HISTORY OF LEPROSY

The history of leprosy was traced to its origins by an international team of 22 geneticists
using comparative genomics of the worldwide distribution of Mycobacterium leprae. 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:

Strain 1 – East Africa, Asia, and the Pacific region

Strain 2 – Ethiopia, Malawi, Nepal/North India, and New Caledonia

Strain 3 – Europe, North Africa, and the Americas; and

Strain 4 – West Africa and the Caribbean.

They created a map of the dissemination of leprosy in the world. This confirmed 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.[1]

In 1873 G.H. Armauer Hansen in Norway discovered the causative agent of leprosy,
Mycobacterium leprae. This was the first bacterium to be identified as causing disease in
humans.From the 19th century, European nations adopted some practices of India and China,
administering naturally occurring oils. They were given by injection and orally, and were
believed to cure some people, but results were often disputed. It was not until the 1940s that
the first effective treatment, promin, became available.The search for additional anti-leprosy
drugs led to the use of clofazimine and rifampicin in the 1960s and 1970s. Later, Indian
scientist Shantaram Yawalkar and his colleagues formulated a combined therapy using
rifampicin and dapsone, intended to mitigate bacterial resistance.Multi-drug therapy (MDT)
combining all three drugs was first recommended by the World Health Organization (WHO) of
the United Nations in 1981. These three anti-leprosy drugs are still used in the standard MDT
regimens.

ETYMOLOGY

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".

Throughout history, individuals with leprosy have been known as lepers. In the 21st century,
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', preferring
'Hansen's disease'. The term 'leprosy' is still used by the U.S. Centers for Disease Control and
Prevention and the World Health Organization.

ANCIENT

The ability to use historical records to trace the spread and treatment of leprosy in antiquity
is greatly limited by confusion over which skin diseases were being discussed.[8] Famously,
the "leprosy" of most translations of the Bible as far back as the Septuagint represents a
multilayered historical process of confusion. The state of ritual impurity known to the
seems to have been a conflation of various skin ]9[)"struck" ,‫ (ָצ ַר ַע ת‬Hebrews as tzara'ath
disorders, owing to the undeveloped state of medical science at that period. The Greek term
employed to translate the Hebrew was lépra (λέπρα, "scaly"), which possessed an entirely
separate diagnostic history which dealt with psoriasis and dandruff, only being applied to
leprosy in a later period.[10] A tumorous skin disease described in the Ebers Papyrus dating
to c.1550 bc has found some identification as leprosy, however, given that the text presents
surgical excision of the tumors as an effective treatment, the implicated disorder likely refers
.to a skin condition such as epidermoid cysts

Debatably, the oldest known records of genuine Hansen's disease are the Indian vedas, whose
kuṣṭha (कु ष्ठ, "eating away") is clearly focused on leprosy by the time of Suśruta's Compendium,
which prescribes chaulmoogra oil as the remedy;[11] unfortunately, its usual dating to 600 bc
is wrong and the present text may be as recent as ad 600.[12] Similarly, the "Great Chronicle"
of Sri Lanka describes royal ancestors of Gautama Buddha who contract leprosy, flee to the
wilderness, and cure themelves using herbal medicine sometime before 700 bc but the
present text dates to the 5th century or later. The Vendidad of the Zoroastrian Avesta,
surviving only in texts after ad 1300 but presumably recording practices nearly as old as the
and prescribes direct application of )𐬀𐬯𐬉𐬀𐬞 :Avestan( Vedas, discusses leprosy as paēsa
cow's urine as a cure.[13] Writing in the 5th century bc, Herodotus mentions the Persian
practice of shunning native lepers and deporting foreign ones as part of a discussion of that
area's peculiar habits; he reported that they considered the condition to have been caused
by offense against the sun god.[14][15] The ancient Greek and Roman doctors considered that
"elephantitis" had been introduced to their areas by the armies of Alexander and Pompey,
respectively. It is discussed in particular by the authors Aulus Cornelius Celsus (25 bc – ad 37)
and Pliny the Elder (ad 23–79).[15][16]

The "Models for Sealing and Investigating" (封診式, Fēngzhěnshì), written between 266 and
246 bc in the State of Qin during the Warring States period, is the earliest known Chinese text
which describes the symptoms of leprosy, termed under the generic word li (癘) used for
various skin disorders.[16] This text mentioned the destruction of the nasal septum in those
with leprosy, an observation that would not be made outside of China until the writings of
Avicenna in the 11th century; according to Katrina McLeod and Robin Yates it also stated
lepers had "swelling of the eyebrows, loss of hair, absorption of nasal cartilage, affliction of
".knees difficult and hoarse respiration, as well as anaesthesia

MODERN

Medical texts from the medieval period have loose and seemingly incorrect depictions of
leprosy, leading some historians to suspect that doctors of the era were not able to
distinguish leprosy from other ailments such as syphilis. Nevertheless, analysis of human
remains in leper colony graveyards shows that the vast majority were affected by advanced
forms of the disease considered as leprosy by modern doctors, so it is possible that medical
practitioners of the era were better at distinguishing the disease than the scholars who wrote
the manuscripts that survived to modern times.

In 1846, Francis Adams compiled The Seven Books of Paulus Aegineta, which included a
commentary on all medical and surgical knowledge and descriptions and remedies from the
Romans, Greeks, and Arabs. Descriptions of what is believed to be leprosy are included.[18]
[19] A proven ancient 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; it was dated by radiocarbon
methods to ad 1–50.[20]

Skin infections causing symptoms similar to leprosy were likely common in the ancient world.
In particular, tinea capitis (fungal scalp infection) and related infections on other body parts
caused by the dermatophyte fungus Trichophyton violaceum are abundant in the late 20th
century throughout North Africa and the Middle East. They may also have been common in
biblical times. Likewise, the disfiguring skin disease favus is caused by Trichophyton
schoenleinii, which appears to have been common throughout Africa and Eurasia before the
advent of modern medicine.[21]

As late as the 17th century in Europe, persons with severe favus and similar fungal diseases
(and potentially also with severe psoriasis and other diseases not caused by microorganisms)
tended to be classified as having leprosy.The painting The Regents of the Leper Hospital in
Haarlem 1667 by Jan de Bray (Frans Hals Museum, Haarlem, the Netherlands) shows a young
Dutchman with a vivid scalp infection. It may have been caused by a fungus, but he is being
cared for by three officials of a charitable home intended for people with leprosy. 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 it is
understood today.
GENETIC ANALYSIS

DNA analysis has been applied to the origins and history of leprosy. Geneticists in 2005 used
comparative genomics to study these aspects, including the paths of how the disease was
spread throughout the world. The researchers 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:[1]

Strain 1 – East Africa, Asia, and the Pacific region

Strain 2 – Ethiopia, Malawi, Nepal/North India, and New Caledonia

Strain 3 – Europe, North Africa, and the Americas; and

Strain 4 – West Africa and the Caribbean.

The researchers created a map showing the dissemination of leprosy by these strains. The
disease clearly accompanied humans along their migration, colonisation, and slave trade
routes taken since ancient times. Some peoples traveled from East Africa to India, millions
were taken in the slave trade from West Africa to the New World, and others traveled from
Africa into Europe and vice versa.[1]

In 2009 skeletal remains from the second millennium BCE were discovered at Balathal, in
Rajasthan, northwest India. Study and analysis of these remains were documented as the
oldest skeletal evidence for leprosy. The scholars who studied these remains suggest that, if
the disease did migrate from Africa to India during the third millennium BCE, "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 so
as to confirm the African origin of the disease."[22] Evidence for the disease was later
confirmed in the human skeletal remains from the archaeological site of Harappa, in Pakistan.
[23] The disease was thus present in the urban centers of the Indus civilization before 2000
BCE, further supporting the hypothesis it migrated here as part of the "third millennium BCE
interaction sphere" – an exchange network that spanned the Arabian Sea.

Discovery of bacterium

After the end of the 17th century, Norway, Iceland, and England were the countries in Western
Europe where leprosy was a significant problem. Norway appointed a medical superintendent
for leprosy in 1854 and established a national register for people with leprosy in 1856. This
was the first national patient register in the world.[24]

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.[2][25] 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 stained these organisms with Ziehl's method and noted the similarities with Koch's
bacillus (Mycobacterium tuberculosis). 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. Hansen worked at St. Jørgens Hospital in Bergen, founded
early in the fifteenth century. St. Jørgens is now preserved as Lepramuseet – a museum
related to the history and research of leprosy.[26]

Hansen's finding was opposed principally by his father-in-law, Daniel Cornelius Danielssen,
who considered it a hereditary disease. He had described it as such 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.[27] While Danielssen's book 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 British Empire, agreed with Danielssen that
leprosy was a hereditary disease. In addition, he said that leprosy was also a constitutional
disease that could be mitigated by improvements to a patient's health, diet, and living
conditions.[28]

Historical treatments

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;
sometimes the blood of children or virgins was required, suggesting associations of ritual
purity.[29] Europeans associated this practice with the Ancient Egyptians, but it appears to
have been developed independently in China. This practice was used 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 blood from dead bodies was sometimes 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. It 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.[31]

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
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 determined to be 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. In 1894 he administered subcutaneous injection of chaulmoogra
oil to 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
wightiana and Hydnocarpus anthelmintica. By comparing material from the 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.

Administration of the oil was difficult. 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. The first successful leprosy treatment was developed in 1916 by African-
American Chemist Alice Ball, who came up with the pioneering injectable oil treatment at the
University of Hawaii. Tragically, Ball died in a lab accident shortly after inventing the
treatment. She was just 24 years old.

Despite these difficulties, a series of 170 patients were studied 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'. He reported that in the advanced cases,
25% (at most) showed any improvement or arrest of their condition; in the incipient cases,
45% showed 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
Heiser the 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. This was at
the suggestion of Merck and Company in Germany to whom Heiser had written. They found
that patients could tolerate this new compound without the nausea that had accompanied
the earlier preparations.

Heiser and Mercado in 1913 administered the oil by injection to two patients, with the result
that they were cured of the disease. Since the doctors had been using the oil in conjunction
with other materials, the results were not clear. Two additional patients were treated by
injections of oil alone and appeared to be cured of the disease. The following year, Heiser
reported on an additional 12 patients, but the results were mixed.

Researchers worked to develop less toxic injectable forms of this oil. Merck of Darmstadt had
already produced a version of the sodium salts in 1891. They named this sodium gynocardate
in the mistaken belief that the origin of the oil was Gynocardia odorata. Bayer in 1908
marketed a commercial version of the esters under the name 'Antileprol'. At the University of
Hawaii, the young chemist Alice Ball developed a chemical process that made the oil less
hydrophobic and therefore more readily absorbed by the body. She died before she could
see the results of her work: After being treated with the modified oil, 78 patients were able to
return home from leper colonies in 1920. Despite the common side effects and continuing
debates about its efficacy, chaulmoogra oil remained the best available treatment for leprosy
into the 1940s.

To ensure a supply of this agent, Joseph Rock, Professor of Systematic Botany at the College
of Hawaii, traveled to Burma to procure seeds of the trees. 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. There continued to be numerous leprosy patients in the
islands.

Asylums

Contrary to popular opinion, people were not universally isolated in leprosy asylums in the
Middle Ages. In Europe, asylums offered shelter to all manner of people, including some who
would have had skin complaints that included leprosy. The expansion of asylums in England
between 1100 and 1250 was not necessarily in response to a major epidemic of leprosy.[35]
(346)

Additionally, leprosy did not disappear in Europe after the medieval period as a result of a
"great confinement" of leprosy-affected people in leprosy asylums. In Portugal, for example,
there were 466 cases in 1898. By 1938 there were sufficient numbers to warrant the
construction of Rovisco Pais, to treat people affected by the disease.[36] This was not only to
treat those returning from the New World, but also for rural dwellers infected within Portugal,
as the records of Rovisco Pais show. Spain also had cases enough to engage public attention.
In 1902, Jesuits Father Carlos Ferris and Joaquin Ballister founded the Patronato San
Francisco de Borja, Fontilles. In 1904, there were still 552 cases treated there and more than
1,000 in total estimated in Spain.[37] This documentation affirms the genetic tracking carried
out by Monot et al.[1] that traces exchanges along the trade and slave routes from Africa, to
Spain and Portugal, to the West Indies, and back again to Spain and Portugal. At the same
time, there was an autochthonous strain that had persisted from an earlier period.
Numerous leprosaria, or leper hospitals, were founded in the Middle Ages; Matthew Paris, a
Benedictine monk, estimated that in the early thirteenth century, there were 19,000 across
Europe.[38] The first recorded leper colony was in Harbledown, England. While leprosaria
were common throughout Europe in the early, middle, and late Middle Ages, how leprosy was
dealt with in the Middle Ages is still viewed through the "distorting lens" of "nineteenth
century attempts by physicians, polemicist, and missionaries" who tried to use "the past for
evidence to support their own campaigns for mandatory segregation."[39] The leprosy asylum
or leprosarium of the past had many designations and variations in structure and degree of
restriction. In the medieval period, it also offered basic support to many indigent people,
amongst whom some would have had leprosy. In England, these houses were run along
monastic lines and required those admitted to take vows of poverty, obedience and chastity.
[40] Those flouting the rules could be expelled. Within the Christian framework, the disease
was associated with symbolic significance. Withdrawal from everyday life was considered
symbolic of ritually separating themselves from the world of the flesh, as a redemptive
action, on behalf of the whole of society.[41]

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. It 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. From
this order was derived the name lazar house.

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. This was as
much to attract attention for charity as to warn people that a diseased person was near.

The leprosaria of the Middle Ages had multiple benefits: They provided treatment and safe
living quarters for people with leprosy who were granted admission; they eased tension
amongst the healthy townspeople; and they provided for a more stable populace for the
authorities to govern.

Modern treatments

Promin was synthesised in 1940 by Feldman of Parke-Davis and company.[43] Although

Parke-Davis synthesised the compound, it seems certain that they were not the first. In the
same year that Gelmo described sulphanilamide (1908), Emil Fromm, professor of chemistry
in the medical faculty of the University of Freiburg im Breisgau, in Germany, described
another compound related to the sulphonamides: this was diaminodiphenylsulphone or
dapsone (DDS). No one recognised the potential of this compound until Buttle and his
colleagues at the Wellcome laboratories and Fourneau and the researchers at the Institut
Pasteur simultaneously found in 1937 that dapsone was ten times as potent against
streptococcal infection in mice and about a hundred times as toxic as sulphanilamide.

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. Robert Cochrane was the first to use DDS, the active
component of promin, at the Lady Willingdon Leprosy Settlement, in Chingleput, near
Madras, India. John Lowe was the first to successfully administer DDS orally at Uzuakoli
Leper Settlement, in Nigeria, in spite of indications that the drug was highly toxic. Both
innovations made it possible to produce a treatment that was cheap, seemingly effective, and
could be distributed on a large scale.

Scientists eventually realised that DDS was 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 ineffective against resistant bacteria.

The search for more effective anti-leprosy drugs led to the use of clofazimine and rifampicin
in the 1960s and 1970s.[4] Later, Indian scientist Shantaram Yawalkar and his colleagues
formulated a combined therapy using rifampicin and dapsone, intended to mitigate bacterial
resistance.[5] 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.

As this treatment was quite expensive, it was not quickly adopted in most countries where
the disease is endemic. 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. This was based on increasing the geographical coverage of
MDT and patients' accessibility to the treatment. Novartis produces this medication for free.