History of leprosy

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G. H. A. Hansen, discoverer of M. leprae

Evidence of leprosy dates back to ancient Egypt in 4000 BCE and was discussed by Hippocrates in 460 BCE.[1] The earliest proven human case was verified by DNA taken from the shrouded remains of a man discovered in a tomb next to the Old City of Jerusalem dated by radiocarbon methods to 1–50 CE[2] The term leprosy is derived from either the Indo–European term lap, which means the removal of scales or the Greek word for scales, lepra.[3] Historical people infected were often confined against their will in leper colonies, and in Medieval Europe were required to carry a bell to identify their presence.[4] Treatments have included arsenic, elephants' teeth, creosote, and mercury.[4]

The causative agent of leprosy, Mycobacterium leprae, was discovered by G. H. Armauer Hansen in Norway in 1873, making it the first bacterium to be identified as causing disease in humans.[5] The first effective treatment (promin) became available in the 1940s.[1] The search for further effective anti-leprosy drugs led to the use of clofazimine and rifampicin in the 1960s and 1970s.[6] Later, Indian scientist Shantaram Yawalkar and his colleagues formulated a combined therapy using rifampicin and dapsone, intended to mitigate bacterial resistance.[7] Multidrug therapy (MDT) combining all three drugs was first recommended by the WHO in 1981. These three anti-leprosy drugs are still used in the standard MDT regimens.

Discovery[edit]

After the end of the 17th century, Norway, Iceland and England were the countries in Western Europe where leprosy was a significant problem. During the 1830s, the number of lepers in Norway, Iceland and England rose rapidly, believed to be caused by frequent visits of sailors who visited Western India, causing an increase in medical research into the condition, and the disease became a political issue. Norway appointed a medical superintendent for leprosy in 1854 and established a national register for lepers in 1856, the first national patient register in the world.[8]

Mycobacterium leprae, the causative agent of leprosy, was discovered by G. H. Armauer Hansen in Norway in 1873, making it the first bacterium to be identified as causing disease in humans.[5][9] The principal opposition to Hansen's view that leprosy was an infectious disease came from his father-in-law, Daniel Cornelius Danielssen who considered it a hereditary disease and had stated this in his book, "Traité de la Spedalskhed ou Elephantiasis des Grecs"—the standard reference book on leprosy from 1848 until the death of Danielssen in 1895.[10] While Danielssen's book in 1847 was a highly used source and provided a solid foundation for worldwide leprosy understanding, it was soon surpassed. In 1867 Dr. Gavin Milroy finished the Royal College of Physicians' Report on leprosy. His work, which compiled data from all corners of the English empire, agreed with Danielssen that leprosy was a hereditary disease, but went further to state that leprosy was also a constitutional disease that could be mitigated by improvements in one's health, diet, and living conditions.[11]

Hansen observed a number of nonrefractile small rods in unstained tissue sections. The rods were not soluble in potassium lye, and they were acid- and alcohol-fast. In 1879, he was able to stain these organisms with Ziehl's method and the similarities with Koch's bacillus (Mycobacterium tuberculosis) were noted. There were three significant differences between these organisms: (1) the rods in the leprosy lesions were extremely numerous, (2) they formed characteristic intracellular collections (globii), and (3) the rods had a variety of shapes with branching and swelling. These differences suggested that leprosy was caused by an organism related to but distinct from Mycobacterium tuberculosis. He worked at St. Jørgens Hospital in Bergen, founded early in the fifteenth century. St. Jørgens is now preserved as a museum, Lepramuseet.[12]

Etymology[edit]

The word leprosy comes from ancient Greek Λέπρα [léprā], "a disease that makes the skin scaly", in turn, a nominal derivation of the verb Λέπω [lépō], "to peel, scale off". Λέπος (Lepos) in ancient Greek means peel, or scale, so from Λέπος we have Λεπερός (Λεπερός = who has peels—scales) --> and then Λεπρός(=leprous).[13] The word came into the English language via Latin and old French. The first attested English use is in the Ancrene Wisse, a 13th-century manual for nuns ("Moyseses hond..bisemde o þe spitel uuel & þuhte lepruse." The Middle English Dictionary, s.v., "leprous"). A roughly contemporaneous use is attested in the Anglo-Norman Dialogues of Saint Gregory, "Esmondez i sont li lieprous" (Anglo-Norman Dictionary, s.v., "leprus").

Throughout history, individuals with leprosy have been known as lepers; however, this term is falling into disuse as a result of the diminishing number of leprosy patients. Because of the stigma to patients, some prefer not to use the word "leprosy," though the term is used by the U.S. Centers for Disease Control and Prevention and the World Health Organization.[14] Historically, the term Tzaraath from the Hebrew Bible was, accurately translated as leprosy, the symptoms of unclean version of Tzaraath were entirely consistent with leprosy. The first mention of leprosy recorded is found in Leviticus 13:2 - "When a man shall have in the skin of his flesh a rising, a scab, or bright spot, and it be in the skin of his flesh like the plague of leprosy; then he shall be brought unto Aaron the priest, or unto one of his sons the priests." There is also the well-known Bible story of the Syrian Naaman, "captain of the host of the king of Syria" (2 Kings 5:2), who apparently had the clean version of Leprosy, or skin disease, which would be manifest by his skin losing its pigment and becoming a Leprous white, in other words a clean leper. This form of Clean Leprosy as described in Leviticus 13:17[15] is described as white skin without the scaly, or bright red or white spots that come along with the unclean version. The clean form of leprosy described upon Moses' hand in Exodus 4:6, 7[15] is what modernity has relabeled as Vitiligo, where the skin is void of Melanin. The reason this is not the unclean version is due to the way the unclean version is kept away from clothes, because if the unclean leprosy comes in contact with any clothes they must be burned due to its contagious properties as described in Leviticus 13:47-59,[15] this was not the case with the miracle that was demonstrated upon Moses hand since he was not told afterwards to destroy his garments since it would be infected.

In particular, tinea capitis (fungal scalp infection) and related infections on other body parts caused by the dermatophyte fungus Trichophyton violaceum are abundant throughout the Middle East and North Africa today and might also have been common in biblical times. Likewise, the related agent of the disfiguring skin disease favusTrichophyton schoenleinii appears to have been common throughout Eurasia and Africa before the advent of modern medicine. Persons with severe favus and similar fungal diseases (and potentially also with severe psoriasis and other diseases not caused by microorganisms) tended to be classed as having leprosy as late as the 17th century in Europe.[16] This is clearly shown in the painting The Regents of the Leper Hospital in Haarlem 1667 by Jan de Bray (Frans Hals Museum, Haarlem, the Netherlands), where a young Dutchman with a vivid scalp infection, it is presumed caused by a fungus, is shown being cared for by three officials of a charitable home intended for leprosy sufferers.[citation needed] The use of the word "leprosy" before the mid-19th century, when microscopic examination of skin for medical diagnosis was first developed, can seldom be correlated reliably with leprosy as we understand it today.[citation needed]

Historical treatments[edit]

The disease was known in Ancient Greece as elephantiasis (elephantiasis graecorum). At various times blood was considered to be a treatment either as a beverage or as a bath.[citation needed] That of virgins or children was considered to be especially potent.[citation needed] This practice seems to have originated with the Ancient Egyptians but was also known in China. This practice persisted until at least 1790, when the use of dog blood was mentioned in De Secretis Naturae. Paracelsus recommended the use of lamb's blood and even blood from dead bodies was used.

Snakes were also used, according to Pliny, Aretaeus of Cappadocia, and Theodorus. Gaucher recommended treatment with cobra venom. Boinet, in 1913, tried increasing doses of bee stings (up to 4000). Scorpions and frogs were used occasionally instead of snakes. The excreta of Anabas (the climbing fish) was also tried.

Alternative treatments included scarification with or without the addition of irritants including arsenic and hellebore. Castration was also practiced in the Middle Ages.

A common pre-modern treatment of leprosy was chaulmoogra oil.

The oil has long been used in India as an Ayurvedic medicine for the treatment of leprosy and various skin conditions. It has also been used in China and Burma, and was introduced to the West by Frederic John Mouat, a professor at Bengal Medical College. He tried the oil as an oral and topical agent in two cases of leprosy and reported significant improvements in an 1854 paper.[17]

This paper caused some confusion. Mouat indicated that the oil was the product of a tree Chaulmoogra odorata, which had been described in 1815 by William Roxburgh, a surgeon and naturalist, while he was cataloging the plants in the East India Company’s botanical garden in Calcutta. This tree is also known as Gynocardia odorata. For the rest of the 19th century, this tree was thought to be the source of the oil. In 1901, Sir David Prain identified the true chaulmoogra seeds of the Calcutta bazaar and of the Paris and London apothecaries as coming from Taraktogenos kurzii, which is found in Burma and Northeast India. The oil mentioned in the Ayurvedic texts was from the tree Hydnocarpus wightiana, known as Tuvakara in Sanskrit and chaulmugra in Hindi and Persian.

The first parenteral administration was given by the Egyptian doctor Tortoulis Bey, personal physician to the Sultan Hussein Kamel of Egypt. He had been using subcutaneous injections of creosote for tuberculosis and in 1894 administered subcutaneous injection of chaulmoogra oil in a 36-year-old Egyptian Copt who had been unable to tolerate oral treatment. After 6 years and 584 injections, the patient was declared cured.

An early scientific analysis of the oil was carried out by Frederick B. Power in London in 1904. He and his colleagues isolated a new unsaturated fatty acid from the seeds, which they named 'chaulmoogric acid'. They also investigated two closely related species: Hydnocarpus anthelmintica and Hydnocarpus wightiana. From these two trees they isolated both chaulmoogric acid and a closely related compound, 'hydnocarpus acid'. They also investigated Gynocardia odorata and found that it produced neither of these acids. Later investigation showed that 'taraktogenos' (Hydnocarpus kurzii) also produced chaulmoogric acid.

Another difficulty with the use of this oil was administration. Taken orally it is extremely nauseating. Given by enema may cause peri-anal ulcers and fissures. Given by injection the drug caused fever and other local reactions. Despite these difficulties, a series of 170 patients were reported in 1916 by Ralph Hopkins, the attending physician at the Louisiana Leper Home in Carville, Louisiana. He divided the patients into two groups - 'incipient' and 'advanced'. In the advanced cases, 25% (at most) showed any improvement or arrest of their condition; in the incipient cases, 45% reported an improvement or stabilization of the disease (mortality rates were 4% and 8%, respectively). The remainder absconded from the Home apparently in improved condition.

Given the apparent usefulness of this agent, a search began for improved formulations. Victor Heiserthe Chief Quarantine Officer and Director of Health for Manila and Elidoro Mercado the house physician at the San Lazaro Hospital for lepers in Manila decided to add camphor to a prescription of chaulmoogra and resorcin, which was typically given orally at the suggestion of Merck and Company in Germany to whom Heiser had written. They found that this new compound was readily absorbed without the nausea that had plagued the earlier preparations.

Heiser and Mercado in 1913 then administered the oil by injection to two patients who were cured of the disease. Since this treatment was administered in conjunction with other materials, the results were not clear. A further two patients were treated with the oil by injection without other treatments and again appeared to be cured of the disease. The following year, Heiser reported a further 12 patients but the results were mixed.

Less toxic injectable forms of this oil were then sought. Between 1920 and 1922, a series of papers were published describing the esters of these oils. These may have been based on the work of Alice Ball—the record is not clear on this point and Ms Ball died in 1916. Trials of these esters were carried out in 1921 and appeared to give useful results.

These attempts had been preceded by others. Merck of Darmstadt had produced a version of the sodium salts in 1891. They named this sodium gynocardate in the mistaken belief that the origin of the oil wasGynocardia odorata. Bayerin 1908 marketed a commercial version of the esters under the name 'Antileprol'.

To ensure a supply of this agent Joseph Rock, Professor of Systematic Botany at the College of Hawaii, traveled to Burma. The local villagers located a grove of trees in seed, which he used to establish a plantation of 2,980 trees on the island of Oahu, Hawaii between 1921 and 1922.

The oil remained a popular treatment despite the common side effects until the introduction of sulfones in the 1940s. Debate about its efficacy continued until it was discontinued.

Asylums[edit]

Medieval leper bell

A common solution to the leper question across Europe and Asia from the 13th century lasting into the 20th century in some parts of the world was a leper asylum, commonly referred to as a leprosarium. These hospitals were oftentimes a voluntary reprieve from constant stigmatization as well as a source of medicine and healing. However, sometimes, particularly during 14th and 19th centuries when fear of leprosy was at a high point, admission to leprosariums was mandatory by all those diagnosed with or thought to have leprosy. When the fear of leprosy was rampant in societies across Europe and Asia there was also an associated rise in crime levels and overall dissatisfaction amongst the population. The leprosariums created during these times had multiple benefits: first, they provided treatment and safe living quarters for all lepers that were admitted; secondly, they eased tension amongst the healthy townspeople; and thirdly, they provided for a more stable populace for the authorities to govern.[11][18]

Numerous leprosaria, or leper hospitals, sprang up in the Middle Ages; Matthew Paris, a Benedictine Monk, estimated that in the early thirteenth century there were 19,000 across Europe.[19] The first recorded Leper colony was in Harbledown, England. These institutions were run along monastic lines and, while lepers were encouraged to live in these monastic-type establishments, this was for their own health as well as quarantine. Indeed, some medieval sources indicate belief that those suffering from leprosy were considered to be going through Purgatory on Earth, and for this reason their suffering was considered holier than the ordinary person's. More frequently, lepers were seen to exist in a place between life and death: They were still alive, yet many chose or were forced to ritually separate themselves from mundane existence.[20] The Order of Saint Lazarus was a hospitaller and military order of monks that began as a leper hospital outside Jerusalem in the twelfth century and remained associated with leprosy throughout its history. The first monks in this order were leper knights, and they originally had leper grand masters, although these aspects of the order changed over the centuries.

Radegund was noted for washing the feet of lepers. Orderic Vitalis writes of a monk, Ralf, who was so overcome by the plight of lepers that he prayed to catch leprosy himself (which he eventually did). The leper would carry a clapper and bell to warn of his approach, and this was as much to attract attention for charity as to warn people that a diseased person was near.

Modern treatments[edit]

MDT patient packs and blisters

It has been said that Promin was first synthesised in 1940 by Feldman of Parke-Davis and company.[21] Although Parke-Davis did in fact synthesise the compound, it seems certain that they were not the first; in cooperation with J. Wittmann, Emil Fromm synthesised both dapsone and some of its derivatives, including promin, in 1908. He was however a chemist and not a medical worker, nor did anyone investigate its medical value until some decades afterwards.[22]

Until the introduction of treatment with promin in the 1940s, there was no effective treatment for leprosy. The efficacy of promin was first discovered by Guy Henry Faget and his co-workers in 1943 at Carville, Louisiana. In the 1950s dapsone was introduced to Carville by Dr. R.G. Cochrane. It is only weakly bactericidal against M. leprae and it was considered necessary for patients to take the drug indefinitely. When dapsone was used alone, the M. leprae population quickly evolved antibiotic resistance; by the 1960s, the world's only known anti-leprosy drug became virtually useless.

The search for more effective anti-leprosy drugs led to the use of clofazimine and rifampicin in the 1960s and 1970s.[6] Later, Indian scientist Shantaram Yawalkar and his colleagues formulated a combined therapy using rifampicin and dapsone, intended to mitigate bacterial resistance.[7] The first trials of combined treatment were carried out in Malta in the 1970s.

Multidrug therapy (MDT) combining all three drugs was first recommended by a WHO Expert Committee in 1981. These three anti-leprosy drugs are still used in the standard MDT regimens. None of them is used alone because of the risk of developing resistance.

This treatment was quite expensive, and was not quickly adopted in most endemic countries. In 1985, leprosy was still considered a public health problem in 122 countries. The 44th World Health Assembly (WHA), held in Geneva in 1991, passed a resolution to eliminate leprosy as a public-health problem by the year 2000 — defined as reducing the global prevalence of the disease to less than 1 case per 10,000. At the Assembly, the World Health Organization (WHO) was given the mandate to develop an elimination strategy by its member states, based on increasing the geographical coverage of MDT and patients’ accessibility to the treatment.

Iran[edit]

The Persian polymath Avicenna (c. 980–1037) was the first outside of China to describe the destruction of the nasal septum in those suffering from leprosy.[23]

India[edit]

Main article: Leprosy in India

The Oxford Illustrated Companion to Medicine holds that the mention of leprosy, as well as cures for it, were already described in the Hindu religious book Atharva-veda.[24] Writing in the Encyclopædia Britannica 2008, Kearns & Nash state that the first mention of leprosy is in the Indian medical treatise Sushruta Samhita (6th century BC).[25] The Cambridge Encyclopedia of Human Paleopathology (1998) holds that: "The Sushruta Samhita from India describes the condition quite well and even offers therapeutic suggestions as early as about 600 BC"[26] The surgeon Sushruta lived in the Indian city of Kashi by the 6th century BC,[27] and the medical treatise Sushruta Samhita—attributed to him—made its appearance during the 1st millennium BC.[25] The earliest surviving excavated written material that contains the works of Sushruta is the Bower Manuscript—dated to the 4th century AD, almost a millennium after the original work.[28] Despite the existence of these earlier works the first generally considered accurate description of the disease was that of Galen of Pergamum in 150 AD.[citation needed]

In 2009, a 4,000-year-old skeleton was uncovered in India that was shown to contain traces of leprosy.[29] The discovery was made at a site called Balathal, which is today part of Rajasthan, and is believed to be the oldest case of the disease ever found.[30] This pre-dated the previous earliest recognized case, dating back to 6th-century Egypt, by 1,500 years.[31] It is believed that the excavated skeleton belonged to a male, who was in his late 30s and belonged to the Ahar Chalcolithic culture.[31][32] Archaeologists have stated that not only does the skeleton represent the oldest case of leprosy ever found, but is also the first such example that dates back to prehistoric India.[33] This finding supports one of the theories regarding the origin of the disease, which is believed to have originated in either India or Africa, before being subsequently spread to Europe by the armies of Alexander the Great.[30]

In 1874, the Missions to Lepers Act was brought about as a means to treat leprosy by segregating males and females in the institutions.[34] The asylum superintendents believe that this separation was beneficial because no children were to be born into families of diseased parents, the act of which was considered a sin. Leprosy at this time was still believed to be hereditarily transmitted from parents to offspring though the bacteria causing leprosy was discovered by Dr. Gerhard Armauer Hansen just one year before.[35]

In 1881, around 120,000 leprosy patients existed in India. The central government passed the Lepers Act of 1898, which provided legal provision for forcible confinement of leprosy sufferers in India.[36]

China[edit]

Main article: Leprosy in China

Regarding ancient China, Katrina C. D. McLeod and Robin D. S. Yates identify the State of Qin's Feng zhen shi 封診式 (Models for sealing and investigating), dated 266-246 BC, as offering the earliest known unambiguous description of the symptoms of low-resistance leprosy, even though it was termed then under li 癘, a general Chinese word for skin disorder.[23] This 3rd-century BC Chinese text on bamboo slip, found in an excavation of 1975 at Shuihudi, Yunmeng, Hubei province, described not only the destruction of the "pillar of the nose" but also the "swelling of the eyebrows, loss of hair, absorption of nasal cartilage, affliction of knees and elbows, difficult and hoarse respiration, as well as anesthesia."[23]

Indonesia[edit]

Across Indonesia the rate of prevalence is slightly under one new case per 10,000 people, with approximately 20,000 new cases detected each year.[37] However, the rate is considerably higher in particular regions, particularly South Sulawesi (with more than three new cases per 10,000 people) and North Maluku (with more than five new cases per ten thousand people).[37] MDT is provided free of charge to patients who require it in Indonesia and there are a number of hospitals in major population centers specifically intended to deal with the medical needs of those affected by the disease.[37] While the early detection and treatment of leprosy has certainly improved over the years, approximately ten percent of patients in Indonesia have already suffered significant nerve or other damage prior to the identification and treatment of their disease, largely due to lack of awareness and to a pervasive stigma that discourages those with the disease from coming forward to seek treatment.[37]

PERMATA (Perhimpunan Mandiri Kusta) Indonesia was established in 2007 with the specific vision of fighting the stigma associated with leprosy and eliminating the discrimination against those identified as suffering from the disease. The organization was founded by a small group of individuals who had all personally been treated for leprosy. The founders worked to establish links with key figures amongst those suffering from the disease in communities in South Sulawesi, East Java and NTT, the three provinces where the rate of incidence of the disease is probably amongst the highest in Indonesia.[38]

Japan[edit]

Main article: Leprosy in Japan

Japan has had a unique history of segregation of patients into sanatoria based on leprosy prevention laws of 1907, 1931, and 1953, and, hence, it intensified leprosy stigma. The 1953 law was abrogated in 1996. There were still 2717 ex-patients in 13 national sanatoria and two private hospitals as of 2008. In a document written in 833, leprosy was described as "caused by a parasite that eats five organs of the body. The eyebrows and eyelashes come off, and the nose is deformed. The disease brings hoarseness, and necessitates amputations of the fingers and toes. Do not sleep with the patients, as the disease is transmittable to those nearby." This was the first document concerning infectivity.[39] Males admitted to leprosaria in Japan were sterilized and females found to be pregnant were forced to have abortions. These extreme actions were done to prevent children of diseased parents from being born lest they also contract the disease. Doctors during this time still mistakenly believed that leprosy was a hereditary disease.[40] Lepers were seen as being incurable and infectious, the main reason they were forced into exile.

References[edit]

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Further reading[edit]