Leprosy

M. leprae, one of the causative agents of leprosy: As an acid-fast bacterium, M. leprae appears red when a Ziehl–Neelsen stain is used.

M. leprae and M. lepromatosis are the mycobacteria that cause leprosy.[30] M. lepromatosis is a relatively newly identified mycobacterium isolated from a fatal case of diffuse lepromatous leprosy in 2008.[5][31] M. lepromatosis is indistinguishable clinically from M. leprae.[32]

M. leprae is an intracellular, acid-fast bacterium that is aerobic and rod-shaped.[33] M. leprae is surrounded by the waxy cell envelope coating characteristic of the genus Mycobacterium.[33]

Genetically, M. leprae and M. lepromatosis lack the genes that are necessary for independent growth.[34] M. leprae and M. lepromatosis are obligate intracellular pathogens, and cannot be grown (cultured) in the laboratory.[34] The inability to culture M. leprae and M. lepromatosis has resulted in a difficulty definitively identifying the bacterial organism under a strict interpretation of Koch's postulates.[5][34]

While the causative organisms have to date been impossible to culture in vitro, it has been possible to grow them in animals such as mice and armadillos.[35][36]

Naturally occurring infection has been reported in nonhuman primates (including the African chimpanzee, the sooty mangabey, and the cynomolgus macaque), armadillos,[37] and red squirrels.[38] Multilocus sequence typing of the armadillo M. leprae strains suggests that they were of human origin for at most a few hundred years.[39] Thus, it is suspected that armadillos first acquired the organism incidentally from early American explorers.[40] This incidental transmission was sustained in the armadillo population, and it may be transmitted back to humans, making leprosy a zoonotic disease (spread between humans and animals).[40]

Red squirrels (Sciurus vulgaris), a threatened species in Great Britain, were found to carry leprosy in November 2016.[41] It has been suggested that the trade in red squirrel fur, highly prized in the medieval period and intensively traded, may have been responsible for the leprosy epidemic in medieval Europe.[42] A pre-Norman era skull excavated in Hoxne, Suffolk, in 2017 was found to carry DNA from a strain of Mycobacterium leprae, which closely matched the strain carried by modern red squirrels on Brownsea Island, UK.[42][43]

The greatest risk factor for developing leprosy is contact with another person infected by leprosy.[4] People who are exposed to a person who has leprosy are 5–8 times more likely to develop leprosy than members of the general population.[6] Leprosy also occurs more commonly among those living in poverty.[3] Not all people who are infected with M. leprae develop symptoms.[44][45]

Conditions that reduce immune function, such as malnutrition, other illnesses, or genetic mutations, may increase the risk of developing leprosy.[6] Infection with HIV does not appear to increase the risk of developing leprosy.[46] Certain genetic factors in the person exposed have been associated with developing lepromatous or tuberculoid leprosy.[47]

Transmission of leprosy occurs during close contact with those who are infected.[4] Transmission of leprosy is through the upper respiratory tract.[9][48] Older research suggested the skin as the main route of transmission, but research has increasingly favored the respiratory route.[49] Transmission occurs through inhalation of bacilli present in upper airway secretion.[50]

Leprosy is not sexually transmitted and is not spread through pregnancy to the unborn child.[4][8] The majority (95%) of people who are exposed to M. leprae do not develop leprosy; casual contact such as shaking hands and sitting next to someone with leprosy does not lead to transmission.[4][51] People are considered non-infectious 72 hours after starting appropriate multi-drug therapy.[52]

Two exit routes of M. leprae from the human body often described are the skin and the nasal mucosa, although their relative importance is not clear. Lepromatous cases show large numbers of organisms deep in the dermis, but whether they reach the skin surface in sufficient numbers is doubtful.[53]

Leprosy may also be transmitted to humans by armadillos, although the mechanism is not fully understood.[8][54][55]

Not all people who are infected or exposed to M. leprae develop leprosy, and genetic factors are suspected to play a role in susceptibility to an infection.[56] Cases of leprosy often cluster in families and several genetic variants have been identified.[56] In many people who are exposed, the immune system is able to eliminate the leprosy bacteria during the early infection stage before severe symptoms develop.[57] A genetic defect in cell-mediated immunity may cause a person to be susceptible to develop leprosy symptoms after exposure to the bacteria.[58] The region of DNA responsible for this variability is also involved in Parkinson's disease, giving rise to current speculation that the two disorders may be linked at the biochemical level.[58]

Several different approaches for classifying leprosy exist. There are similarities between the classification approaches.

• The World Health Organization system distinguishes "paucibacillary" and "multibacillary" based upon the proliferation of bacteria.[64] ("pauci-" refers to a small quantity.)
• The Ridley-Jopling scale provides five gradations.[65][66][67]
• The ICD-10, though developed by the WHO, uses Ridley-Jopling and not the WHO system. It also adds an indeterminate ("I") entry.[53]
• In MeSH, three groupings are used.

Leprosy may also occur with only neural involvement, without skin lesions.[4][70][71][72][73][74]

A number of leprostatic agents are available for treatment. A three-drug regimen of rifampicin, dapsone and clofazimine is recommended for all people with leprosy, for six months for paucibacillary leprosy and 12 months for multibacillary leprosy.[9]

Multidrug therapy (MDT) remains highly effective, and people are no longer infectious after the first monthly dose.[4] It is safe and easy to use under field conditions because of its presentation in calendar blister packs.[4] Post-treatment relapse rates remain low.[4] Resistance has been reported in several countries, although the number of cases is small.[87] People with rifampicin-resistant leprosy may be treated with second line drugs such as fluoroquinolones, minocycline, or clarithromycin, but the treatment duration is 24 months because of their lower bactericidal activity.[88] Evidence on the potential benefits and harms of alternative regimens for drug-resistant leprosy is not available.[9]

For people with nerve damage, protective footwear may help prevent ulcers and secondary infection.[30] Canvas shoes may be better than PVC boots.[30] There may be no difference between double rocker shoes and below-knee plaster.[30]

Topical ketanserin seems to have a better effect on ulcer healing than clioquinol cream or zinc paste, but the evidence for this is weak.[30] Phenytoin applied to the skin improves skin changes to a greater degree when compared to saline dressings.[30]

The number of new leprosy cases is difficult to measure and monitor because of leprosy's long incubation period, delays in diagnosis after onset of the disease, and lack of medical care in affected areas.[98] The registered prevalence of the disease is used to determine disease burden.[99] Registered prevalence is a useful proxy indicator of the disease burden, as it reflects the number of active leprosy cases diagnosed with the disease and receiving treatment with MDT at a given point in time.[99] The prevalence rate is defined as the number of cases registered for MDT treatment among the population in which the cases have occurred, again at a given point in time.[99]

Using comparative genomics, in 2005, geneticists traced the origins and worldwide distribution of leprosy from East Africa or the Near East along human migration routes. They found four strains of M. leprae with specific regional locations:[101] Monot et al. (2005) determined that leprosy originated in East Africa or the Near East and traveled with humans along their migration routes, including those of trade in goods and slaves. The four strains of M. leprae are based in specific geographic regions where each predominantly occurs:[101]

• strain 1 in Asia, the Pacific region, and East Africa;
• strain 2 in Ethiopia, Malawi, Nepal, north India, and New Caledonia;
• strain 3 in Europe, North Africa, and the Americas;
• strain 4 in West Africa and the Caribbean.

This confirms the spread of the disease along the migration, colonisation, and slave trade routes taken from East Africa to India, West Africa to the New World, and from Africa into Europe and vice versa.[102]

Skeletal remains discovered in 2009 represent the oldest documented evidence for leprosy, dating to the 2nd millennium BC.[103][104] Located at Balathal, Rajasthan, in northwest India, the discoverers suggest that, if the disease did migrate from Africa to India during the 3rd millennium BC "at a time when there was substantial interaction among the Indus Civilization, Mesopotamia, and Egypt, there needs to be additional skeletal and molecular evidence of leprosy in India and Africa to confirm the African origin of the disease".[105] A proven human case was verified by DNA taken from the shrouded remains of a man discovered by researchers from the Hebrew University of Jerusalem in a tomb next to the Old City of Jerusalem, Israel, dated by radiocarbon methods to the first half of the 1st century.[106]

The oldest strains of leprosy known from Europe are from Great Chesterford in southeast England and dating back to AD 415–545. These findings suggest a different path for the spread of leprosy, meaning it may have originated in Western Eurasia. This study also indicates that there were more strains in Europe at the time than previously determined.[107]

Literary attestation of leprosy is unclear because of the ambiguity of many early sources, including the Indian Atharvaveda and Kausika Sutra, the Egyptian Ebers papyrus, and the Hebrew Bible's various sections regarding signs of impurity (tzaraath).[108] Clearly leprotic symptoms are attested in the Indian doctor Sushruta's Compendium, originally dating to c. 600 BC but only surviving in emended texts no earlier than the 5th century. They were separately described by Hippocrates in 460 BC. However, Hansen's disease probably did not exist in Greece or the Middle East before the Common Era.[109][110][111] In 1846, Francis Adams produced The Seven Books of Paulus Aegineta which included a commentary on all medical and surgical knowledge and descriptions and remedies to do with leprosy from the Romans, Greeks, and Arabs.[112][113]

Leprosy did not exist in the Americas before colonization by modern Europeans[114] nor did it exist in Polynesia until the middle of the 19th century.[115]

Distribution of leprosy around the world in 1891

The causative agent of leprosy, M. leprae, was discovered by Gerhard Armauer Hansen in Norway in 1873, making it the first bacterium to be identified as causing disease in humans.[116]

The first effective treatment (promin) became available in the 1940s.[117] In the 1950s, dapsone was introduced. The search for further effective antileprosy drugs led to the use of clofazimine and rifampicin in the 1960s and 1970s.[118] Later, Indian scientist Shantaram Yawalkar and his colleagues formulated a combined therapy using rifampicin and dapsone, intended to mitigate bacterial resistance.[119] Multi-drug therapy (MDT) combining all three drugs was first recommended by the WHO in 1981. These three antileprosy drugs are still used in the standard MDT regimens.[120]

Leprosy was once believed to be highly contagious and was treated with mercury, as was syphilis, which was first described in 1530. Many early cases thought to be leprosy could actually have been syphilis.[121]

Resistance has developed to initial treatment. Until the introduction of MDT in the early 1980s, leprosy could not be diagnosed and treated successfully within the community.[122]

Japan still has sanatoriums (although Japan's sanatoriums no longer have active leprosy cases, nor are survivors held in them by law).[123]

The importance of the nasal mucosa in the transmission of M. leprae was recognized as early as 1898 by Schäffer, in particular, that of the ulcerated mucosa.[124] The mechanism of plantar ulceration in leprosy and its treatment was first described by Ernest W. Price.[125]

In 1898, the colonial government in British India enacted the Leprosy Act of 1898, which mandated the compulsory segregation of lepers by authorities in newly established leper asylums, where they were segregated by sex to prevent sexual activity. The act, which proved difficult to enforce, was repealed in 1983 by the Indian government after multidrug therapy had become widely available in India. In 1983, the National Leprosy Elimination Programme, previously the National Leprosy Control Programme, changed its methods from surveillance to the treatment of people with leprosy. India still accounts for over half of the global disease burden. According to WHO, new cases in India during 2019 diminished to 114,451 patients (57% of the world's total new cases).[126][127] Until 2019, Indians could justify a petition for divorce with their spouse's diagnosis of leprosy.[128]

Between 1995 and 1999, the WHO, with the aid of the Nippon Foundation, supplied all endemic countries with free multidrug therapy in blister packs, channeled through ministries of health.[4] This free provision was extended in 2000 and again in 2005, 2010 and 2015 with donations by the multidrug therapy manufacturer Novartis through the WHO. In the latest agreement signed between the company and the WHO in October 2015, the provision of free multidrug therapy by the WHO to all endemic countries will run until the end of 2025.[129][4] At the national level, nongovernment organizations affiliated with the national program will continue to be provided with an appropriate free supply of multidrug therapy by the WHO.[130]

Written accounts of leprosy date back thousands of years. Various skin diseases translated as leprosy appear in the ancient Indian text, the Atharava Veda, by 600 BC.[131] Another Indian text, the Manusmriti (200 BC),  prohibited contact with those infected with the disease and made marriage to a person infected with leprosy punishable.[132]

The Hebraic root tsara or tsaraath (צָרַע, – tsaw-rah' – to be struck with leprosy, to be leprous) and the Greek (λεπρός–lepros), are of broader classification than the more narrow use of the term related to Hansen's Disease.[133] Any progressive skin disease (a whitening or splotchy bleaching of the skin, raised manifestations of scales, scabs, infections, rashes, etc....), as well as generalized molds and surface discoloration of any clothing, leather, or discoloration on walls or surfaces throughout homes all, came under the "law of leprosy" (Leviticus 14:54–57).[134] Ancient sources such as the Talmud (Sifra 63) make clear that tzaraath refers to various types of lesions or stains associated with ritual impurity and occurring on cloth, leather, or houses, as well as skin. Traditional Judaism and Jewish rabbinical authorities, both historical and modern, emphasize that the tsaraath of Leviticus is a spiritual ailment with no direct relationship to Hansen's disease or physical contagions. The relation of tsaraath to "leprosy" comes from translations of Hebrew Biblical texts into Greek and ensuing misconceptions.[135]

All three Synoptic Gospels of the New Testament describe instances of Jesus healing people with leprosy (Matthew 8:1–4, Mark 1:40–45, and Luke 5:12–16). The Bible's description of leprosy is congruous (if lacking detail) with the symptoms of modern leprosy, but the relationship between this disease, tzaraath, and Hansen's disease has been disputed.[136] The biblical perception that people with leprosy were unclean can be found in a passage from Leviticus 13: 44–46. While this text defines the leper as impure, it did not explicitly make a moral judgement on those with leprosy.[137] Some Early Christians believed that those affected by leprosy were being punished by God for sinful behavior. Moral associations have persisted throughout history. Pope Gregory the Great (540–604) and Isidor of Seville (560–636) considered people with the disease to be heretics.[138]

Medieval leper bell

The social perception of leprosy in the general population was in general mixed. On one hand, people feared getting infected with the disease and thought of people suspected of leprosy to be unclean, untrustworthy, and occasionally morally corrupt.[138] On the other hand, Jesus' interaction with lepers, the writing of church leaders and the Christian focus on charitable works led to viewing the lepers as "chosen by God"[139] or seeing the disease as a means of obtaining access to heaven.[140]

Early medieval understanding of leprosy was influenced by early Christian writers such as Gregory of Nazianzus and John Chrysostom, whose writings were later embraced by Byzantine and Latin writers.[141] Gregory, for example, did not only compose sermons urging Christians to assist victims of the disease, but also condemned pagans or Christians who justified rejecting lepers on the allegation that God had sent them the disease to punish them. As cases of leprosy increased during these years in the Eastern Roman Empire, becoming a major health issue, the ecclesiastic leaders of the time discussed how to assist those affected as well as change the attitude of society towards them. They also tried this by using the name "Holy disease" instead of the commonly used "Elephant's disease" (elephantiasis), implying that God did not create this disease to punish people but to purify them for heaven.[142] Although not always successful in persuading the public and a cure was never found by Greek medicians, they created an environment where victims could get palliative care and were never expressly banned from society, as sometimes happened in Western Europe. Theodore Balsamon, a 12th-century jurist in Constantinople, noted that lepers were allowed to enter the same churches, cities and assemblies that healthy people attended.[141]

As the disease became more prevalent in Western Europe in the fifth century, first efforts to set up permanent institutions to house and feed lepers. These efforts were, inclusively, the work of bishops in France at the end of the sixth century, such as in Chalon-sur-Saône.[141] The increase in hospitals or leprosaria (sing. leprosarium) that treated people with leprosy in the 12th and 13th century seems to indicate a rise in cases,[143][144][145] possibly in connection with the increase in urbanisation [146] as well as returning crusaders from the Middle East.[141] France alone had nearly 2,000 leprosaria during this period.[147] Additionally to the new leprosia, further steps were taken by secular and religious leaders to prevent further spread of the disease. The third Lateran Council of 1179 required lepers to have their own priests and churches[146] and a 1346 edict by King Edward expelled lepers from city limits. Segregation from mainstream society became common, and people with leprosy were often required to wear clothing that identified them as such or carry a bell announcing their presence.[147] As in the East, it was the Church who took care of the lepers due to the still persisting moral stigma and who ran the leprosaria.[138][148] Although the leprosaria in Western Europe removed the sick from society, they were never a place to quarantine them or from which they could not leave: lepers would go beg for alms for the upkeep of the leprosaria or meet with their families.[146][141]

Norway was the location of a progressive stance on leprosy tracking and treatment and played an influential role in European understanding of the disease. In 1832, Dr. JJ Hjort conducted the first leprosy survey, thus establishing a basis for epidemiological surveys. Subsequent surveys resulted in the establishment of a national leprosy registry to study the causes of leprosy and for tracking the rate of infection.

Early leprosy research throughout Europe was conducted by Norwegian scientists Daniel Cornelius Danielssen and Carl Wilhelm Boeck. Their work resulted in the establishment of the National Leprosy Research and Treatment Center. Danielssen and Boeck believed the cause of leprosy transmission was hereditary. This stance was influential in advocating for the isolation of those infected by sex to prevent reproduction.[149][150][151]

Father Damien on his deathbed in 1889

Though leprosy rates were again on the decline in the Western world by the 1860s, authorities in the West frequently embraced isolation treatment due to a combination of reasons, including fears of the disease spreading from the Global South, efforts by Christian missionaries and a lack of understanding concerning bacteriology, medical diagnosis and how contagious the disease was.[127] The rapid expansion of Western imperialism during the Victorian era resulted in Westerners coming into increasing contact with regions where the disease was endemic, including British India. English surgeon Henry Vandyke Carter observed isolation treatment for leprosy patients first-hand while visiting Norway, applying these methods in British India with the financial and logistical assistance of Protestant missionaries. Colonialist and religious viewpoints of the disease continued to be a major factor in the treatment and public perception of the disease in the Global South until decolonization in the mid-twentieth century.[127]

The National Leprosarium at Carville, Louisiana, known in 1955 as the Louisiana Leper Home, was the only leprosy hospital on the mainland United States. Leprosy patients from all over the United States were sent to Carville in order to be kept in isolation away from the public, as not much about leprosy transmission was known at the time and stigma against those with leprosy was high (see Leprosy stigma). The Carville leprosarium was known for its innovations in reconstructive surgery for those with leprosy. In 1941, 22 patients at Carville underwent trials for a new drug called promin. The results were described as miraculous, and soon after the success of promin came dapsone, a medicine even more effective in the fight against leprosy.[152]

In 2022 cases of leprosy were reported to be increasing in central Florida.[153]

Despite now effective treatment and education efforts, leprosy stigma continues to be problematic in developing countries where the disease is common. Leprosy is most common amongst impoverished populations where social stigma is likely to be compounded by poverty. Fears of ostracism, loss of employment, or expulsion from family and society may contribute to a delayed diagnosis and treatment.[154]

Folk beliefs, lack of education, and religious connotations of the disease continue to influence social perceptions of those affected in many parts of the world. In Brazil, for example, folklore holds that leprosy is a disease transmitted by dogs, or that it is associated with sexual promiscuity, or that it is a punishment for sins or moral transgressions (distinct from other diseases and misfortunes, which are in general thought of as being according to the will of God).[155] Socioeconomic factors also have a direct impact. Lower-class domestic workers who are often employed by those in a higher socioeconomic class may find their employment in jeopardy as physical manifestations of the disease become apparent. Skin discoloration and darker pigmentation resulting from the disease also have social repercussions.[156]

In extreme cases in northern India, leprosy is equated with an "untouchable" status that "often persists long after individuals with leprosy have been cured of the disease, creating lifelong prospects of divorce, eviction, loss of employment, and ostracism from family and social networks."[157]

• 
  Leprosy in Tahiti, c. 1895
• 
  A 26-year-old woman with leprous lesions
• 
  A 13-year-old boy with severe leprosy

In some instances in India, community-based rehabilitation is embraced by local governments and NGOs alike. Often, the identity cultivated by a community environment is preferable to reintegration, and models of self-management and collective agency independent of NGOs and government support have been desirable and successful.[161]