Leprosy

Leprosy
Classification and external resources
A 24-year-old man from Norway, infected with leprosy, 1886.
ICD-10	A30
ICD-9	030
OMIM	246300
DiseasesDB	8478
MedlinePlus	001347
eMedicine	med/1281 derm/223 neuro/187
MeSH	D007918

Leprosy, also known as Hansen's disease (HD), is a chronic infection caused by the bacterium Mycobacterium leprae and Mycobacterium lepromatosis.^[1][2] Leprosy takes its name from the Latin word Lepra, which means "scaly", while the term "Hansen's disease" is named after the physician Gerhard Armauer Hansen. It is primarily a granulomatous disease of the peripheral nerves and mucosa of the upper respiratory tract; skin lesions are the primary external sign.^[3] Left untreated, leprosy can be progressive, causing permanent damage to the skin, nerves, limbs and eyes. Contrary to folklore, leprosy does not cause body parts to fall off, although they can become numb or diseased as a result of secondary infections; these occur as a result of the body's defenses being compromised by the primary disease.^[4][5] Secondary infections, in turn, can result in tissue loss causing fingers and toes to become shortened and deformed, as cartilage is absorbed into the body.^[4][5][6]

Treatment for multibacillary leprosy consists of rifampicin, dapsone, and clofazimine taken over 12 months.^[7] Single dose multidrug therapy (MDT) for single lesion leprosy consists of rifampicin, ofloxacin, and minocycline. The move toward single-dose treatment strategies has reduced the rates of disease in some regions. World Leprosy Day was created to draw awareness to those affected by leprosy.

In 1995, the World Health Organization (WHO) estimated that between two and three million people were permanently disabled because of leprosy at that time.^[8] In the past 20 years, 15 million people worldwide have been cured of leprosy.^[9]

Leprosy has affected humanity for over 4,000 years,^[10] and was recognized in the civilizations of ancient China, Egypt, Israel, and India.^[11] Although the forced quarantine or segregation of patients is unnecessary in places where adequate treatments are available, many leper colonies still remain around the world in countries such as India (where there are still more than 1,000 leper colonies),^[9] China,^[12] and Japan (although Japan's sanatoriums no longer have active leprosy cases, nor are survivors held in them by law).^[13] Leprosy was once believed to be highly contagious and was treated with mercury—all of which applied to syphilis, which was first described in 1530. It is possible that many early cases thought to be leprosy could actually have been syphilis.^[14] The age-old social stigma^[15] associated with the advanced form of leprosy lingers in many areas, and remains a major obstacle to self-reporting and early treatment. Effective treatment first appeared in the late 1940s. Resistance has developed to initial treatment. It was not until the introduction of MDT in the early 1980s that the disease could be diagnosed and treated successfully within the community.^[7]

Signs and symptoms

Leprosy is primarily a granulomatous disease of the peripheral nerves and mucosa of the upper respiratory tract; skin lesions are the primary external sign.^[3] Left untreated, leprosy can be progressive, causing permanent damage to the skin, nerves, limbs and eyes. Contrary to folklore, leprosy does not cause body parts to fall off, although they can become numb or diseased as a result of secondary infections; these occur as a result of the body's defenses being compromised by the primary disease.^[4][5] Secondary infections, in turn, can result in tissue loss causing fingers and toes to become shortened and deformed, as cartilage is absorbed into the body.^[4][5][6]

Cause

Mycobacterium leprae

Mycobacterium leprae and Mycobacterium lepromatosis are the causative agents of leprosy. M. lepromatosis is a relatively newly identified mycobacterium isolated from a fatal case of diffuse lepromatous leprosy in 2008.^[2][3]

An intracellular, acid-fast bacterium, M. leprae is aerobic and rod-shaped, and is surrounded by the waxy cell membrane coating characteristic of Mycobacterium species.^[16]

Due to extensive loss of genes necessary for independent growth, M. leprae and M. lepromatosis are obligate pathogens, and unculturable in the laboratory, a factor that leads to difficulty in definitively identifying the organism under a strict interpretation of Koch's postulates.^[2][17] The use of non-culture-based techniques such as molecular genetics has allowed for alternative establishment of causation.

While the causative organisms have to date been impossible to culture in vitro, it has been possible to grow them in animals.

Naturally occurring infection also has been reported in non-human primates including the African chimpanzee, sooty mangabey, and cynomolgus macaque, as well as in armadillos.

Genetics

Name	Locus	OMIM	Gene
LPRS1	10p13	609888
LPRS2	6q25	607572	PARK2, PACRG
LPRS3	4q32	246300	TLR2
LPRS4	6p21.3	610988	LTA
LPRS5	4p14	613223	TLR1
LPRS6	13q14.11	613407

Several genes have been associated with a susceptibility to leprosy. It is believed that around 95% of people are naturally immune.^[18][19] Recent research suggests that there is a defect in cell-mediated immunity that causes susceptibility to leprosy. 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 in some way at the biochemical level.^[20]

Risk factors

At highest risk are those living in endemic areas with poor conditions such as inadequate bedding, contaminated water, and insufficient diet, or other diseases that compromise immune function.

There appears to be little interaction between HIV and the risk of leprosy.^[21]

Transmission

Although the mode of transmission of leprosy remains uncertain, many think that M. leprae is usually spread from person to person in nasal droplets.^[22] Studies have shown that leprosy can be transmitted to humans by armadillos.^[23][24][25] Leprosy is not known to be either sexually transmitted or highly infectious after treatment. Approximately 95% of people are naturally immune and sufferers are no longer infectious after as little as two weeks of treatment.^[26]

Pathophysiology

The precise mechanism of transmission of leprosy is unknown; however, both prolonged close contact and transmission by nasal droplet are thought to be implicated.^[11] In addition to humans, leprosy has been observed in the nine-banded armadillo, (which, it has recently been confirmed, is among the primary sources of new cases of leprosy in Americans^[27]), and three species of non-human primates.^[28] The bacterium can also be grown in the laboratory by injection into the footpads of mice.^[29] There is evidence that not all people who are infected with M. leprae develop leprosy, and genetic factors have long been thought to play a role, due to the observation of clustering of leprosy around certain families, and the failure to understand why certain individuals develop lepromatous leprosy while others develop other types of leprosy.^[30] It is estimated that due to genetic factors, only 5% of the population is susceptible to leprosy.^[31] This is mostly because the body is naturally immune to the bacteria, and those persons that do become infected experience severe allergic reactions to the disease. However, the role of genetic factors is not entirely clear in determining this clinical expression. In addition, malnutrition and prolonged exposure to infected persons may play a role in development of the overt disease.

The most widely held belief is that the disease is transmitted by contact between infected persons and healthy persons.^[32] In general, closeness of contact is related to the dose of infection, which in turn is related to the occurrence of disease. Of the various situations that promote close contact, contact within the household is the only one that is easily identified, although the incidence among contacts and the relative risk for them appear to vary considerably in different studies. In incidence studies, infection rates for contacts of lepromatous leprosy have varied from 6.2 per 1000 per year in Cebu, Philippines^[33] to 53 per 1000 per year in part of Western India to 55.8 per 1000 per year in a part of Southern India.^[34]

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.^[35] Although there are reports of acid-fast bacilli being found in the desquamating epithelium (sloughing of superficial layer of skin) of the skin, Weddell et al. had reported in 1963 that they could not find any acid-fast bacilli in the epidermis, even after examining a very large number of specimens from patients and contacts.^[36] In a recent study, Job et al. found fairly large numbers of M. leprae in the superficial keratin layer of the skin of lepromatous leprosy patients, suggesting that the organism could exit along with the sebaceous secretions.^[37]

The importance of the nasal mucosa was recognized as early as 1898 by Schäffer, in particular that of the ulcerated mucosa.^[38] The quantity of bacilli from nasal mucosal lesions in lepromatous leprosy was demonstrated by Shepard as large, with counts ranging from 10,000 to 10,000,000.^[39] Pedley reported that the majority of lepromatous patients showed leprosy bacilli in their nasal secretions as collected through blowing the nose.^[40] Davey and Rees indicated that nasal secretions from lepromatous patients could yield as much as 10 million viable organisms per day.^[41]

The entry route of M. leprae into the human body is also not definitively known: The skin and the upper respiratory tract are most likely. While older research dealt with the skin route, recent research has increasingly favored the respiratory route. Rees and McDougall succeeded in the experimental transmission of leprosy through aerosols containing M. leprae in immune-suppressed mice, suggesting a similar possibility in humans.^[42] Successful results have also been reported on experiments with nude mice when M. leprae were introduced into the nasal cavity by topical application.^[43] In summary, entry through the respiratory route appears the most probable route, although other routes, particularly broken skin, cannot be ruled out.

In leprosy, both the reference points for measuring the incubation period and the times of infection and onset of disease are difficult to define, the former because of the lack of adequate immunological tools and the latter because of the disease's slow onset. Even so, several investigators have attempted to measure the incubation period for leprosy. The minimum incubation period reported is as short as a few weeks and this is based on the very occasional occurrence of leprosy among young infants.^[44] The maximum incubation period reported is as long as 30 years, or over, as observed among war veterans known to have been exposed for short periods in endemic areas but otherwise living in non-endemic areas. It is generally agreed that the average incubation period is between three and five years.

Diagnosis

Diagnosis in the U.S. is often delayed because healthcare providers are unaware of leprosy and its symptoms. Early diagnosis and treatment prevents nerve involvement, the hallmark of leprosy, and the disability it causes.^[45]

There are many kinds of leprosy but there are common symptoms, including: runny nose; dry scalp; eye problems; skin lesions; muscle weakness; reddish skin; smooth shiny diffuse thickening of facial skin, ear, and hand; loss of sensation in fingers and toes; thickening of peripheral nerves; and flat nose due to destruction of nasal cartilage. There is also phonation and resonation of sound during speech. Often there is atrophy of the testes and impotency.

Classification

There are several ingenious different approaches for classifying leprosy; however, parallels exist.

• The World Health Organization system distinguishes "paucibacillary" and "multibacillary" based upon the proliferation of bacteria^[46]("pauci-" refers to a low quantity.)
• The SHAY scale provides five gradations.^[47][48]
• The ICD-10, though developed by the WHO, uses Ridley-Jopling and not the WHO system. It also adds an indeterminate ("I") entry.^[35]
• In MeSH, three groupings are used.

WHO	Ridley-Jopling	ICD-10	MeSH	Description	Lepromin test	Immune target
Paucibacillary	tuberculoid ("TT"), borderline tuberculoid ("BT")	A30.1, A30.2	Tuberculoid	It is characterized by one or more hypopigmented skin macules and anaesthetic patches, where skin sensations are lost because of damaged peripheral nerves that have been attacked by the human host's immune cells.	Positive	bacillus (Th1)
Multibacillary	midborderline or borderline ("BB")	A30.3	Borderline	Borderline leprosy is of intermediate severity and is the most common form. Skin lesions resemble tuberculoid leprosy but are more numerous and irregular; large patches may affect a whole limb, and peripheral nerve involvement with weakness and loss of sensation is common. This type is unstable and may become more like lepromatous leprosy or may undergo a reversal reaction, becoming more like the tuberculoid form.
Multibacillary	borderline lepromatous ("BL"), and lepromatous ("LL")	A30.4, A30.5	Lepromatous	It is associated with symmetric skin lesions, nodules, plaques, thickened dermis, and frequent involvement of the nasal mucosa resulting in nasal congestion and epistaxis (nose bleeds), but, typically, detectable nerve damage is late.	Negative	plasmid inside bacillus [citation needed] (Th2)

There is a difference in immune response to the tuberculoid and lepromatous forms.^[49]

Leprosy may also be divided into the following types:^{[50]:344–346}

• Early and indeterminate leprosy
• Tuberculoid leprosy
• Borderline tuberculoid leprosy
• Borderline leprosy
• Borderline lepromatous leprosy
• Lepromatous leprosy
• Histoid leprosy
• Diffuse leprosy of Lucio and Latapí

This disease may also occur with only neural involvement, without skin lesions.^{[11][51][52][53][54][55]} This disease is also known as Hansen's disease.

The first symptom of leprosy which is most obvious is excess eye fluid.

Prevention

Medications can decrease the risk of those living with people with leprosy from acquiring the disease and likely those with whom people with leprosy come into contact outside the home.^[56] There are however concerns of resistance, cost, and disclosure of a person's infection status when doing follow up of contacts, thus the WHO however recommends that people who live in the same household be examined for leprosy and only be treated if symptoms are present.^[56]

The Bacillus Calmette–Guérin (BCG) vaccine offers a variable amount of protection against leprosy in addition to tuberculosis.^[57] It appears to be 26 to 41% effective (based on controlled trials) and about 60% effective based on observational studies with two doses possibly working better than one.^[58][59] Development of a more effective vaccine is ongoing as of 2011.^[56]

Treatment

A number of leprostatic agents are available for treatment. For paucibacillary (PB or tuberculoid) cases treatment with daily dapsone and monthly rifampicin for six months is recommended.^[60] While for multibacillary (MB or lepromatous) cases treatment with daily dapsone and clofazimine along with monthly rifampicin for twelve months is recommended.^[60]

MDT remains highly effective, and people are no longer infectious after the first monthly dose.^[11] It is safe and easy to use under field conditions due to its presentation in calendar blister packs.^[11] Relapse rates remain low, and there is no known resistance to the combined drugs.^[11]

In 1987, Venezuelan researcher Jacinto Convit was awarded the Prince of Asturias Awards for his recognition as the discoverer of a cure for this disease.^[61]

Epidemiology

Globally in 2012 the number of current cases of leprosy was 180,000.^[62] In 2011 the approximate number of new cases diagnosed was 220,000.^[62] The number of cases has decreased significantly from the 1960s to the 2010s.^[22]

In 1995 two to three million people were estimated to be permanently disabled because of leprosy.^[8] India has the greatest number of cases, with Brazil second and Myanmar third. In 2000, the World Health Organization (WHO) listed 91 countries in which leprosy is endemic. India, Burma, and Nepal contained 70% of cases. India reports over 50% of the world's leprosy cases.^[63] In 2002, 763,917 new cases were detected worldwide, and in that year the WHO listed Brazil, Madagascar, Mozambique, Tanzania, and Nepal as having 90% of leprosy cases. Although the number of cases worldwide continues to fall, pockets of high prevalence continue in certain areas such as Brazil, South Asia (India, Nepal), some parts of Africa (Tanzania, Madagascar, Mozambique), and the western Pacific.

Disease burden

Although the number of new leprosy cases occurring each year is important as a measure of transmission, it is difficult to measure due to leprosy's long incubation period, delays in diagnosis after onset of the disease, and the lack of laboratory tools to detect it in the very early stages. Instead, the registered prevalence is used. 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. 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.^[64]

New case detection is another indicator of the disease that is usually reported by countries on an annual basis. It includes cases diagnosed with onset of disease in the year in question (true incidence) and a large proportion of cases with onset in previous years (termed a backlog prevalence of undetected cases).

Endemic countries also report the number of new cases with established disabilities at the time of detection, as an indicator of the backlog prevalence. Determination of the time of onset of the disease is, in general, unreliable, is very labor-intensive, and is seldom done in recording these statistics.

History

Evidence of leprosy dates back to ancient Egypt in 4000 BC and was discussed by Hippocrates in 460 BC.^[65] 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 AD.^[66] The earliest writings on healing from leprosy is documented in the Synoptic Gospels (Gospel of Mark, Gospel of Matthew,and Gospel of Luke) where Jesus is described as cleansing multiple victims of their infirmity.^{[67][68][69][70]}

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.^[71] 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.^[72] Attempted treatments have included arsenic, elephants' teeth, creosote, and mercury.^[72]

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.^[73] The first effective treatment (promin) became available in the 1940s.^[65] In the 1950s dapsone was introduced. The search for further effective anti-leprosy drugs led to the use of clofazimine and rifampicin in the 1960s and 1970s.^[74] Later, Indian scientist Shantaram Yawalkar and his colleagues formulated a combined therapy using rifampicin and dapsone, intended to mitigate bacterial resistance.^[75] 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.

Society and culture

Treatment cost

Between 1995 and 1999, WHO, with the aid of the Nippon Foundation, supplied all endemic countries with free MDT in blister packs, channelled through Ministries of Health. This free provision was extended in 2000 and again in 2005 with donations by the MDT manufacturer Novartis through WHO. In the latest agreement signed between the company and WHO in October 2010, the provision of free MDT by WHO to all endemic countries will now run until at least the end of 2015. At the national level, non-government organizations (NGOs) affiliated to the national programme will continue to be provided with an appropriate free supply of this WHO supplied MDT by the government.

Stigma in India

Leprosy patients in India, like many parts of the world, suffer under some of the worst conditions and stereotypes about their disease. Depending on the level of disfigurement a leper could receive harsher stigma and ostracism. Leprosy sufferers are markedly disadvantaged with respect to income with 16-44% of victims reporting a decrease in pay as a result of having leprosy. Women suffer greater restrictions and social stigma than men. Leprosy prevents mothers from getting too close to their children out of fear that they could infect them. In a report, 49% of women stopped breast-feeding their babies as a result of having leprosy. Doctors and other health care providers and NGOs are working hard to educate people about the disease. In one study when leprosy treatment and education were mixed in with the local healthcare program the attitudes towards the disease were somewhat alleviated as people had a better understanding of it. Now the disease prevalence has been reduced to less than 1 per million population in most parts of the country.^[76]

Notable cases

• Saint Damien DeVeuster, a Roman Catholic priest from Belgium who ministered to the people with leprosy who had been placed under a government-sanctioned medical quarantine on the island of Molokaʻi in the Kingdom of Hawaiʻi.^[77]
• Baldwin IV of Jerusalem, who was a king of Latin Jerusalem and was portrayed as a character in the film Kingdom of Heaven^[78]
• Vietnamese poet Han Mac Tu^[79]
• Ōtani Yoshitsugu, a Japanese daimyo^[80]
• In the Torah (also included within the Christian Old Testament) there are references to Moses^[81] and his sister Miriam^[82] are afflicted by a dreaded skin disease transliterated as tzaraath, which is widely but not exclusively understood to mean leprosy.
• In the Books of Kings, included in the Jewish Nevi'im and Christian Old Testament, Naaman the Syrian and later the prophet Elisha's servant Gehazi^[83] being afflicted by a dreaded skin disease transliterated as tzaraath, which is widely but not exclusively understood to mean leprosy.
• In the Books of Chronicles, included in the Jewish Ketuvim and Christian Old Testament, King Uzziah was suddenly struck with the dreaded skin disease tzaraat, which is widely but not exclusively understood to mean leprosy.

References

Further reading

• 1877: Lewis, T. R.; D. D. Cunningham (1877). Leprosy In India. Calcutta: Office Of The Superintendent Of Government Printing. Retrieved 2009-08-07.  Cite uses deprecated parameters (help)
• 1895: Ashmead, Albert S. (1895). Pre-Columbian Leprosy. Chicago: American Medical Association Press. Retrieved 2009-08-07. 
• 1895: Prize Essays On Leprosy. London: The New Sydenham Society. 1895. Retrieved 2009-08-07. 
• 1896: Impey, S. P. (1896). A Handbook On Leprosy. Philadelphia: P. Blakiston, Son & Co. Retrieved 2009-08-07. 
• 1916: Page, Walter Hines; Page, Arthur Wilson (January 1916). "Fighting Leprosy In The Philippines". The World's Work: A History of Our Time XXXI: 310–320. Retrieved 2009-08-04.  Cite uses deprecated parameters (help)
• 1991: William Jopling. Leprosy stigma. Lepr Rev 1991, 62, 1–12.
• 1993: Anne Bargès. Leprosy history and ethnology in Mali. In French.

External links

Wikimedia Commons has media related to Leprosy.

• 's_Disease/ Leprosy on the Open Directory Project
• Dr. George J. Hill Leprosy Collection, Marshall University Virtual exhibit of books on leprosy.

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