Leprosy

For the Biblical term and its varied meanings, see Tzaraath. For other uses, see Leprosy (disambiguation).
Leprosy

A 24-year-old man from Norway, infected with leprosy, 1886
Classification and external resources
Pronunciation /ˈlɛprəsi/[1]
Specialty Infectious disease
ICD-10 A30
ICD-9-CM 030
OMIM 246300
DiseasesDB 8478
MedlinePlus 001347
eMedicine med/1281 derm/223 neuro/187
Patient UK Leprosy
MeSH D007918

Leprosy, also known as Hansen's disease (HD), is a chronic infection caused by the bacteria Mycobacterium leprae[2] and Mycobacterium lepromatosis.[3] Initially, infections are without symptoms and typically remain this way from 5 to as long as 20 years.[2] Symptoms that develop include granulomas of the nerves, respiratory tract, skin, and eyes.[2] This may result in a lack of ability to feel pain and thus loss of parts of extremities due to repeated injuries or infection due to unnoticed wounds.[4] Weakness and poor eyesight may also be present.[4]

Leprosy is spread between people. It is believed to occur through a cough or contact with fluid from the nose of an infected person.[5] Leprosy occurs more commonly among those living in poverty and is believed to be transmitted by respiratory droplets.[4] Contrary to popular belief, it is not very contagious.[4] The two main types of disease are based on the number of bacteria present: paucibacillary and multibacillary.[4] The two types are differentiated by the number of poorly pigmented, numb skin patches present, with paucibacillary having five or fewer and multibacillary having more than five.[4] The diagnosis is confirmed by finding acid-fast bacilli in a biopsy of the skin or by detecting the DNA using polymerase chain reaction.[4]

Leprosy is curable with a treatment known as multidrug therapy (MDT).[2] Treatment for paucibacillary leprosy is with the medications dapsone and rifampicin for six months.[4] Treatment for multibacillary leprosy consists of rifampicin, dapsone, and clofazimine for 12 months.[4] These treatments are provided free of charge by the World Health Organization.[2] A number of other antibiotics may also be used.[4] Globally in 2012, the number of chronic cases of leprosy was 189,000 down from some 5.2 million in the 1980s.[2][6][7] The number of new cases was 230,000.[2] Most new cases occur in 16 countries, with India accounting for more than half.[2][4] In the past 20 years, 16 million people worldwide have been cured of leprosy.[2] About 200 cases are reported per year in the United States.[8]

Leprosy has affected humanity for thousands of years.[4] The disease 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.[4] Separating people by placing them in leper colonies still occurs in places such as India,[9] China,[10] and Africa.[11] However, most colonies have closed since leprosy has been determined to not be very contagious.[11] Social stigma has been associated with leprosy for much of history, which continues to be a barrier to self-reporting and early treatment.[2] Some consider the word leper offensive, preferring the phrase "persons affected with leprosy".[12] World Leprosy Day was started in 1954 to draw awareness to those affected by leprosy.[13]

Signs and symptoms

Leprosy is primarily a granulomatous disease of the peripheral nerves and mucosa of the upper respiratory tract; skin lesions (light or dark patches) are the primary external sign.[14] If untreated, leprosy can progress and cause 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.[15][16] 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.[15][16][17]

Cause

M. leprae

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.
Main article: Mycobacterium leprae

M. leprae and M. 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.[3][14]

An intracellular, acid-fast bacterium, M. leprae is aerobic and rod-shaped, and is surrounded by the waxy cell membrane coating characteristic of the Mycobacterium genus.[18]

Due to extensive loss of genes necessary for independent growth, M. leprae and M. lepromatosis are obligate intracellular 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.[3][19] The use of nonculture-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 such as mice and armadillos.

Naturally occurring infection also has been reported in nonhuman primates, including the African chimpanzee, sooty mangabey, and cynomolgus macaque, as well as in armadillos and red squirrels.[20]

Risk factors

At highest risk are those living in areas with polluted water and poor diet or people suffering from diseases that compromise immune function. Little interaction appears to exist between HIV and the risk of leprosy.[21] Genetic predisposition appears to play a role in susceptibility.

Transmission

Transmission of leprosy occurs during close contact with those who are infected.[22] Transmission is believed to be by nasal droplets.[7][22]

Leprosy is not known to be either sexually transmitted or highly infectious. People are no longer infectious after as little as two weeks of treatment.[23]

Leprosy may also be transmitted to humans by armadillos[24] and may be present in three species of non-human primates.[25]

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.[26]

The skin and the upper respiratory tract are most likely entry route. While older research dealt with the skin route, recent research has increasingly favored the respiratory route. Experimental transmission of leprosy through aerosols containing M. leprae in immunosuppressed mice was accomplished, suggesting a similar possibility in humans.[27]

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. Many people's immune systems are able to eliminate leprosy during the early infection stage before severe symptoms develop.[28] Research suggests a defect in cell-mediated immunity 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.[29] Some evidence indicates 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]

Pathophysiology

How the infection produces the symptoms of the disease is not known.[7]

Diagnosis

According to the World Health Organization, diagnosis in areas where people are frequently infected is based on one of these main signs:

Skin lesions can be single or multiple, usually hypopigmented, although occasionally reddish or copper-colored. The lesions may be macules (flat), papules (raised), or nodular. Sensory loss at the skin lesion is important because this feature can help differentiate from other causes of skin lesions such as tinea versicolor. Thickened nerves are associated with leprosy and can be accompanied by loss of sensation or muscle weakness. However, without the characteristic skin lesion and sensory loss, muscle weakness is not considered a reliable sign of leprosy.

Positive skin smears: In some case, acid-fast leprosy bacilli are considered diagnostic; however, the diagnosis is clinical.[31]

Diagnosis in areas where the disease is uncommon, like the United States, is often delayed because healthcare providers are unaware of leprosy and its symptoms. Early diagnosis and treatment prevent nerve involvement, the hallmark of leprosy, and the disability it causes.[32]

Many kinds of leprosy are known, but some symptoms are common, 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. Also, phonation and resonation of sound occurs during speech. Often, atrophy of the testes and impotency happen.

Classification

Several different approaches for classifying leprosy exist, but parallels exist.

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
(Th2)

A difference in immune response to the tuberculoid and lepromatous forms is seen.[36]

Leprosy may also be divided into:[37]:344–346

This disease may also occur with only neural involvement, without skin lesions.[22][38][39][40][41][42]

Prevention

Early detection of the disease is important, since physical and neurological damage may be irreversible even if cured. 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.[43] However, concerns are known of resistance, cost, and disclosure of a person's infection status when doing follow-up of contacts. Therefore, the WHO recommends that people who live in the same household be examined for leprosy and only be treated if symptoms are present.[43]

The Bacillus Calmette–Guérin (BCG) vaccine offers a variable amount of protection against leprosy in addition to tuberculosis.[44] 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.[45][46] Development of a more effective vaccine is ongoing as of 2015.[43][47][48]

Treatment

MDT antileprosy drugs: standard regimens

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.[4] While for multibacillary (MB or lepromatous) cases, treatment with daily dapsone and clofazimine along with monthly rifampicin for twelve months is recommended.[4]

Multidrug therapy (MDT) remains highly effective, and people are no longer infectious after the first monthly dose.[22] It is safe and easy to use under field conditions due to its presentation in calendar blister packs.[22] Relapse rates remain low, and no resistance to the combined drugs is seen.[22]

Epidemiology

World distribution of leprosy, 2003[49]
Disability-adjusted life year for leprosy per 100,000 inhabitants in 2004[50]
  no data
  <1.5
  1.5–3
  3–4.5
  4.5–6
  6–7.5
  7.5–9
  9–10.5
  10.5–12
  12–13.5
  13.5–15
  15–20
  >20

Globally in 2012, the number of cases of leprosy was 180,000.[6] In 2011, the approximate number of new cases diagnosed was 220,000.[6] The number of cases has decreased significantly from the 1960s to the 2010s.[7]

In 1995, two to three million people were estimated to be permanently disabled because of leprosy.[51] India has the greatest number of cases, with Brazil second and Myanmar third. In 2000, the 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.[52] 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.

While the number of cases of leprosy was in the tens of millions in the 1960s, a series of national (The International Federation of Anti-Leprosy Associations) and international (the WHO's "Global Strategy for Reducing Disease Burden Due to Leprosy") initiatives have reduced the total number and the number of new cases of the disease.[53]

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.[54]

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

Main article: History of leprosy
G. H. A. Hansen, discoverer of M. leprae

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 that there were four strains of M leprae with specific regional locations. Strain 1 occurs predominately in Asia, the Pacific region, and East Africa; strain 4, in West Africa and the Caribbean; strain 3 in Europe, North Africa, and the Americas; and strain 2 only in Ethiopia, Malawi, Nepal/north India, and New Caledonia.

On the basis of this, they offer a map of the dissemination of leprosy in the world. This confirms the spread of the disease along the migration, colonisation, and slave trade routes taken from West Africa to India, East Africa to the New World, and from Africa into Europe and vice versa.[55]

Although it is difficult to retrospectively identify descriptions of leprosy-like symptoms, what appears to be leprosy was discussed by Hippocrates in 460 BC. 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.[56]

Interpretations of the presence of leprosy have been made on the basis of descriptions in ancient Indian (Atharva Verda and Kausika Sutra), Greek, and Middle Eastern documentary sources that describe skin afflictions.[57]

Skeletal remains from the second millennium B.C., discovered in 2009, represent the oldest documented evidence for leprosy. Located at Balathal, in Rajasthan, northwest India, the discoverers suggest that if the disease did migrate from Africa, to India, during the third millennium B.C. “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.” [58] A 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.[59]

The causative agent of leprosy, M. 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.[60] The first effective treatment (promin) became available in the 1940s.[61] 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.[62] Later, Indian scientist Shantaram Yawalkar and his colleagues formulated a combined therapy using rifampicin and dapsone, intended to mitigate bacterial resistance.[63] Multidrug 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.

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. Many early cases thought to be leprosy could actually have been syphilis.[64] Resistance has developed to initial treatment. Until the introduction of MDT in the early 1980s, the disease could not be diagnosed and treated successfully within the community.[65]

Japan still has sanatoriums (although Japan's sanatoriums no longer have active leprosy cases, nor are survivors held in them by law).[66]

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.[67]

Society and culture

Treatment cost

Between 1995 and 1999, the WHO, with the aid of the Nippon Foundation, supplied all endemic countries with free multidrug treatment (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 the WHO. In the latest agreement signed between the company and the WHO in October 2010, the provision of free MDT by the WHO to all endemic countries will now run until at least the end of 2015. At the national level, nongovernment organizations (NGOs) affiliated with the national programme will continue to be provided with an appropriate free supply of this WHO-supplied MDT by the government.

Two lepers denied entrance to town, 14th century

Bible

Many English translations of the Bible translate tzaraath as "leprosy," a confusion that derives from the use of the koine cognate "Λέπρα" (which can mean any disease causing scaly skin) in the Septuagint. 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. It may sometimes be a symptom of the disease described in this article, but has many other causes, as well. The New Testament describes instances of Jesus healing people with leprosy (Luke 5:10), although the precise relationship between this, tzaraath, and Hansen's disease is not established.

Stigma

See also: Leprosy stigma
Medieval leper bell

People with leprosy often encounter discrimination. Depending on the level of disfigurement, a person with leprosy receives varying stigma and ostracism. People with leprosy earn less: 16-44% of them report their pay dropped 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 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 one per million population in most parts of the United States.[68]

Organizations which work with leprosy recommend a move away from the use of the term "leper."[69] It is generally thought that this term alienates people due its colloquial use as a term for the shunned.

Notable cases

References

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