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Keywords:

  • diagnosis;
  • disability;
  • leprosy;
  • Mycobacterium leprae;
  • social stigma

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology
  5. Bacteriology And Genomics
  6. Transmission And Pathology
  7. Clinical Features
  8. Diagnosis And Laboratory Tests
  9. Treatments
  10. Lepra Reactions
  11. Disability And Stigma
  12. Conclusions And Future Perspectives
  13. References

Leprosy has affected humans for millennia and remains an important health problem worldwide, as evidenced by nearly 250 000 new cases detected every year. It is a chronic infectious disorder, caused by Mycobacterium leprae, that primarily affects the skin and peripheral nerves. Recent advances in basic science have improved our knowledge of the disease. Variation in the cellular immune response is the basis of a range of clinical manifestations. The introduction of multidrug therapy has significantly contributed to a decrease in the prevalence of the disease. However, leprosy control activities, including monitoring and prevention programs, must be maintained.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology
  5. Bacteriology And Genomics
  6. Transmission And Pathology
  7. Clinical Features
  8. Diagnosis And Laboratory Tests
  9. Treatments
  10. Lepra Reactions
  11. Disability And Stigma
  12. Conclusions And Future Perspectives
  13. References

Leprosy, or Hansen’s disease, is a chronic infectious disease caused by the acid-fast bacterium Mycobacterium leprae. Norwegian physician Gerhard Armauer Hansen identified the bacillus in the patients in 1873, making leprosy the first disease ascribed to a bacterial origin. Leprosy usually affects the dermis of the skin and peripheral nerves, but has a wide range of clinical manifestations. It can be progressive and cause permanent damage if left without treatment. Divided into paucibacillary (TB; tuberculoid pole) or multibacillary (MB; lepromatous pole), depending on the bacillary load, the disease manifests first in discoloration of the skin and then in rashes and nodules. The introduction of dapsone (diphenyl sulfone, DDS) in 1941 brought the first effective therapy, and multidrug therapy (MDT) was introduced by the World Health Organization (WHO) in 1981 to limit the development of drug resistance. Endemic leprosy has declined markedly and the disease is now rare in most industrialized countries. It is still a major public health problem in developing countries, where hundreds of thousands of new cases are diagnosed each year. In many of these countries, social stigmatization is an additional burden. Therefore, it is important that control activities continue if the disease burden and damaging impacts of leprosy are to be reduced. Dermatologists should be familiar with leprosy and other diseases needed for differential diagnosis.

Epidemiology

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology
  5. Bacteriology And Genomics
  6. Transmission And Pathology
  7. Clinical Features
  8. Diagnosis And Laboratory Tests
  9. Treatments
  10. Lepra Reactions
  11. Disability And Stigma
  12. Conclusions And Future Perspectives
  13. References

The WHO publishes an annual report on the worldwide incidence of leprosy, including the number of new cases, prevalence and disabilities.1 The detection of new cases by the WHO has declined from 514 718 in 2003 to 244 796 in 2009, but the rate of decrease is getting smaller each year. Among 244 796 new cases in 2009, 16 countries that reported 1000 or more new cases accounted for 93% of the total. These countries and the number of cases detected in 2009 are: India (133 717 cases), Brazil (37 610 cases), Indonesia (17 260 cases), Bangladesh (5239 cases), the Democratic Republic of the Congo (5062 cases), Ethiopia (4417 cases), Nepal (4394 cases), Nigeria (4219 cases), Myanmar (3147 cases), the United Republic of Tanzania (2654 cases), Sudan (2100 cases), Sri Lanka (1875 cases), the Philippines (1795 cases), China (1597 cases), Madagascar (1572 cases) and Mozambique (1191 cases).

The proportion of new cases with multibacillary leprosy ranged from 32.70% in the Comoros in Africa to 95.04% in the Philippines. The proportion of females among newly detected cases ranged from 6.50% in Ethiopia to 59.11% in the Central African Republic. The proportion of children among new cases ranged from 0.60% in Argentina to 30.30% in Papua New Guinea. Grade 2 disabilities in new cases ranged from 1.45% in Liberia to 22.8% in China. As the number of new cases declines, the damaging impact of the disease on the physical, social and economic well-being of individuals and families affected by leprosy are also expected to decline.

Very few new leprosy patients are registered in developed countries. When leprosy is detected, it is primarily found among immigrants from countries where the disease is still endemic. There is an association between the incidence of leprosy and socioeconomic factors such as gross national product (GNP), personal housing expenditures and the number of persons per household, suggesting that improvements in socioeconomic conditions greatly contribute to the reduction of leprosy.2 The proportion of children under the age of 15 years among newly detected cases would be a good indicator of the situation in a country/region. Similarly, the proportion of cases with grade 2 and visible disabilities among newly detected cases would be a reflection of early detection and treatment.

Bacteriology And Genomics

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology
  5. Bacteriology And Genomics
  6. Transmission And Pathology
  7. Clinical Features
  8. Diagnosis And Laboratory Tests
  9. Treatments
  10. Lepra Reactions
  11. Disability And Stigma
  12. Conclusions And Future Perspectives
  13. References

Mycobacterium leprae is an obligate intracellular parasite that cannot be cultivated in vitro. It grows very slowly with an approximate generation time of 12–14 days. The inability to cultivate in vitro and the lack of animal models have been major disadvantages for leprosy research. However, the availability of the M. leprae genome sequence has contributed to knowledge of the disease. The first genome sequence of M. leprae, completed in 2001,3 revealed that only half of the small genome contains protein-coding genes, while the remainder consists of pseudogenes and non-coding regions (Fig. 1). The number of pseudogenes is much larger in the M. leprae genome than in other mycobacteria,4 and the number and proportion are exceptionally large in comparison with other pathogenic and non-pathogenic bacteria and archaea.5,6 Many of the M. leprae pseudogenes are the result of stop codon insertions thought to be caused by the dysfunction of sigma factors or the insertion of repetitive sequences derived from transposons.7–9 Despite this genetic damage, a specialized intracellular environment free from evolutionary competition has allowed the organism to survive.3,10,11 It has been speculated that M. leprae has lost over 1500 genes from its genome and that non-coding regions are functionally silent and useless.12 However, analyses have demonstrated that some of the pseudogenes and non-coding regions are highly expressed at the RNA level, and that expression of these RNA in clinical samples shows varying patterns among patients, suggesting as yet unknown functions.13–16

image

Figure 1.  Only half of the Mycobacterium leprae genome contains functional genes. The percentage of functional genes, pseudogenes and non-coding regions are illustrated for M. leprae and Mycobacterium tuberculosis genomes.

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Single nucleotide polymorphisms (SNP) and short or variable number tandem repeats have been used for M. leprae genotyping. SNP analysis revealed four primitive subtypes of M. leprae and the number is increasing as the analysis progresses.17–19 Some reports have also presented the possibility of dual infections or phenotypically distinct strains of M. leprae; however, these situations are still somewhat obscure.20,21

Transmission And Pathology

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology
  5. Bacteriology And Genomics
  6. Transmission And Pathology
  7. Clinical Features
  8. Diagnosis And Laboratory Tests
  9. Treatments
  10. Lepra Reactions
  11. Disability And Stigma
  12. Conclusions And Future Perspectives
  13. References

It is evident that humans are the major reservoir of M. leprae infection, while naturally occurring infection has been reported in wild animals, including the nine-banded armadillo and several species of primates.22–32 A recent study found that the same genotypic strain of M. leprae was detected at high incidence in wild armadillos and leprosy patients in the southern USA, suggesting that leprosy may be a zoonosis in regions in which armadillos serve as a reservoir.33

Although transmission of M. leprae is not entirely understood, it is thought that long-term exposure of the respiratory system to airborne droplets is the main route of infection.34,35M. leprae is not very virulent, meaning that most people affected with leprosy are non-infectious, probably because the bacilli remain within the infected cells. Multibacillary patients, however, excrete M. leprae from their nasal mucosa and skin.36 Close and repeated contact with these patients is also a source of transmission. Upon MDT treatment, however, the patients rapidly lose infectivity.

Even if infected, a long incubation period is required before clinical manifestation. The long incubation period of leprosy was demonstrated by an SNP analysis of an M. leprae genome derived from one of four spontaneous leprosy cases in chimpanzees. The chimpanzee was infected with M. leprae during infancy in West Africa, but the pathogenic signs of leprosy did not appear for at least 30 years.30

Mycobacterium leprae primarily infects histiocytes (or tissue macrophages) in the dermis and Schwann cells in the peripheral nerves. The unique tropism for peripheral nerves can lead to deformities even after the pathogen is successfully treated. The outcome of infection and clinical manifestation depend on the cellular immunity of the host, which is the first line of defense against M. leprae infection. There is a relationship between clinical manifestation and cytokine profiles within the skin lesions. T-helper cell (Th)1 cytokines, such as interleukin (IL)-2 and γ-interferon, play important roles in cellular immune responses in paucibacillary leprosy. Th2 cytokines, including IL-4, IL-5 and IL-10, augment humoral immune responses and predominate in multibacillary leprosy. Thus, there is an inverse correlation in the cytokine profiles that create the basis of paucibacillary and multibacillary leprosy.

Mycobacterium leprae should be recognized by the innate immune system and phagocytized by host macrophages. Toll-like receptor (TLR)2, in conjunction with TLR1, recognizes the cell wall lipids of M. leprae and subsequently activates innate immune responses.37,38 However, some bacilli escape this initial attack of innate immunity and successfully parasitize the phagosome of macrophages. CORO1A, an actin-binding scaffold protein in the cell membrane of host cells, inhibits the phagosome/lysosome fusion, thereby helping the pathogen escape digestion.38–40

Mycobacterium leprae parasitization of macrophages occurs in a foamy or enlarged phagosome filled with lipids.40,41 Because it is aerobic, it may survive in a granuloma environment with a relatively low oxygen tension gradient using lipids and fatty acids as carbon sources.42M. leprae creates a lipid-rich phagosome environment that is favorable for its survival.43 Adipose differentiation-related protein (ADRP) and perilipin expression, which contribute to lipid intake, significantly increase following M. leprae infection. Infection also has a pronounced effect on Schwann cell lipid homeostasis via regulation of lipid droplet biogenesis and traffic, which favors M. leprae intracellular survival.44

It was long thought that leprosy might have a strong host genetic component. With the use of gene expression profiling, gene expression patterns associated with host immune response in lesions of human leprosy have been clarified.45 Genes belonging to the leukocyte immunoglobulin-like receptor (LIR) family were significantly upregulated in lesions of lepromatous patients suffering from the disseminated form of the infection.45 A genome-wide search for loci affecting the susceptibility to leprosy mapped a susceptibility locus to chromosome 6q25-q26.46 There is a close relationship between leprosy susceptibility and SNP in the genes encoding tumor necrosis factor (TNF)-α and IL-10.47

Clinical Features

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology
  5. Bacteriology And Genomics
  6. Transmission And Pathology
  7. Clinical Features
  8. Diagnosis And Laboratory Tests
  9. Treatments
  10. Lepra Reactions
  11. Disability And Stigma
  12. Conclusions And Future Perspectives
  13. References

Leprosy is a systemic disease that primarily affects the skin, nerves and eyes. M. leprae infection induces diverse clinical manifestations depending on the host immune responses. Paucibacillary leprosy is a milder disease characterized by few (≤5) hypopigmented, anesthetic skin lesions. The multibacillary form is associated with multiple (>5) skin lesions, nodules, plaques, thickened dermis or skin infiltration, and in some instances, involvement of the nasal mucosa, resulting in nasal congestion and epistaxis. The involvement of certain peripheral nerves may also be noted. In most cases of both paucibacillary and multibacillary disease, the diagnosis is straightforward. However, the small proportion of suspected cases that do not exhibit anesthetic patches require examination by a specialist to find other cardinal signs of the disease, including nerve involvement and a positive laboratory test for acid-fast bacilli.

Patients commonly present with weakness or numbness as the result of a peripheral-nerve lesion, or a burn or ulcer in an anesthetic hand or foot. In typical multibacillary leprosy, diffuse infiltration of the skin is evident. There may be many lesions that are not hypoaesthetic, while only a few hypopigmented lesions with reduced sensation are seen in paucibacillary patients. Careful inspection of the entire body is important. The great auricular nerve, ulnar nerve, median nerve, radial-cutaneous nerve, posterior tibial nerve and lateral popliteal nerve are frequently involved with enlargement, with or without tenderness, and standard regional patterns of sensory and motor loss.48 Neuritic leprosy in India and Nepal is characterized by asymmetrical involvement of peripheral nerve trunks without visible skin lesions.49–51

The Ridley–Jopling classification system,52 based on the M. leprae-specific immunological resistance status of the host, is clinically relevant and widely used, although the WHO only distinguishes between paucibacillary and multibacillary for simplicity of use in endemic countries. Ridley–Jopling divided the disease into six categories based on dermatological, neurological and histopathological findings: indeterminate (I), tuberculoid (TT), borderline tuberculoid (BT), mid-borderline (BB), borderline lepromatous (BL) and lepromatous (LL) (Fig. 2). TT leprosy can be associated with rapid and severe nerve damage, whereas LL is associated with chronicity and long-term complications. Borderline disease is unstable and can be complicated by lepra reactions as described in the “Lepra Reactions” section.

image

Figure 2.  Typical dermatological views of leprosy patients. A multibacillary case (lepromatous) showing multiple nodules in the arms (a) and ears (b), and a paucibacillary case (borderline tuberculoid) with large erythema annulare, with discoloration in the middle of the lesion accompanied by loss of sensation (c).

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Diagnosis And Laboratory Tests

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology
  5. Bacteriology And Genomics
  6. Transmission And Pathology
  7. Clinical Features
  8. Diagnosis And Laboratory Tests
  9. Treatments
  10. Lepra Reactions
  11. Disability And Stigma
  12. Conclusions And Future Perspectives
  13. References

Leprosy exerts systemic effects in addition to skin lesions, which is evident in the infiltration of bacilli into the nasal mucosa, bones and other organs of multibacillary patients.53 Severe skeletal lesions, the hallmark of lepromatous leprosy, have been observed in excavated skeletal remains,54–58 and M. leprae DNA has been isolated from such lesions (Fig. 3).59 Eye damage is frequently seen in multibacillary patients resulting from both nerve damage and direct bacillary invasion.60 Typically, lagophthalmos is caused by involvement of the zygomatic and temporal branches of the facial nerve. Other facial nerve damage, such as involvement of the ophthalmic branch of the trigeminal nerve, causes anesthesia of the cornea and conjunctiva, resulting in dryness and the risk of ulceration.

image

Figure 3.  Skeletal lesions of leprosy and isolation of lesion-associated Mycobacterium leprae DNA.59 Frontal view (a) and left side view (b) of archaeological skeletal remains showing erosive deformity of the nasal aperture and disappearance of the anterior nasal spine (arrows) and severe atrophy of the alveolar bone in the maxilla/palatal process with loss of anterior teeth (arrowheads) in panels (c) and (d). Polymerase chain reaction detection of M. leprae DNA from skeletal samples (samples 1–4). Samples 5–7 were taken from other skeletons found in the same cemetery, which had no leprous changes as a negative control. M. leprae DNA was detected in sample 1 (maxillary palate) and 4 (fibula) (e).

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A diagnosis of leprosy is made based on cardinal signs such as hypopigmented or reddish patches with definite loss of sensation, thickened peripheral nerves and acid-fast bacilli in slit-skin smears or biopsy materials.61,62 Smear and biopsy samples are subjected to acid-fast staining in addition to conventional histopathological diagnosis in order to demonstrate the presence of mycobacterium; however, bacilli are not usually detected in paucibacillary cases. The presence of neural inflammation is a histological characteristic of leprosy that can differentiate it from other granulomatous disorders. The polymerase chain reaction (PCR) is a sensitive method for the detection of M. leprae DNA that is widely used for differential diagnosis in advanced countries, although it cannot determine if viable organisms are present because DNA can persist long after microorganisms are dead.15,30,59,63 Serum antibodies against M. leprae phenolic glycolipid-I (PGL-I) are found in multibacillary patients and some household contacts, although its specificity is relatively low.30,64–66 Non-endemic countries do not usually consider leprosy during the differential diagnosis of skin lesions; however, it should be considered in a case of peripheral neuropathy or persistent skin lesions if patients are from endemic countries. Late diagnosis leads to continued transmission and increased risk of disability.67,68

Treatments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology
  5. Bacteriology And Genomics
  6. Transmission And Pathology
  7. Clinical Features
  8. Diagnosis And Laboratory Tests
  9. Treatments
  10. Lepra Reactions
  11. Disability And Stigma
  12. Conclusions And Future Perspectives
  13. References

The implementation of MDT for leprosy treatment has been successful over the past three decades. The WHO has designed two easy-to-use blister pack medication kits for paucibacillary and multibacillary patients. The kits contain enough medication for 28 days and are supplied at no cost to registered patients. The treatment for paucibacillary patients include daily doses of 100 mg DDS and a monthly dose of 600 mg rifampicin (RFP) over a 6-month period. Multibacillary patients are administrated 100 mg DDS and 50 mg clofazimine (CLF) once a day in addition to monthly administration of 600 mg RFP and 300 mg CLF for 12 months. Treatment is usually automatically terminated at the end of the proscribed regimen because, in public health terms, it is reasonable to conclude that infectiousness is unlikely after starting MDT (Fig. 4).69 Many countries, however, prefer longer treatments, especially for multibacillary cases. Although there has been little standard monitoring of clinical outcomes and relapse rates, accurate diagnosis of relapse requires clinical, bacteriological and histopathological evidence.70

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Figure 4.  Female chimpanzee at leprosy diagnosis (a) and 3 months after the initiation of multidrug therapy (MDT), showing significant improvement of facial lesions (b).30 Intact Mycobacterium leprae bacilli before treatment (c) fragmented and showed a granular staining pattern 6 months after MDT (d).

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Rifampicin is an effective bactericidal agent against M. leprae. Within a few days of administrating a single 600-mg dose to multibacillary patients, the bacilli are no longer viable when inoculated into mouse footpads.71 DDS is bacteriostatic or weakly bactericidal against M. leprae and was the mainstay leprosy treatment for many years until widespread resistant strains appeared. CLF binds preferentially to mycobacterial DNA and exerts a slow bactericidal effect on M. leprae by inhibiting mycobacterial growth. Skin discoloration ranging from red to black, is one of the most troublesome side-effects of CLF, although the pigmentation fades slowly in most cases after withdrawal. A characteristic ichthyosis is also sometimes evident. Other effective chemotherapeutic agents against M. leprae include ofloxacin (OFLX), minocycline (MINO), levofloxacin (LVFX), sparfloxacin (SPFX), moxifloxacin (MFLX) and clarithromycin (CAM).72

As with most chemotherapies, drug-resistant strains are becoming a problem in leprosy, which is a potential threat to the success of current leprosy control efforts. Dapsone resistance is associated with missense mutations in the folP1 gene encoding dihydropteroate synthase.73,74 Resistance to RFP is induced by a mutation in rpoB, which encodes DNA-dependent RNA polymerase subunit-b.75 PCR analysis can provide a simple assessment for possible susceptibility to these drugs.73,74

Lepra Reactions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology
  5. Bacteriology And Genomics
  6. Transmission And Pathology
  7. Clinical Features
  8. Diagnosis And Laboratory Tests
  9. Treatments
  10. Lepra Reactions
  11. Disability And Stigma
  12. Conclusions And Future Perspectives
  13. References

Lepra reactions (or reactional states) are acute inflammatory complications that occur in treated or untreated leprosy and often present as medical emergencies. There are two major clinical types of lepra reactions that affect 30–50% of all leprosy patients.76–78 Severe inflammation associated with these reactions results in nerve injury accompanied by subsequent loss of sensation, paralysis and deformity. The different types of reactions appear to have different underlying immunological mechanisms; however, the factors that initiate them are unknown.

Reversal reactions (type 1 reactions) manifest as erythema and edema of dermal lesions and tender peripheral nerves with rapid loss of nerve function. It generally occurs during the first several months of treatment, and occasionally after MDT is completed.79,80 Treatment is aimed at controlling acute inflammation, easing pain, reversing nerve and eye damage, and reassuring the patient. Standard courses of corticosteroids have been used to treat patients for several weeks to months. Erythema nodosum leprosum (ENL or type 2 reactions) occurs in lepromatous and borderline lepromatous patients with higher bacterial loads in their lesions.81 ENL can begin during the first or second year of treatment. Patients are febrile with skin nodules accompanied by iritis, neuritis, lymphadenitis, orchiitis, bone pain, dactylitis, arthritis, and proteinuria that is difficult to treat.82 CLF has an anti-inflammatory effect on ENL, and thalidomide is better than steroids in controlling ENL, although thalidomide is not available in many countries because of its teratogenic effects.83 The use of monoclonal antibodies or inhibitors of TNF-α, as used in rheumatoid arthritis, Crohn’s disease and psoriasis, seems to be a logical choice for treatment, but more evidence is needed.84

Disability And Stigma

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology
  5. Bacteriology And Genomics
  6. Transmission And Pathology
  7. Clinical Features
  8. Diagnosis And Laboratory Tests
  9. Treatments
  10. Lepra Reactions
  11. Disability And Stigma
  12. Conclusions And Future Perspectives
  13. References

Leprosy is a leading cause of permanent physical disability among communicable diseases. The disease and its associated deformities have been responsible for social stigmatization and discrimination against patients and their families in many societies. If unchecked, the disease gradually spreads over the entire body, attacks the soft tissue of the nose and throat, impairs vision and damages the nervous system. The morbidity and disability associated with leprosy are secondary to nerve damage (Fig. 5). Ultimately, the extremities become deformed and paralyzed, and may fall off after repeated but unperceived injuries. Therefore, timely diagnosis and treatment of the patient, before nerve damage has occurred, is extremely important in preventing disabilities. Management of lepra reactions and neuritis is also effective in preventing or minimizing the development of further disabilities.

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Figure 5.  Leprosy with peripheral nerve damage. Swelling of the great auricular nerve (a), facial nerve paralysis (b), dropped wrist, clawed fingers with stiff joints due to ulnar and median nerve damage (c), and foot ulceration due to loss of sensation (d).

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The occurrence of leprosy in families has led to the misinterpretation that the disease is hereditary. The progressive symptoms and sometimes lethal secondary infections probably led to the assumption that patients are beyond medical support and that death is inevitable. In many societies, public stigmatization and exclusion coexist, and in some countries, the stigma is promoted by legislation against leprosy patients.85 The accumulation of misnomers and misunderstandings have triggered unreasonable reactions in people, which have been difficult to overcome.

Self-awareness is crucial if the patient is to minimize damage. Treatment and/or surgical management, including reconstructions, should be provided for ulcers, and it is important that the patient understand the need for daily self-care and inspection for trauma.86,87 Protective footwear and other tools are available to help patients improve their abilities and quality of life.88 Community-based rehabilitation programs and other socioeconomic rehabilitation are required to support patients and families.89

Conclusions And Future Perspectives

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology
  5. Bacteriology And Genomics
  6. Transmission And Pathology
  7. Clinical Features
  8. Diagnosis And Laboratory Tests
  9. Treatments
  10. Lepra Reactions
  11. Disability And Stigma
  12. Conclusions And Future Perspectives
  13. References

Leprosy has affected humans for millennia. However, the MDT regimen recommended by the WHO has had a significant impact in reducing the global burden of leprosy, and research activities have led to increased knowledge of M. leprae genomic structure and host responses. Health-care workers and researchers should continue to support the intensive implementation of the elimination strategy and address issues related to the detection of M. leprae-infected individuals as a matter of urgency. Sustained quality patient care that is equitably distributed, affordable and easily accessible is still needed. A goal of the WHO is to bring institutional and management changes that strengthen the operational capacity of leprosy control programs. Improvement is needed in efforts to provide appropriate information to societies, dermatologists and patients. M. leprae is a very unique microorganism. It is expected that basic research for leprosy can be sustained.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology
  5. Bacteriology And Genomics
  6. Transmission And Pathology
  7. Clinical Features
  8. Diagnosis And Laboratory Tests
  9. Treatments
  10. Lepra Reactions
  11. Disability And Stigma
  12. Conclusions And Future Perspectives
  13. References