for microscopic observation. The gold standard for the diagnosis of active pulmonary TB is, to this day, based on these two methods developed in Koch's laboratory more than 120 years ago. Another diagnostic test, the skin test was described in 1909. The BCG vaccine was first administered to humans in 1921. It was many years before scientists found a cure for TB, but they did. In 1944, soil microbiologist Selman Waxman and his colleagues at Rutgers University announced they had discovered an antibiotic that could kill the TB germ. That drug, , soon performed miraculous cures TB patients who were deathly ill. Other such "miracles" followed, and by the early 1950s, scientists had discovered several other anti- TB drugs. Four such drugs, when taken in combination for 6-8 months, can cure TB [14, 15]. Mtb is a microscopic, slow growing, rod shaped bacterium that is transmitted through the air when the infected person coughs, sings, spits or sneezes., Acid Fast bacterium that can remain in dried aerosol droplets for as long as eight months. The dust from the dried saliva or sputum might also contain TB bacilli. As the water in these droplets evaporates, microscopic "droplet nuclei" form; the droplets can be inhaled into the deepest recesses of the lungs of another person. The disease can affect any part of the body-except, hair and teeth-but in 85% of cases, this single - celled bacillus primarily attacks the lungs. TB infection is characterized by the formation of tubercles or hard nodules in the lungs that are the results of interaction between the bacteria the hosts immune system. After reaching to the lungs, is engulfed by special cells known as macrophages, but these are unable to digest the bacteria due to its outer waxy cell wall. It begins to multiply within the macrophages. The infected, macrophages result in an inflammatory response, attracts more macrophages, deposition of collagen fibers around the packed macrophages and finally forming a "tubercle". The cells at the center of the tubercle may eventually die giving rise to necrotic /dead tissue. Transmission typically requires extended indoor contact with a person with active pulmonary TB, as TB germs are killed by the ultraviolet light in sunlight [15, 16]. In other words, the tubercle bacillus grows in the "social soil" we give it. If our goal is to control the global TB epidemic, then understanding the social soil in which TB thrives will be just as important as understanding the TB germ itself and how it interacts with the human organism. Even today, despite the availability of a preventive vaccine and potent drugs to contain this disease, TB remains a daunting adversary.

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21 4. World Health Organization. Global Tuberculosis Report 2018. Geneva: World Health Organization. Available from: http://www.who.int/tb/ publications/global report/en/2018. 5. Waksman, Selman A. The Conquest of Tuberculosis. University of California Press Berkeley and Los Angeles. 1964 6. Zink A, Sola C, Reischl U, Grabner W, Rastogi N, et al, Characterization of Mycobacterium tuberculosis complex DNAs from Egyptian mummies by spoligotyping J Clin Microbiol 2003; 41 (1): 359-67. 7. Dubos R J, Dubos J. The White Plague: Tuberculosis, Man, and Society. Rutgers University Press. 1987 8. Rubin SA, Tuberculosis. Captain of all these men of death. Radiol Clin North Am. 1995 ; 33(4):619-39. 9. Kant S, Srivastava K, Singh S et al, Update history of tuberculosis. LMJ, 2011; 1(1):2-11. 10. Barnes, David S. The Making of a Social Disease: Tuberculosis in Nineteenth-century France. University of California Press. 1995.ISBN 0520087720. 11. Steinbach G Percivall Pott: tuberculous spondylitis. J Emerg Med. 1996;14(1):79-83. 12. Webb GB , Tuberculosis, New York: Hoeber; 1936 13. McCarthy OR, The key to the sanatoria J R Soc Med, 2001; 94 (8): 413-7. 14. Sakula A Robert Koch, Centenary on the discovery of the tubercle bacillus.1882.Thorax 1983; 37; 246-51 15. Koch R (10 April 1882). "Die Ätiologie der Tuberculose". Berliner Klinischen Wochenschrift 15: 221-230.32 16. Paolo W, Nosanchuk J, Tuberculosis in New York City: recent lessons and a look ahead. Lancet Infect Dis, 2004; 4 (5): 287- 93.

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