Leprosy

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Leprosy
Classification & external resources

A 24 year old man infected with leprosy.
ICD-10	A30.
ICD-9	030
OMIM	246300
DiseasesDB	8478
MedlinePlus	001347
eMedicine	med/1281  derm/223 neuro/187
MeSH	C01.252.410.040.552.386

Leprosy or Hansen's Disease is a chronic infectious disease caused by the bacterium Mycobacterium leprae.^[1] Leprosy is primarily a granulomatous disease of the peripheral nerves, mucosa of the upper respiratory tract, and skin lesions.^[2] If left untreated, there can be progressive and permanent damage to the skin, nerves, limbs and eyes.

Leprosy has affected humanity since at least 600 BC, and was well-recognized in the civilizations of ancient China, Egypt and India.^[3] In 1995, the World Health Organization (WHO) estimated that between two and three million individuals were permanently disabled because of leprosy.^[4] Although the forced quarantine or segregation of patients is unnecessary, and can be considered unethical, a few leper colonies still remain around the world, in countries such as India, Vietnam, and the Philippines.

The age-old stigma associated with the advanced form of the disease still lingers in many endemic countries, and remains a major obstacle to self-reporting and early treatment. Effective treatment for leprosy appeared in the late 1940s with the introduction of dapsone and its derivatives. However, leprosy bacilli resistant to dapsone gradually appeared and became widespread, and it was not until the introduction of multidrug therapy (MDT) in the early 1980s that the disease could be diagnosed and treated successfully within the community.

Contents 1 Historical background 2 Transmission 3 M. leprae genome 3.1 Disease burden 4 Global Situation 5 Incidence 6 Risk groups 7 Clinical features 8 Treatment of leprosy 9 See also 10 References 10.1 Further reading 11 External links

[edit] Historical background

A very great number of leprosaria, or leper hospitals, sprang up in the Middle ages, particularly in England, where there were 250 by A.D. 1230.^{[citation needed]} The first recorded leprosarium was in Harbledown. (See Leper colony) These institutions were run along monastic lines, and while lepers were encouraged to live in these monastic-type establishments, this was for their own health as well as quarantine. Indeed, some medieval sources indicate belief that those suffering from leprosy were considered to be going through Purgatory on Earth, and for this reason their suffering was considered more holy than the ordinary person's. More frequently, lepers were seen to exist in a place between life and death: they were still alive, yet many chose or were forced to completely separate themselves from mundane existence.^{[citation needed]}

Radegund was noted for washing the feet of lepers, and Orderic Vitalis writes of a monk, Ralf, who was so overcome by the plight of the leper that he prayed to catch leprosy himself (which he eventually did). The leper would carry a clapper and bell to warn of his approach, and this was as much to attract attention for charity as to warn people that a diseased person was near.

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 man.^[5][6] Historically, individuals with Hansen's disease have been known as lepers, however, this term is falling into disuse as a result of the diminishing number of leprosy patients and the pejorative connotations of the term. The term most widely accepted among people and agencies working in the field of Hansen's Disease is "people affected by Hansen's Disease".

Historically, the term Tzaraath from the Hebrew Bible is commonly translated as leprosy, although the symptoms of Tzaraath are not entirely consistent with leprosy and might refer to a variety of skin disorders other than Hansen's disease.^[7]

In particular tinea capitis (fungal scalp infection) and related infections on other body parts caused by the dermatophyte fungus Trichophyton violaceum, are abundant throughout the Middle East and North Africa today, and might also have been common in biblical times. Similarly, the related agent of the disfiguring skin disease favus, Trichophyton schoenleinii, appears to have been common throughout Eurasia and Africa prior to the advent of modern medicine. Persons with severe favus and similar fungal diseases (and potentially also with severe psoriasis and other diseases not caused by microorganisms) tended to be classed as having leprosy as late as the 17th century in Europe:^[8] this is vividly as shown in the painting Governors of the Home for Lepers at Haarlem 1667 by Jan de Bray (Frans Hals Museum, Haarlem, the Netherlands), where a young Dutch man with a vivid scalp infection, almost certainly caused by a fungus, is shown being cared for by three officials of a charitable home intended for leprosy sufferers (painting reproduced in reference just cited). The use of the word "leprosy" prior to the mid-19th century, when microscopic examination of skin for medical diagnosis was first developed, can seldom be correlated reliably with Hansen's disease as we understand it today.

The word "leprosy" derives from the ancient Greek words lepros, a scale, and lepein, to peel.^[9] The word came into the English language via Latin and Old French. The first attested English use is in the Ancrene Wisse, a 13th-century manual for nuns ("Moyseses hond..bisemde o þe spitel uuel & þuhte lepruse." The Middle English Dictionary, s.v., "leprous"). A roughly contemporaneous use is attested in the Anglo-Norman Dialogues of Saint Gregory, "Esmondez i sont li lieprous" (Anglo-Norman Dictionary, s.v., "leprus").

[edit] Transmission

The exact mechanism of transmission of leprosy is not known. M. leprae has never been grown in the laboratory; as a result it has been difficult to study the pathogenic mechanisms. 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.^{[citation needed]} However, what is not clear is the role of genetics vis-à-vis other factors in determining this clinical expression. In addition, malnutrition and possible prior exposure to other environmental mycobacteria 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.^{[citation needed]} 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 actual 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^[10] to 55.8 per 1000 per year in a part of Southern India.^[11]

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. It is true that lepromatous cases show large numbers of organisms deep down in the dermis. However, whether they reach the skin surface in sufficient numbers is doubtful. Although there are reports of acid-fast bacilli being found in the desquamating epithelium of the skin, Weddell et al have reported 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.^[12] 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.^[13]

The importance of the nasal mucosa was recognized as early as 1898 by Schäffer, ^[14] particularly that of the ulcerated mucosa. 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.^[15] Pedley reported that the majority of lepromatous patients showed leprosy bacilli in their nasal secretions as collected through blowing the nose.^[16] Davey and Rees indicated that nasal secretions from lepromatous patients could yield as much as 10 million viable organisms per day.^[17]

The entry route of M. leprae into the human body is not definitely known. However, the two seriously considered are the skin and the upper respiratory tract. With regard to the respiratory route of entry of M. leprae, the evidence in its favour is on the increase in spite of the long-held belief that the skin was the exclusive route of entry. 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.^[18] Successful results have also been reported on experiments with nude mice when M. leprae were introduced into the nasal cavity by topical application. ^[19] In summary, entry through the respiratory route appears the most probable route, although other routes, particularly broken skin, cannot be ruled out. The CDC notes the following assertion about the transmission of the disease: "Although the mode of transmission of Hansen's disease remains uncertain, most investigators think that M. leprae is usually spread from person to person in respiratory droplets."^[20]

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 insidious nature of the onset of leprosy. 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. ^[21] 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 3 to 5 years.

[edit] M. leprae genome

Mycobacterium leprae has the longest doubling time of all known bacteria and has thwarted every effort at culture in the laboratory. Comparing the genome sequence of Mycobacterium leprae with that of Mycobacterium tuberculosis provides clear explanations for these properties and reveal an extreme case of reductive evolution. Less than half of the genome contains functional genes. Gene deletion and decay appear to have eliminated many important metabolic activities, including siderophore production, part of the oxidative and most of the microaerophilic and anaerobic respiratory chains, and numerous catabolic systems and their regulatory circuits. ^[22]

The genome sequence of a strain of Mycobacterium leprae, originally isolated in Tamil Nadu and designated 'TN', has been completed recently. The sequence was obtained by a combined approach, employing automated DNA sequence analysis of selected cosmids and whole-genome 'shotgun' clones. After the finishing process, the genome sequence was found to contain 3,268,203 base-pairs (bp), and to have an average G+C content of 57.8%, values much lower than the corresponding values for M. tuberculosis, which are 4, 441,529 bp and 65.6% G+C. There are 1500 genes which are common to both M. leprae and M. tuberculosis. The comparative analysis suggests that both mycobacteria derived from a common ancestor and, at one stage, had gene pools of similar size. Downsizing from a genome of 4.42 Mb, such as that of M. tuberculosis, to one of 3.27 Mb would account for the loss of some 1200 protein coding sequences. There is evidence that many of the genes were present in the genome of M. leprae have truly been lost. ^[23]

Information from the completed genome can be useful to develop diagnostic skin tests, understanding the mechanism of nerve damage, drug resistance and to identify novel drug targets for rational design of new therapeutic regimens and drugs to treat leprosy and its complications.

[edit] Disease burden

Although annual incidence—the number of new leprosy cases occurring each year—is important as a measure of transmission, it is difficult to measure in leprosy due to its long incubation period, delays in diagnosis after onset of the disease and the lack of laboratory tools to detect leprosy in its 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 retrieving 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.^[24]

New case detection is another indicator of the disease burden and 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). The new case detection rate (NCDR) is defined by the number of newly detected cases, previously untreated, during a year divided by the population in which the cases have occurred.

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

[edit] Global Situation

As reported to WHO by 115 countries and territories in 2006, and published in the Weekly Epidemiological Record ^[25] the global registered prevalence of leprosy at the beginning of the year was 219,826 cases. New case detection during the previous year (2005 - the last year for which full country information is available) was 296,499. The reason for the annual detection being higher than the prevalence at the end of the year can be explained by the fact that a proportion of new cases complete their treatment within the year and therefore no longer remain on the registers. The global detection of new cases continues to show a sharp decline, falling by 110,000 cases (27%) during 2005 compared with the previous year.

Table 1 below shows that global annual detection has been declining since 2001. The African region reported an 8.7% decline in the number of new cases compared with 2004. The comparable figure for the Americas was 20.1%, for South-East Asia 32% and for the Eastern Mediterranean it was 7.6%. The Western Pacific area, however, showed a 14.8% increase during the same period.

Table 1: Prevalence at beginning of 2006, and trends in new case detection 2001-2005, excluding Europe

Region	Registered Prevalence (rate/10,000 pop.)	New Case Detection during the year
	Start of 2006	2001	2002	2003	2004	2005
Africa	40,830 (0.56)	39,612	48,248	47,006	46,918	42,814
Americas	32,904 (0.39)	42,830	39,939	52,435	52,662	41,780
South-East Asia	133,422 (0.81)	668,658	520,632	405,147	298,603	201,635
Eastern Mediterranean	4,024 (0.09)	4,758	4,665	3,940	3,392	3,133
Western Pacific	8,646 (0.05)	7,404	7,154	6,190	6,216	7,137
Totals	219,826	763,262	620,638	514,718	407,791	296,499

Table 2 below shows the leprosy situation in the six major countries which have yet to achieve the goal of elimination at the national level.

Table 2: Prevalence and Detection, countries still to reach elimination

Countries	Registered Prevalence (rate/10,000 pop.)			New Case Detection (rate/100,000 pop.)
	Start of 2004	Start of 2005	Start of 2006	During 2003	During 2004	During 2005
Brazil	79,908 (4.6)	30,693 (1.7)	27,313 (1.5)	49,206 (28.6)	49,384 (26.9)	38,410 (20.6)
Democratic Republic of the Congo	6,891 (1.3)	10,530 (1.9)	9,785 (1.7)	7,165 (13.5)	11,781 (21,1)	10,737 (18.7
Madagascar	5,514 (3.4)	4,610 (2.5)	2,094 (1.1)	5,104 (31.1)	3,710 (20.5)	2,709 (14.6)
Mozambique	6,810 (3.4)	4,692 (2.4)	4,889 (2.5)	5,907 (29.4)	4,266 (22.0)	5,371 (27.1
Nepal	7,549 (3.1)	4,699 (1.8)	4,921 (1.8)	8,046 (32.9)	6,958 (26.2)	6,150 (22.7
Tanzania	5,420 (1.6)	4,777 (1.3)	4,190 (1.1)	5,279 (15.4)	5,190 (13.8)	4,237 (11.1
Totals	112,092	60,001	53,192	80,707	81,289	67,614

Notes:

1) Elimination is defined as a prevalence of less than 1 case per 10,000 population.

2) Madagascar reached elimination at the national level in September 2006.

3) Nepal detection reported from mid-November 2004 to mid-November 2005.

[edit] Incidence

Worldwide, one to two million people are permanently disabled because of Hansen's disease.^{[citation needed]} India has the greatest number of HD cases, with Brazil second and Myanmar third.

In 1999, the world incidence of Hansen's disease was estimated to be 640,000; in 2000, 738,284 cases were identified. In 1999, 108 cases occurred in the United States. In 2000, the World Health Organization (WHO) listed 91 countries in which Hansen's disease is endemic. India, Myanmar and Nepal contained 70% of cases. 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 Hansen's disease cases.

According to recent figures from the WHO, new cases detected worldwide have decreased by approximately 107,000 cases (or 21%) from 2003 to 2004. This decreasing trend has been consistent for the past three years. In addition, the global registered prevalence of HD was 286,063 cases; 407,791 new cases were detected during 2004.

Hansen's disease is tracked by the Centers for Disease Control and Prevention (CDC). Its prevalence in the United States has remained low and relatively stable. There are decreasing numbers of cases worldwide, though 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.

Aside from humans, other creatures that are known to be susceptible to leprosy include the armadillo, mangabey monkeys, rabbits, and mice (on their footpads).

[edit] Risk groups

At highest risk are those living in endemic areas with poor conditions such as inadequate bedding, contaminated water and insufficient diet, or other diseases (such as HIV) that compromise immune function. Recent research suggests that there is a defect in cell-mediated immunity that causes susceptibility to the disease. Less than ten percent of the world's population are actually capable of acquiring the disease. 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. In addition, men are two times more likely to contract leprosy than women.

[edit] Clinical features

The clinical manifestations of leprosy vary, but primarily affects the skin, nerves and mucous membranes.^[26] Patients with this chronic infectious disease are classified as having paucibacillary (tuberculoid leprosy), multibacillary Hansen's disease (lepromatous leprosy) or borderline leprosy. Borderline leprosy (also termed multibacillary), of intermediate severity, 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. Paucibacillary Hansen's disease is characterized by one or more hypopigmented skin macules and anaesthetic patches, i.e. damaged peripheral nerves which have been attacked by the human host's immune cells. Multibacillary Hansen's disease 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 no nerve damage. Contrary to popular belief, Hansen's bacillus does not cause rotting of the flesh; rather, a long investigation by Dr. Paul Brand yielded that insensitivity in the limbs extremities was the reason why unfelt wounds or lesions, however minute, lead to undetected deterioration of the tissues, the lack of pain not triggering an immediate response as in a fully functioning body. Recently, leprosy has also emerged as a problem in HIV patients on antiretroviral drugs.^[27]

[edit] Treatment of leprosy

Until the development of dapsone in the 1940s there existed no effective cure for leprosy. However, dapsone is only weakly bactericidal against M.leprae and it was considered necessary for patients to take the drug indefinitely. Moreover, when dapsone used as monotherapy it soon resulted in a widespread emergence of resistance and by the 1960s the world’s only known anti-leprosy drug became virtually useless.

The search for more effective anti-leprosy drugs to dapsone led to the use of clofazimine and rifampicin in the 1960s and 1970s .^[28] and later, to avoid the danger of resistance combined therapy was formulated by Shantaram Yawalkar and colleagues using rifampicin and dapsone.^[29] Multidrug therapy, commonly called MDT and 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, and none of them should be used as monotherapy because of the risk of developing resistance.

Despite its known effectiveness against M.leprae, the uptake of MDT was slow and sporadic in most endemic countries over the next decade, due mainly to the high cost of the combined treatment. In 1985 leprosy was still considered a public health problem in 122 countries. A new impetus was provided the 44th. World Health Assembly (WHA), held in Geneva in 1991, which 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 100,000. At the Assembly, the World Health Organization (WHO) was given the mandate to develop an elimination strategy by its member states, based on increasing the geographical coverage of MDT and patients’ accessibility to the treatment.

The WHO Study Group's report on the Chemotherapy of Leprosy in 1993 ^[30] recommended two types of standard MDT regimen be adapted. The first was a 24 months treatment for multibacillary (MB or lepromatous) cases using rifampicin, clofazimine and dapsone. The second was a 6 months treatment for paucibacillary (PB or tuberculoid) cases, using rifampicin and dapsone. At the First International Conference on the Elimination of Leprosy as a Public Health Problem, held in Hanoi the next year, the global strategy was endorsed and funds provided to WHO for the procurement and supply of MDT to all endemic countries.

Since 1995, WHO has supplied all endemic countries with free MDT in blister packs, supplied through Ministries of Health. This free provision was extended in 2000 and again in 2005, and will run until at least the end of 2010 and at the country level, non-government organisations (NGOs) affiliated to the national programme will continue to be provided with an appropriate free supply of this MDT by the government.

MDT remains highly effective and patients are no longer infectious after the first monthly dose, ^[3] safe, ^[3] and easy to use under field conditions due to its presentation in calendar blister packs. Relapse rates remain low ^[3] and there is no known resistance to the combined drugs.^[3] The Seventh WHO Expert Committee on Leprosy, ^[31] reporting in 1997, concluded that the MB duration of treatment - then standing at 24 months - could safely be shortened to 12 months "without significantly compromising its efficacy."

Improving detection of the disease is important, as is education about its cause, providing patients with high-quality services, moving people in at-risk areas toward healthier living and fighting social taboos about a disease where, in the past, patients were considered to be "unclean" or "cursed by God" as outcasts. The last issue is important to address, because in such societies, patients may be forced to hide their condition (and thus avoid seeking treatment) in order to avoid discrimination, since the lack of awareness about Hansen's disease leads people to falsely believe that the disease is highly contagious and incurable.

[edit] See also

• Leper colony

[edit] References

[edit] Further reading

[edit] External links

• Hansen's Disease (Leprosy) - Centers for Disease Control and Prevention
• World Health Organization (WHO) leprosy website
• American Leprosy Missions
• National Hansen's Disease Programs (NHDP)
• The Global Campaign to Eliminate Leprosy article from PLoS Medicine

History of leprosy

• ILA Global Project on the History of Leprosy

• BBC News: Slave trade key to leprosy spread

• Interview with author John Tayman (The Colony) (MP3 audio: runtime = 00:23:20, 10.7 mb). IT Conversations Tech Nation (2006-02-07). Retrieved on March 22, 2007.

Research

• Pathology Images of Leprosy and Other Granulomatous diseases Yale Rosen, M.D.
• INFOLEP Leprosy Information Services
• International Journal of Leprosy and Other Mycobacterial Diseases
• Leprosy Review