Leprosy

Compiled and Summarized by Anthony
Leprosy, or Hansen's disease, is a chronic infectious disease caused by the bacterium Mycobacterium leprae. Leprosy is primarily a granulomatous disease of the peripheral nerves and mucosa of the upper respiratory tract; skin lesions are the primary external symptom. Left untreated, leprosy can be progressive, causing permanent damage to the skin, nerves, limbs, and eyes. Contrary to popular conception, leprosy does not cause body parts to simply fall off, and it differs from tzaraath, the malady described in the Hebrew scriptures and previously translated into English as leprosy.

Historically, leprosy has affected humanity since at least 300 BC, and was well-recognized in the civilizations of ancient China, Egypt and India. In 1995, the World Health Organization (WHO) estimated that between two and three million individuals were permanently disabled because of leprosy. 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, and Vietnam.

The age-old social stigma associated with the advanced form of leprosy lingers in many areas, 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 evolved 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.

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. 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."

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 before 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. This is clearly 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. 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 Hansen's disease as we understand it today.

The word "leprosy" derives from the ancient Greek words lepros, a scale, and lepein, to peel. The word came into the English language via Latin and Old French.

Signs and Symptoms

The clinical manifestations of leprosy vary but primarily affect the skin, nerves, and mucous membranes. 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 anesthetic patches, i.e., damaged peripheral nerves that 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 detectable nerve damage is late.

Contrary to popular belief, Hansen's bacillus does not cause rotting of the flesh; rather, a long investigation by 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.

Causative Agent

Mycobacterium leprae is the causative agent of leprosy. An intracellular, acid-fast bacterium, M. leprae is aerobic, gram-positive, and rod-shaped, and is surrounded by the waxy cell membrane coating characteristic of Mycobacterium species.

Due to extensive loss of genes necessary for independent growth, M. leprae is unculturable in the laboratory, a factor which leads to difficulty in definitively identifying the organism under a strict interpretation of Koch's postulates.[9] The use of non-culture-based techniques such as molecular genetics has allowed for alternative establishment of causation

Mode of Transmission

The mode of transmission is not clearly established. The disease is probably transmitted from person to person by aerosol with a high subclinical rate of infection. Household and prolonged close contact seem important. There is anecdotal evidence that rarely it may be transmitted by inoculation, such as by contaminated tattoo needles.

Diagnosis

Clinical suspicion is the crucial factor in making an early diagnosis of leprosy in non-endemic areas. Leprosy should always be considered in any undiagnosed patient with chronic skin lesions or a peripheral neuropathy. This is particularly important if they have spent more than brief periods in areas where the disease is endemic, or they have been a contact of a patient known to have leprosy.

Confirmation of diagnosis depends on the form:

· lepromatous disease requires demonstration of plentiful acid-fast bacilli in skin or nasal smears. Skin smears are made by scraping a small amount of tissue fluid from a superficial scalpel cut over a lesion and smearing it on a glass slide.

· tuberculoid disease requires demonstration of typical granulomata with sparse acid-fast bacilli, in biopsies of either skin or nerve lesions.

Incubation Period

In leprosy, 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. The maximum incubation period reported is as long as 30 years or more, 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.

Pathogenesis

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Pathophysiology

Leprosy is not a highly infectious disease. The principal means of transmission is by aerosol spread from infected nasal secretions to exposed nasal and oral mucosa. Leprosy is not generally spread by means of direct contact through intact skin, though close contacts are most vulnerable. The incubation period is 6 months to 40 years or longer. The mean incubation period is 4 years for tuberculoid leprosy (TT) and 10 years for lepromatous leprosy (LL).

The areas most commonly affected are the superficial peripheral nerves, skin, mucous membranes of the upper respiratory tract, anterior chamber of the eyes, and testes. These areas tend to be cool parts of the body. Tissue damage depends on the degree to which cell-mediated immunity is expressed, the type and extent of bacillary spread and multiplication, the appearance of tissue-damaging immunologic complications (ie, lepra reactions), and the development of nerve damage and its sequelae.

M. leprae is an obligate intracellular acid-fast gram-positive bacillus with an affinity for macrophages and Schwann cells. For Schwann cells in particular, the mycobacterium binds to the G domain of the alpha-chain of laminin 2 (found only in peripheral nerves) in the basal lamina. Its slow replication within the Schwann cell will eventually stimulate a cell-mediated immune response, which creates a chronic inflammatory reaction. As a result, swelling occurs in the perineurium, leading to ischemia, fibrosis, and axonal death.

The genomic sequence of M. leprae was only recently completed. One important discovery is that though it depends on its host for metabolism, the microorganism retains genes for the formation of a mycobacterial cell wall. Components of the cell wall stimulate a host immunoglobulin M (IgM) antibody and cell-mediated immune response, while also moderating the bactericidal abilities of macrophages.

The strength of the host's immune system influences the clinical form of the disease. A strong cell-mediated immunity and a weak humoral response results in mild forms of disease, with a few well-defined nerves involved and lower bacterial loads. A strong humoral response but relatively absent cell-mediated immunity results in LL, with widespread lesions, extensive skin and nerve involvement, and high bacterial loads. Therefore, a spectrum of disease exists such that cell-mediated immunity dominates in mild forms of leprosy and decreases with increasing clinical severity. Meanwhile, humoral immunity is relatively absent in mild disease and increases with the severity of disease.

Toll-like receptors (TLRs) may also play a role in the pathogenesis of leprosy. M. leprae activate TLR2 and TLR1, which are found on the surface of Schwann cells, especially with TT. Although this cell-mediated immune defense is most active in mild forms of the disease, it is also likely responsible for the activation of apoptosis genes and consequently the hastened onset of nerve damage found in mild disease. Alpha-2 laminin receptors found in the basal lamina of Schwann cells are also a target of entry for M. leprae into these cells, while activation of ErbB2 receptor tyrosine kinase signaling pathway has been identified as a mediator of demyelination in leprosy.

The activation of macrophages and dendritic cells, both antigen-presenting cells, is involved in the host immune response to M. leprae. Interleukin-1 beta produced by antigen-presenting cells infected by mycobacteria has been shown to impair the maturation and function of dendritic cells. Because bacilli have been found in the endothelium of skin, nervous tissue, and nasal mucosa, endothelial cells are also thought to contribute to the pathogenesis of leprosy.

A sudden increase in T-cell immunity is responsible for type I reversal reactions. Type II reactions result from activation of tumor necrosis factor-alpha (TNF-alpha) and deposition of immune complexes in tissues with neutrophilic infiltration and from complement activation in organs. One study found that cyclooxygenase 2 was expressed in microvessels, nerve bundles, and isolated nerve fibers in the dermis and subcutis during reversal reactions.

Prevention

Household contacts of patients with lepromatous disease should be monitored annually for 5 years after diagnosis.

· Children especially should be observed for the development of disease.

· In endemic countries, chemoprophylaxis may be useful in controlling the disease.

· In the United Kingdom, close contacts of LL patients younger than 12 years are given rifampin 15 mg/kg once a month for 6 months as prophylaxis.

Attempts have been made to develop a vaccine against leprosy. Although not widely used, antileprosy vaccination can be immunoprophylactic and therapeutic. Current vaccines with various degrees of use are the bacille Calmette-Guérin (BCG) vaccine; the Mycobacterium w vaccine; the Mycobacterium avium-intracellulare complex (Mycobacterium ICRC) vaccine; the BCG plus heat-killed M. leprae, Mycobacterium tufu, and Mycobacterium habana vaccine.

· The BCG vaccine has variable results in protecting certain populations; therefore, it is not widely prescribed. However, repeat immunization with BCG may result in further protection. In the United Kingdom, the BCG vaccine is given to household contacts younger than 12 years.

· In India, the Mycobacterium w and Mycobacterium ICRC vaccines are given. Mycobacterium w has a synergistic effect with chemotherapy, with accelerated clearing of the infection and shortening of treatment.

Treatment

Until the development of dapsone, rifampin, and clofazimine in the 1940s, there was 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 was used alone, the M. leprae population quickly evolved antibiotic resistance; 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. Later, Shantaram Yawalkar and colleagues formulated a combined therapy using rifampicin and dapsone, intended to mitigate bacterial resistance. Multidrug therapy (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. None of them are used alone because of the risk of developing resistance.

Because this treatment is quite expensive, it was not quickly adopted in most endemic countries. 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 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 recommended two types of standard MDT regimen be adapted. The first was a 24-month treatment for multibacillary (MB or lepromatous) cases using rifampicin, clofazimine, and dapsone. The second was a six-month 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. At the national level, non-government organizations (NGOs) affiliated to the national program 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. It is safe and easy to use under field conditions due to its presentation in calendar blister packs. Relapse rates remain low, and there is no known resistance to the combined drugs. The Seventh WHO Expert Committee on Leprosy, 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."

Persistent obstacles to the elimination of the disease include improving detection, educating patients and the population about its cause, and fighting social taboos about a disease for which patients have historically been considered "unclean" or "cursed by God" as outcasts. Where taboos are strong, patients may be forced to hide their condition (and avoid seeking treatment) to avoid discrimination. The lack of awareness about Hansen's disease can lead people to falsely believe that the disease is highly contagious and incurable.

See List of Medications and their dosage here.

Complications

Reactional states occur in about one third of patients and are acute inflammations of the disease. A leprous reaction should be considered a medical emergency requiring immediate care. These states can result in permanent neurologic sequelae, resulting in disability and deformity. Patients at the highest risk are those with multibacillary leprosy and/or preexisting nerve impairment.

o Lepra type I (reversal) reactions usually affect patients with borderline disease. Reversal reactions are a shift toward the tuberculoid pole after the start of therapy, and they are type IV cell-mediated allergic hypersensitivities. Puberty, pregnancy, and childbirth can also precipitate type I reactions. These reactions usually result in skin erythema, with edema and tenderness of peripheral nerves. The peak time for type I reactions is during the first 2 months of therapy and for up to 12 months. Corticosteroid treatment is aimed at controlling acute inflammation, relieving pain, and reversing nerve and eye damage. With treatment, approximately 60-70% of the patient's nerve function is recovered. If neuritis is absent, nonsteroidal anti-inflammatory drugs (NSAIDs) may be helpful.

o Lepra type II reactions, or ENL, occur in about 10% of patients with BL and in 20% of patients with LL. These reactions are type III humoral hypersensitivities, with a systemic inflammatory response to immune complex deposition. The most common presenting symptoms are crops of painful erythematous nodules of the skin and subcutaneous tissue. Bullae, ulcers, and necrosis may also occur. The reaction usually manifests after a few years of therapy, and, although a single acute episode is possible, relapses occur intermittently over several years. Associated fever, malaise, arthralgias, neuralgia, iridocyclitis, dactylitis, orchitis, and proteinuria may be present.

· · The use of clofazimine in MDT substantially reduces the incidence of ENL to 5%. Clofazimine has also been used to treat ENL.

· · Thalidomide is effective except in the case of neuritis or iritis, in which case, corticosteroids should be used.

· · Other treatment therapies reported to be effective include colchicine, pentoxifylline, cyclosporine A, intravenous immunoglobulin (IVIG), and infliximab.

· · Lowering the dose of dapsone may decrease the severity of bullae and ulcers.

o Lucio phenomenon is an unusual type II reaction that is sometimes designated a type II reaction. It is common in Mexico and Central America and is characterized by cutaneous hemorrhagic infarcts in patients with diffuse LL. Thalidomide is ineffective in treating this type of reaction. Azathioprine or cyclophosphamide with corticosteroids with or without plasmapheresis has been used.

The real challenge in managing leprosy is the treatment of reactional states.

o If the course of MDT is not complete, continue taking those medications as directed.

o Systemic steroids are effective in reducing inflammation and edema in reversal reactions; therefore, they are the most helpful medications in preventing nerve damage.

o Prednisone 40-80 mg/d should be given for 5-7 days then tapered slowly over 3-6 months. This long course is necessary to decrease the severity of disabilities and deformities. One study recommended a low-dose (30 mg/d) regimen for 20 weeks for controlling type I reactions.

o Clofazimine can also be used as a steroid-sparing agent for reversal reactions, alone or with corticosteroids.

o Although the WHO does not support its use for ENL, thalidomide is highly effective with ENL. It is ineffective for the treatment of reversal reactions.

Neuropathy induced by leprosy can result in trauma, pressure necrosis, or secondary infection that goes unnoticed, leading to amputation of digits or limbs. Wrist and foot drop are also common. Silent neuropathy can occur in the absence of overt signs of nerve or skin inflammation. Even with corticosteroid treatment, only about 60% of nerve function is recovered. Cyclosporine A may be useful in controlling nerve impairment and pain.

Injuries can result in ulcerations, cellulitis, scarring, and bony destruction. Foot ulcers caught early should be treated with rest because they heal if they are not subject to weightbearing.

Osteoporosis and fractures can result from bony changes due to leprosy. Risedronate and other bisphosphates may help improve lumbar bone mineral density.

Contractures can develop and result in fixation. Common sequelae include clawing of hands and feet.

Eye damage can result in loss of the corneal reflex, lagophthalmos, ectropion, entropion, and blindness. One study found the risk of ocular complications in patients with multibacillary disease, after completion of MDT, to be 5.6% with eye-threatening complications to be 3.9%.

Skin drying and fissures can be caused by autonomic disruption.

References

http://www.wikipedia.org
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http://www.emedicine.com
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http://www.health.vic.gov.au/
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