Leprosy

تُعدّ المتفطرة الجذامية (Mycobacterium leprae) والمتفطرة الجذامية الورمية (Mycobacterium lepromatosis) من أنواع المتفطرات المسببة لمرض الجذام. ^{[ 29 ]} تُعتبر المتفطرة الجذامية الورمية نوعًا حديثًا نسبيًا من المتفطرات، وقد عُزلت من حالة وفاة بمرض الجذام الورمي المنتشر عام 2008. ^{[ 5 ] [ 30 ]} لا يمكن التمييز سريريًا بين المتفطرة الجذامية والمتفطرة الجذامية . ^{[ 31 ]} المتفطرة الجذامية بكتيريا هوائية عصوية الشكل، مقاومة للأحماض، ذات غلاف خلوي شمعي،وهو ما يميز جنس المتفطرات . ^{[ 32 ]} تُعتبر كل من المتفطرة الجذامية والمتفطرة الجذامية الورمية من مسببات الأمراض الإجبارية داخل الخلايا ، ولا يمكنها النمو أو الاستزراع خارج أنسجة العائل. ^{[ 5 ] [ 33 ]} ومع ذلك، يمكن استزراعها باستخدام حيوانات التجارب مثل الفئران والمدرعات . ^{[ 34 ] [ 35 ]}

تم الإبلاغ عن حالات عدوى طبيعية في الرئيسيات غير البشرية (بما في ذلك الشمبانزي الأفريقي ، والمنغابي السخامي ، وقرد المكاك السيانومولغوس )، والمدرعات، ^{[ 36 ]} والسناجب الحمراء . ^{[ 37 ]} يشير تحليل تسلسل المواقع المتعددة لسلالات المتفطرة الجذامية في المدرعات إلى أنها كانت من أصل بشري لبضع مئات من السنين على الأكثر. ^{[ 38 ]} وبالتالي، يُشتبه في أن المدرعات قد اكتسبت الكائن الحي لأول مرة بشكل عرضي من المستكشفين الأوروبيين الأوائل للأمريكتين. ^{[ 39 ]} استمر هذا الانتقال العرضي في مجتمع المدرعات. وقد ينتقل مرة أخرى إلى البشر، مما يجعل الجذام مرضًا حيوانيًا (ينتقل بين البشر والحيوانات). ^{[ 39 ]}

Red squirrels (Sciurus vulgaris), a threatened species in Great Britain, were found to carry leprosy in November 2016.^[40] 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.^[41] A pre-Norman era skull excavated in Hoxne, Suffolk, in 2017 was found to carry DNA from a strain of M. leprae which closely matched the strain carried by modern red squirrels on Brownsea Island.^[41][42]

The greatest risk factor for developing leprosy is contact with another person infected with 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 occurs more commonly among those living in poverty.^[3] Not all people who are infected with M. leprae develop symptoms.^[43][44]

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.^[45] Certain genetic factors in the person exposed have been associated with developing lepromatous or tuberculoid leprosy.^[46]

Transmission of leprosy occurs during close contact with those who are infected.^[4] Transmission of leprosy is through the upper respiratory tract.^[9][47] Older research suggested the skin as the main route of transmission, but research has increasingly favored the respiratory route.^[48] Transmission occurs through inhalation of bacilli present in upper airway secretion.^[49]

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][50] People are considered non-infectious 72 hours after starting appropriate multi-drug therapy.^[51] Two exit routes of M. leprae from the human body that are 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.^[52] Humans can acquire a leprosy infection from armadillos by handling them or consuming armadillo meat.^[53][54] The mechanism is not fully understood.^[8][55][56]

Not all people infected or exposed to M. leprae develop leprosy, and genetic factors are suspected to play a role in susceptibility to an infection.^[57] Cases of leprosy often cluster in families, and several genetic variants have been identified.^[57] In many who are exposed, the immune system can eliminate the leprosy bacteria during the early infection stage before severe symptoms develop.^[58] A genetic defect in cell-mediated immunity may cause a person to be susceptible to develop leprosy symptoms after exposure to the bacteria.^[59] 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.^[59]

Leprosy exhibits polarized host responses along a Th1–Th2 spectrum that underpins the Ridley–Jopling clinicopathological forms. At the tuberculoid pole (TT/BT), cellular immunity is dominated by Th1 cytokines—notably IL-12, IFN-γ and TNF-α—which activate macrophages, favor granuloma organization, and restrict bacillary multiplication; at the lepromatous pole (BL/LL), there is Th2/regulatory bias (e.g., IL-4, IL-10), weaker cell-mediated immunity, and high bacillary loads with widespread dissemination.^[61] This polarization is shaped by antigen-presenting cell function and pattern-recognition events: recognition of mycobacterial ligands by Toll-like receptors—particularly TLR1/2 heterodimers on macrophages, dendritic cells, and Schwann cells—drives Th1-skewing in paucibacillary disease, whereas IL-10-rich regulatory circuits dampen effector responses at the multibacillary pole.^[61]

Histopathology reflects these immune states. Tuberculoid lesions show well-formed granulomas composed of epithelioid macrophages and multinucleated giant cells with dense T-cell cuffs, consistent with attempts at bacillary containment; bacilli are scant and often absent on routine sections. By contrast, lepromatous lesions display diffuse sheets of vacuolated "foamy" macrophages packed with bacilli (including globi), fewer cytotoxic effectors, and more permissive tissue microenvironments.^[62] Macrophage programs diverge across the spectrum: microbicidal, nitric-oxide–producing phenotypes are more characteristic of the Th1 side, whereas alternative (M2-like), lipid-rich programs prevail at the Th2/regulatory pole.^[61]

Additional T-cell axes contribute to bacterial control and tissue damage: Th17/IL-17 responses, typically higher in tuberculoid disease, align with granulomatous inflammation, while FoxP3+ T-regulatory cells and TGF-β/IL-10 pathways are more prominent in multibacillary disease and can suppress protective immunity.^[61][62] Superimposed acute "reactions" represent abrupt shifts on this immunologic continuum. Type 1 (reversal) reactions, usually in borderline disease, involve amplification of Th1-driven inflammation with edema of pre-existing lesions and neuritis. Type 2 reactions (erythema nodosum leprosum) are systemic inflammatory episodes linked to high antigen load and immune-complex formation, with fever, tender nodules, neutrophilia, and other organ involvement; their pathobiology features surges of TNF-α, IL-6, and IL-8, and neutrophil-rich infiltrates.^[62][61]

Beyond T cells and macrophages, humoral immunity and B-cell subsets are also implicated. B-1–like cells (by PAX5/CD5 labeling) and marginal zone B cells in human cutaneous lesions—together with Be1 cells—were more abundant in tuberculoid and type 1 reaction lesions than in lepromatous, type 2 reaction, and indeterminate forms, consistent with Th1-skewed inflammation; IL-10–producing regulatory B cells were infrequent.^[63] These findings expand the repertoire of cellular players involved at the paucibacillary/Th1 pole of the leprosy spectrum.^[63]

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

• The World Health Organization (WHO) system distinguishes patients with five or fewer skin lesions and no bacilli in a skin smear as "paucibacillary" ("pauci-" refers to a small quantity) from patients with more lesions or detected bacilli as "multibacillary".^[69]
• The Ridley-Jopling scale provides five gradations.^[70][71][72]
• The ICD-10, though developed by the WHO, uses Ridley-Jopling, not the WHO system. It also adds an indeterminate ("I") entry.^[52]
• In MeSH, three groupings are used.

Leprosy may also occur with only neural involvement, without skin lesions.^{[4][75][76][77][78][79]}

باستخدام علم الجينوم المقارن ، تتبع علماء الوراثة في عام 2005 أصول مرض الجذام وانتشاره العالمي من شرق أفريقيا أو الشرق الأدنى على طول طرق الهجرة البشرية. ووجدوا أربع سلالات من بكتيريا المتفطرة الجذامية ( M. leprae) في مواقع جغرافية محددة: ^{[ 107 ]} وقد حدد مونوت وآخرون (2005) أن مرض الجذام نشأ في شرق أفريقيا أو الشرق الأدنى وانتقل مع البشر على طول طرق هجرتهم، بما في ذلك طرق تجارة البضائع والعبيد. وتتواجد سلالات المتفطرة الجذامية الأربع في مناطق جغرافية محددة حيث تنتشر كل منها بشكل رئيسي: ^{[ 107 ]}

• السلالة 1 في آسيا ومنطقة المحيط الهادئ وشرق أفريقيا؛
• السلالة 2 في إثيوبيا، وملاوي ، ونيبال، وشمال الهند، وكاليدونيا الجديدة ؛
• السلالة 3 في أوروبا وشمال إفريقيا والأمريكتين؛
• السلالة 4 في غرب إفريقيا ومنطقة البحر الكاريبي.

يؤكد هذا انتشار المرض على طول طرق الهجرة والاستعمار وتجارة الرقيق التي سلكتها أفريقيا من شرق أفريقيا إلى الهند، ومن غرب أفريقيا إلى العالم الجديد، ومن أفريقيا إلى أوروبا والعكس. ^{[ 108 ]}

Skeletal remains discovered in 2009 represent the oldest documented evidence for leprosy, dating to the 2nd millennium BC.^[109][110] 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".^[111] 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 in Akeldama, next to the Old City of Jerusalem dated by radiocarbon methods to the first half of the 1st century.^[112]

The oldest strains of leprosy known from Europe are from Great Chesterford in southeast England and date 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.^[113]

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).^[114] 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 fifth century BC. Symptoms consistent with leprosy were possibly described by Hippocrates in 460 BC.^[115] However, Hansen's disease probably did not exist in Greece or the Middle East before the Common Era.^{[116][117][118]} 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.^[119]

The first known causative agent of leprosy, M. leprae, was discovered by Gerhard Armauer Hansen in Norway in 1873, making it one of the first species of pathogenic bacteria to be identified.^[120] Leprosy was once believed to have been absent from the Americas before the age of Discovery and the arrival of Europeans.^[121] In 2008, a different causative agent for leprosy, Mycobacterium lepromatosis was discovered. DNA studies have revealed that this pathogen exists primarily in the Americas and was already present before Europeans arrived.^[122] It is believed that it did not exist in Polynesia until the middle of the 19th century.^[123]

Leprosy was once believed to be highly contagious and was treated with mercury.^[124]Chaulmoogra tree oil was used topically to manage Hansen's disease for centuries. Chaulmoogra oil could not be taken orally without causing nausea or injected without forming an abscess. In 1915, Alice Ball discovered how to make the oil water-soluble, which produced marked improvements in patients with Hansen's disease.^[125][126]

The first effective drug (promin) became available in the 1940s.^[127] 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.^[128] Later, Indian scientist Shantaram Yawalkar and his colleagues formulated a combined therapy using rifampicin and dapsone, intended to mitigate bacterial resistance.^[129] Combining all three drugs was first recommended by the WHO in 1981. These three drugs are still used in the standard MDT regimens.^[130] 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.^[131]

The importance of the nasal mucosa in the transmission of M. leprae was recognized as early as 1898 by Schäffer, particularly the ulcerated mucosa.^[132] The mechanism of plantar ulceration in leprosy and its treatment was first described by Ernest W. Price.^[133]

Between 1995 and 1999, the WHO, with the aid of the Nippon Foundation, supplied all endemic countries with free MDT 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 MDT manufacturer Novartis through the WHO.^[134][4] At the national level, non-governmental organizations (NGOs) affiliated with the national program will continue to be provided with an appropriate free supply.^[135]

Written accounts of leprosy date back thousands of years. By 600 BC, various skin diseases translated as leprosy appear in the Atharva Veda, a principal Hindu scripture.^[137] Another Hindu scripture, the Manusmriti (200 BC), prohibits contact with those infected with the disease and makes marriage to a person infected with leprosy punishable.^[138]

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.^[139] 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).^[140] 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.^[141]

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.^[142] 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 does not explicitly make a moral judgement on those with leprosy.^[143] Some early Christians believed that God was punishing those affected by leprosy for sinful behavior. Moral associations have persisted throughout history. In the 6th century, Pope Gregory the Great and Isidore of Seville considered people with the disease to be heretics.^[144]

The general population's perception of leprosy was 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.^[144] 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"^[145] or seeing the disease as a means of obtaining access to heaven.^[146]

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.^[147] Gregory, for example, composed sermons urging Christians to assist victims of the disease, and he 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 in the Eastern Roman Empire, becoming a major health issue, the ecclesiastic leaders discussed how to assist those affected as well as how to 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.^[148] 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.^[147]

As the disease became more prevalent in Western Europe in the fifth century, efforts began to establish 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.^[147] The increase in hospitals or leprosaria (sing. leprosarium) that treated people with leprosy in the 12th and 13th centuries seems to indicate a rise in cases,^{[149][150][151]} possibly in connection with the increase in urbanisation^[152] as well as returning crusaders from the Middle East.^[147] France alone had nearly 2,000 leprosaria during this period.^[153] 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^[152] 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.^[153] As in the East, it was the Church who took care of the lepers due to the persisting moral stigma and who ran the leprosaria.^[144][154] 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.^[152][147]

Multiple groups in Western Europe from the Middle Ages faced social ostracization and discrimination that was justified, in part, due to claims that they were the descendants of lepers. These groups included the Cagots and the Caquins.^{[155][156][157]}

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 led to the establishment of a national leprosy registry to study the causes of leprosy and to track 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.^{[158][159][160]}

Though leprosy rates were on the decline in the Western world by the 1860s, authorities 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.^[161] 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-20th century.^[161]

في عام 1898، سنّت الحكومة الاستعمارية في الهند البريطانية قانون الجذام لعام 1898، الذي فرض عزل المصابين بالجذام إجبارياً في ملاجئ مخصصة لهم، حيث تم فصلهم حسب الجنس لمنع النشاط الجنسي. وقد أُلغي هذا القانون، الذي ثبتت صعوبة تطبيقه، في عام 1983 من قبل الحكومة الهندية بعد أن أصبح العلاج متعدد الأدوية متاحاً على نطاق واسع في الهند. وفي عام 1983 أيضاً، غيّر البرنامج الوطني للقضاء على الجذام، الذي كان يُعرف سابقاً بالبرنامج الوطني لمكافحة الجذام، أساليبه من المراقبة إلى علاج المصابين. ولا تزال الهند تُسجّل أكثر من نصف العبء العالمي للمرض. ووفقاً لمنظمة الصحة العالمية، انخفضت الحالات الجديدة في الهند خلال عام 2019 إلى 114,451 مريضاً (57% من إجمالي الحالات الجديدة في العالم). ^{[ 162 ] [ 161 ]} وحتى عام 2019، كان بإمكان الهنود تبرير طلب الطلاق بتشخيص إصابة أزواجهم بالجذام. ^{[ 163 ]}

كان مستشفى كارڤيل الوطني للجذام في لويزيانا ، المعروف عام ١٩٥٥ باسم "دار لويزيانا للجذام"، المستشفى الوحيد لعلاج الجذام في الولايات المتحدة الأمريكية. كان يُرسل مرضى الجذام من جميع أنحاء الولايات المتحدة إلى كارڤيل لعزلهم بعيدًا عن العامة، نظرًا لقلة المعلومات المتوفرة آنذاك حول طرق انتقال المرض، وارتفاع مستوى الوصمة الاجتماعية ضد المصابين به . اشتهر مستشفى كارڤيل للجذام بابتكاراته في الجراحة الترميمية لمرضى الجذام. في عام ١٩٤١، خضع ٢٢ مريضًا في كارڤيل لتجارب سريرية على دواء جديد يُدعى برومين. وُصفت النتائج بالمعجزة، وبعد نجاح برومين بفترة وجيزة، ظهر دابسون، وهو دواء أكثر فعالية في مكافحة الجذام. ^{[ ١٦٤ ]} بلغ معدل الإصابة بالجذام ذروته في الولايات المتحدة عام ١٩٨٣، ثم انخفض بشكل حاد. ^{[ 165 ]} مع ذلك، عادت أعداد الحالات للارتفاع ببطء منذ عام 2000. وفي عام 2020، تم الإبلاغ عن 159 حالة في البلاد. ^{[ 165 ]}

تصويرات لامرأة تبلغ من العمر 26 عامًا مصابة بآفات الجذام، وصبي يبلغ من العمر 13 عامًا مصاب بالجذام الحاد، في كتاب دانيال كورنيليوس " أوم سبيدالسخيد " عام 1847

على الرغم من فعالية العلاج والتوعية، لا تزال وصمة العار المرتبطة بمرض الجذام مشكلةً في البلدان النامية حيث ينتشر المرض. ويُعدّ الجذام أكثر شيوعًا بين السكان الفقراء، حيث يتفاقم الوصم الاجتماعي بسبب الفقر. وقد تُسهم مخاوف النبذ ​​الاجتماعي، أو فقدان الوظيفة، أو الطرد من الأسرة والمجتمع في تأخير التشخيص والعلاج. ^{[ 166 ]}

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).^[167] 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.^[168]

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."^[169]