Leprosy type 1 reaction (formerly reversal reaction).

Nerve damage leading to impairment and permanent disability is the major problem in the course of a leprosy infection. Most of the damage occurs during two types of leprosy reactions, type 1 reaction (T1R) and type 2 reaction (T2R). Timely and adequate treatment may prevent this damage. Particular T1R reactions, however, are often diagnosed too late and are even missed. Clinical symptoms and warning signs are therefore covered, as are the immunology and pathophysiology of nerve damage. The differences between upgrading and downgrading, old terms but still relevant, are explained. Methods to detect reactions and to monitor their treatment are given. Triggering factors, the mechanisms of the reactions, including autoimmunity, and the presence of physical compression are discussed. Treatment over the years is placed in its context, and based on this information a treatment schedule is recommended.

Leprosy type 1 reaction (formerly reversal reaction)

Nerve damage leading to impairment and permanent disability is the major problem in the course of a leprosy infection. Most of the damage occurs during two types of leprosy reactions, type 1 reaction (T1R) and type 2 reaction (T2R). Timely and adequate treatment may prevent this damage. Particular T1R reactions, however, are often diagnosed too late and are even missed. Clinical symptoms and warning signs are therefore covered, as are the immunology and pathophysiology of nerve damage. The differences between upgrading and downgrading, old terms but still relevant, are explained. Methods to detect reactions and to monitor their treatment are given. Triggering factors, the mechanisms of the reactions, including autoimmunity, and the presence of physical compression are discussed. Treatment over the years is placed in its context, and based on this information a treatment schedule is recommended.

Post-kala-azar dermal leishmaniasis and leprosy: case report and literature review.

BACKGROUND: Post-kala-azar dermal leishmaniasis (PKDL) is a dermal complication of visceral leishmaniasis (VL), which may occur after or during treatment. It has been frequently reported from India and the Sudan, but its occurrence in South America has been rarely reported. It may mimic leprosy and its differentiation may be difficult, since both diseases may show hypo-pigmented macular lesions as clinical presentation and neural involvement in histopathological investigations. The co-infection of leprosy and VL has been reported in countries where both diseases are endemic. The authors report a co-infection case of leprosy and VL, which evolved into PKDL and discuss the clinical and the pathological aspects in the patient and review the literature on this disease. CASE PRESENTATION: We report an unusual case of a 53-year-old female patient from Alagoas, Brazil. She presented with leprosy and a necrotizing erythema nodosum, a type II leprosy reaction, about 3 month after finishing the treatment (MDT-MB) for leprosy. She was hospitalized and VL was diagnosed at that time and she was successfully treated with liposomal amphotericin B. After 6 months, she developed a few hypo-pigmented papules on her forehead. A granulomatous inflammatory infiltrate throughout the dermis was observed at histopathological examination of the skin biopsy. It consisted of epithelioid histiocytes, lymphocytes and plasma cells with the presence of amastigotes of Leishmania in macrophages (Leishman's bodies). The diagnosis of post-kala-azar dermal leishmaniasis was established because at this time there was no hepatosplenomegaly and the bone marrow did not show Leishmania parasites thus excluding VL. About 2 years after the treatment of PKDL with liposomal amphotericin B the patient is still without PKDL lesions. CONCLUSION: Post-kala-azar dermal leishmaniasis is a rare dermal complication of VL that mimics leprosy and should be considered particularly in countries where both diseases are endemic. A co-infection must be seriously considered, especially in patients who are non-responsive to treatment or develop persistent leprosy reactions as those encountered in the patient reported here.

Cutaneous and mucocutaneous leishmaniasis resembling borderline-tuberculoid leprosy: a new clinical presentation?

Both cutaneous and mucocutaneous leishmaniasis are endemic in Northern Ethiopia. The different clinical presentations depend on the responsible organism and the host's immune response. Localized cutaneous leishmaniasis is the type most frequently seen. Diffuse cutaneous leishmaniasis is relatively rare and usually associated with mucous membrane involvement. Diffuse cutaneous leishmaniasis presents with multiple lesions, can be difficult to diagnose and responds less favourably to treatment. We report here 2 patients with unusual presentations of diffuse cutaneous leishmaniasis presenting with large hypopigmented skin lesions mimicking borderline-tuberculoid leprosy. To our knowledge this presentation has not been described before and may present difficulties in making a definite diagnosis in regions where both leprosy and cutaneous leishmaniasis are endemic. Lepromatous leprosy and diffuse cutaneous leishmaniasis are regularly confused, particularly when no skin smears for acid-fast bacillus or Leishman-Donovan bodies are performed.

Leprosy and tuberculosis co-infection: clinical and immunological report of two cases and review of the literature.

A review of the records of patients seen between 2004 and 2011 at the Dermatology Clinic of the São Paulo University Medical School showed that only two leprosy patients had been co-infected with tuberculosis (TB). One patient showed a type 1 leprosy reaction during the first 3 months of treatment of pleural TB and in the other patient, pulmonary TB was diagnosed during the first 3 months of treatment of a type 1 leprosy reaction. Both patients showed normal cellular immune response tests, including those of the interferon-gamma (IFN-γ)/interleukin 12 (IL-12) axis. Although both mycobacterial infections are endemic in developing countries like Brazil, the co-infection has hardly been reported in the last decade. There is no suitable explanation for this observation. The reports on the interaction between the two mycobacteria are highly speculative: some studies suggest that leprosy, especially the anergic form, would predispose to TB, whereas other investigations suggested an antagonism between the two diseases.

Association between neuropathic pain and A-waves in leprosy patients with type 1 and 2 reactions.

Neuropathic pain (NP) is a well-recognized feature of leprosy neuropathy. However, the diagnosis of NP is difficult using only clinical criteria. In the study reported here, by means of conventional nerve conduction studies, the authors sought for an association between long-latency responses and NP complaints in leprosy patients with type 1 and 2 reactions. Of the 27 ulnar nerves of leprosy patients, 18 with type 1 reaction (T1R) and 9 with type 2 reaction (T2R) were followed-up for 6 months before and after steroid treatment. Clinical characteristics of pain complaints and clinical function were assessed, as well as the presence of F- and A-waves of the ulnar nerve using nerve conduction studies. The clinical and the neurophysiologic findings were compared to note positive concordances (presence of NP and A-waves together) and negative concordances (absence of NP and A-waves together) before and after treatment. Both reactions presented a high frequency of A-waves (61.1% in T1R and 66.7% in T2R, P < 0.05) and prolonged F-waves (69.4% in T1R and 65.8% in T2R, P = 0.4). No concordances were seen between pain complaints and F-waves. However, significant concordances between NP and A-waves were observed, although restricted to the T2R group (χ(2) = 5.65, P = 0.04). After treatment, there was a significant reduction in pain complaints, as well as the presence of F- and A-waves in both groups (P < 0.05 for all comparisons). In conclusion, the presence of A-waves correlates well with pain complaints of neuropathic characteristics in leprosy patients, especially in those with type 2 reaction. Probably, such response shares similar mechanisms with the small-fiber dysfunction seen in these patients with NP, such as demyelination, intraneural edema, and axonal sprouting. Further studies using specific tools for small-fiber assessment are warranted to confirm our findings.

Leprosy and HIV coinfection: a critical approach.

An increase in leprosy among HIV patients, similar to that observed in patients with TB, was expected approximately 20 years ago. Studies conducted in the 1990s together with those reported recently seemed to indicate that a coinfection with HIV did not alter the incidence and the clinical spectrum of leprosy and that each disease progressed as a single infection. By contrast, in countries with a high seroprevalence of HIV, TB was noted to increase. Explanations may be provided by the differences in the incubation time, the biology and toxicity of Mycobacterium leprae and Mycobacterium tuberculosis. After the introduction of HAART the leprosy-HIV coinfection manifested itself as an immune reconstitution inflammatory syndrome (IRIS), typically as paucibacillary leprosy with type 1 leprosy reaction. The incidence of leprosy in HIV-infected patients has never been properly investigated. IRIS-leprosy is probably underestimated and recent data showed that the incidence of leprosy in HIV patients under HAART was higher than previously thought.

Association between neuropathic pain and A-Waves in leprosy patients with type 1 and 2 reactions

Neuropathic pain (NP) is a well-recognized feature of leprosy neuropathy. However, the diagnosis of NP is difficult using only clinical criteria. In the study reported here, by means of conventional nerve conduction studies, the authors sought for an association between long-latency responses and NP complaints in leprosy patients with type 1 and 2 reactions. Of the 27 ulnar nerves of leprosy patients, 18 with type 1 reaction (T1R) and 9 with type 2 reaction (T2R) were followed-up for 6 months before and after steroid treatment. Clinical characteristics of pain complaints and clinical function were assessed, as well as the presence of F- and A-waves of the ulnar nerve using nerve conduction studies. The clinical and the neurophysiologic findings were compared to note positive concordances (presence of NP and A-waves together) and negative concordances (absence of NP and A-waves together) before and after treatment. Both reactions presented a high frequency of A-waves (61.1% in T1R and 66.7% in T2R, P < 0.05) and prolonged F-waves (69.4% in T1R and 65.8% in T2R, P = 0.4). No concordances were seen between pain complaints and F-waves. However, significant concordances between NP and A-waves were observed, although restricted to the T2R group (χ(2) = 5.65, P = 0.04). After treatment, there was a significant reduction in pain complaints, as well as the presence of F- and A-waves in both groups (P < 0.05 for all comparisons). In conclusion, the presence of A-waves correlates well with pain complaints of neuropathic characteristics in leprosy patients, especially in those with type 2 reaction. Probably, such response shares similar mechanisms with the small-fiber dysfunction seen in these patients with NP, such as demyelination, intraneural edema, and axonal sprouting. Further studies using specific tools for small-fiber assessment are warranted to confirm our findings.

Enhancing sensitivity of detection of immune responses to Mycobacterium leprae peptides in whole-blood assays.

Although worldwide leprosy prevalence has been reduced considerably following multidrug therapy, new case detection rates remain relatively stable, suggesting that transmission of infection still continues. This calls for new efforts, among which is development of assays that can identify subclinical/early-stage Mycobacterium leprae-infected subjects, a likely source of transmission. Areas in which leprosy is endemic often lack sophisticated laboratories, necessitating development of field-friendly immunodiagnostic tests for leprosy, like short-term whole-blood assays (WBA). In classical, peripheral blood mononuclear cell (PBMC)-based gamma interferon (IFN-gamma) release assays, M. leprae peptides have been shown to discriminate in a more specific fashion than M. leprae proteins between M. leprae-exposed contacts and patients as opposed to healthy controls from the same area of endemicity. However, peptides induced significantly lower levels of IFN-gamma than did proteins, particularly when whole blood was used. Therefore, possibilities of specifically enhancing IFN-gamma production in response to M. leprae peptides in 24-h WBA were sought by addition of various cytokines and antibodies or by mannosylation of peptides. In addition, other cytokines and chemokines were analyzed as potential biomarkers in WBA. We found that only interleukin 12 (IL-12), not other costimulants, increased IFN-gamma production in WBA while maintaining M. leprae peptide specificity, as evidenced by lack of increase of IFN-gamma in control samples stimulated with IL-12 alone. The IL-12-induced increase in IFN-gamma was mainly mediated by CD4+ T cells that did not produce IL-2 or tumor necrosis factor (TNF). Mannosylation further allowed the use of 100-fold-less peptide. Although not statistically significantly, macrophage inflammatory protein 1beta (MIP-1beta) and macrophage c protein 1 (MCP-1) levels specific for M. leprae peptide tended to be increased by IL-12. IP-10 production was also found to be a useful marker of M. leprae peptide responses, but its production was enhanced by IL-12 nonspecifically. We conclude that IFN-gamma-based WBA combined with IL-12 represents a more sensitive and robust assay for measuring reactivity to M. leprae peptides.

A randomized clinical trial of oral steroids for ulnar neuropathy in type 1 and type 2 leprosy reactions.

BACKGROUND: Steroids regimens in leprosy neuropathies are still controversial in botth types of reactions. METHOD: For this trial, 21 patients with ulnar neuropathy were selected from 163 leprosy patients, 12 with type 1 reaction (T1R) and nine with type 2 (T2R). One experimental group started with prednisone 2 mg/kg/day and the control group with 1 mg/kg/day. A clinical score based on tests for spontaneous pain, nerve palpation, sensory and muscle function was used. Neurophysiological evaluation consisted on the motor nerve conduction of the ulnar nerve in three segments. Student "t" test for statistical analysis was applied on the results: before treatment, first week, first month and sixth month, between each regimen and types of reaction. CONCLUSION: In both reactions during the first month higher doses of steroids produced better results but, earlier treatment with lower dose was as effective. Short periods of steroid, 1 mg/Kg/day at the beginning and,tapering to 0,5 mg/Kg/day or less in one month turned out to be efficient in T2R.

A randomized clinical trial of oral steroids for ulnar neuropathy in type 1 and type 2 leprosy reactions / Ensaio clínico sobre o tratamento com esteróides via oral da neuropatia ulnar em reação tipo 1 e tipo 2 da hanseníase

BACKGROUND: Steroids regimens in leprosy neuropathies are still controversial in botth types of reactions. METHOD: For this trial, 21 patients with ulnar neuropathy were selected from 163 leprosy patients, 12 with type 1 reaction (T1R) and nine with type 2 (T2R). One experimental group started with prednisone 2 mg/kg/day and the control group with 1 mg/kg/day. A clinical score based on tests for spontaneous pain, nerve palpation, sensory and muscle function was used. Neurophysiological evaluation consisted on the motor nerve conduction of the ulnar nerve in three segments. Student "t" test for statistical analysis was applied on the results: before treatment, first week, first month and sixth month, between each regimen and types of reaction. CONCLUSION: In both reactions during the first month higher doses of steroids produced better results but, earlier treatment with lower dose was as effective. Short periods of steroid, 1 mg/Kg/day at the beginning and,tapering to 0,5 mg/Kg/day or less in one month turned out to be efficient in T2R.

INTRODUÇÃO: O tratamento da neuropatia da hanseníase com esteróides é ainda controverso nos dois tipos de reações. MÉTODO: Neste ensaio, de 163 pacientes foram selecionados 21 com neuropatia ulnar, 12 com reação tipo 1 e 9 com tipo 2. Um grupo experimental iniciou com 2 mg/kg/dia e o grupo controle com 1 mg/kg/dia. Foi composto um escore clínico pela avaliação da sensação dolorosa espontânea, palpação de nervos e funções sensitiva e motora. Realizou-se a condução nervosa motora do nervo ulnar em três segmentos. Aplicaram-se os estudos estatísticos com o teste t de Student nos resultados: antes do tratamento, primeira semana, primeiro mês e sexto mês. CONCLUSÃO: Em ambas as reações dosagens mais elevadas iniciais produziram melhores resultados, mas a dose menor quando administrada precocemente foi igualmente efetiva. Períodos curtos com doses efetivas, 1 mg/Kg/dia no início e reduzindo-se para 0,5 mg/Kg/dia ou menos em um mês foram eficientes na reação tipo 2.

Treatment of leprosy: science or politics?

OBJECTIVE: To review the history of the treatment of leprosy and leprosy reactions after World War II. METHODS: Treatments based on experience and clinical evidence are compared with those advised by the WHO in their quest to eliminate leprosy by the year 2000, later extended to 2005. RESULTS: Leprosy is not eliminated. Analyses of data on reaction treatment suggest that the treatment regimens for leprosy reactions as advised by the WHO may lead to more impairment among leprosy patients than the 'old' established regimes. CONCLUSION: WHO policies to eliminate leprosy may have jeopardized the proper treatment of leprosy for years to come.

Leprosy and HIV co-infection in five patients.

In a retrospective study, five patients are reported who suffered from a Mycobacterium leprae/HIV co-infection and were treated for their HIV infection with HAART. In four patients, this revealed their leprosy and induced a type I leprosy reaction. Two patients who were lepromin negative at diagnosis were retested after about 1 year of anti-retroviral treatment, and found to be positive.

Deteccao de determinantes antigenicos compartilhados entre a proteina de choque termico 65 do Mycobacterium leprae e proteina de choque termico 60 humana / Detection of shared antigenic determinantes between Mycobacterium leprae heat shock protein 65 and human heat shock protein 60

Nestes estudos foram investigados se o Mycobacterium leprae (M. leprae) e o homem compartilham determinantes antigenicos que podem estar localizados nas Proteinas de Choque Termico (HSPs) e que podem ser responsaveis pela destruicao tecidual. Usando-se tecnica de coloracao unica pela imunoperoxidase em cortes feitos com criostato, observaram-se tres anticorpos que eram dirigidos contra HSP-60 (anticorpos policlonais SPA-804, SP-805 e o anticorpo monoclonal SPA-807, que provavelmente reagiram especificamente com macrofagos e celular epitelioides em biopsia cutaneas de pacientes com hanseniase. No Western Blot foi observado que todos os anticorpos contra HSP-60 humana a anticorpos monoclonais (MoAbs) contra HSP-65 do M. leprae (F47-10, F67-18, F88-1) reagiram intensamente com as proteinas do M. leprae sonicado com peso molecular de 65 kDa, indicando semelhanca de alguns determinantes antigenicos entre HSP-60 humana e HSP-65 do M. leprae. Subsequentemente, um estudo imunohistoquimico comparativo dos padroes de coloracao de anticorpos contra HSP-60 humana e anticorpos contra HSP-65 do M. leprae, usando cortes cutaneos feito em criostato de hanseniase paucibacilar (PB), multibacilar (MB) e outras doencas granulomatosas, revelaram que os MoAbs F47-10 e F67-18 reagiram somente fracamente com os granulomas em hanseniase PB e em outras doencas granulomatosas cutaneas, mas coravam o granuloma da hanseniase MB intensamente. O MoAb F88-1 e os anticorpos policlonais SPA-804, SPA-805 e o MoAb SPA 807 coraram os granulomas dos pacientes PB e de outros doencas cutaneas granulomatosas com a mesma intensidade daquela nos pacientes MB. Utilizando-se uma tecnica de dupla coloracao, observou-se que os determinantes antigenicos reconhecidos pelo MoAb contra HSP-60 humana (SPA-807) e os MoBbs contra a HSP-65 do M. leprae (F67-18, F47-10, F88-1) estavam, na maioria das vezes, localizados nos macrofagos. Esses achados nao contradizem nossa hipotese de que semelhancas entre determinantes antigenicos nas HSPs no M. leprae e no hospedeiro humano podem ser, no minimo em parte, responsaveis pela inducao de uma reacao autoimune na hanseniase causando formacao de granuloma com subsequente dano tecidual. Os resultados deste estudo tambem indicaram que alguns destes determinantes estao provavelmente localizados na HSP-60. Uma explicacao similar possivelmente se aplique aos achados em...

Detection of shared antigenic determinants between Mycobacterium leprae heat shock protein 65 and human heat shock protein 60

In these studies, it was investigated whether M. leprae and man share antigenic determinants which may be located on Heat Shock Proteins (HSPs), and which may be responsible for tissue destruction. Using immunoperoxidase single-staining technique on cryostat sections it was observed that three antibodies which are directed against HSP 60 (polyclonal antibodies SPA 804 and SPA 805 and monoclonal antibody SPA 807) probably reacted specifically with macrophages and epitheloid cells in leprosy skin sections. On Western Blotting, it was observed that the antibodies againts human HSP 60 nomoclonal antibodies (MoAbs) against M. leprae HSP 65 (F 47-10, F 67-18, F 88-1) all reacted strongly with sonicated M. leprae proteins with a molecular mass of 65 kDa undicating similarity of some antigenic determinants between human HSP 60 and M. leprae HSP 65. Subsequently, a comparative immunohistochemical study of the staining patterns of antibodies against human HSP 60 and antibodies against M. leprae HSP 65 using cryostat skin section of paucibacillary (PB) leprosy multibacillary (MB) leprosy and other granulomatous skin disorders revealed that the MoAbs F 47-10 and F 67-18 reacted only weakly with the granulomas in PB leprosy and in other granulomatous skin diseases, but stained MB leprosy granuloma strongly. The MoAb F 88-1 and the polyclonal antibodies SPA 804, SPA 805 and the MoAb SPA 807 stained granulomas of PB patients and of other granulomatous skin disorders with the same intensity as that MB patients. Using a double-staining technique, it was observed that the antigenic determinants recognized by the MoAb against human HSP 60 (SPA 807) and the MoAbs against M. leprae HSP 65 (F 67-18, F 47-10, F 88-1) were mostly located in the macrophages. These findings do not contradict our suggestion, Heath Shock Proteins of M. leprae and the human host may be at least in part responsible for the induction of an autoimmune reaction causing granuloma formation with subsequent tissue damage in leprosy. The results of this study also indicated that some of these determinats are probably located on HSP 60. A similar explanation possibly applies to the findings in the other granulomatous disease e.g. sarcoidosis probably micobacterial induced and necrobiosis lipoidica related to diabetis, in which antigenic similarities between bacterial HSP 65 and human HSP 60 are considered to play a part.

Anti-Mycobacterium leprae monoclonal antibodies cross-react with human skin: an alternative explanation for the immune reponses in leprosy

A panel of 17 mouse monoclonal antibodies (MoAb) raised against Mycobacterium leprae (M. leprae) antigens was used to detect antigenic determinants in normal human skin. An indirect immunoperoxidase technique was used. Eight of the MoAb detected epidermal antigens similar to patterns well known for human sera. Five of these MoAb detected determinants in the dermis, too. These observations may indicate a certain degree of similarity between the antigenic determinants occurring in M. leprae and in the human host. We propose that such a similarity on the one hand may facilitate the survical of M. leprae in the human host when the antigens are not recognized as "non-self", a situation which seems to ocuur in lepromatous leprosy, when the patients' tissues are loaded with bacteria virtually without any immune response. On the other hand, M. leprae antigens which mimic host antigens may induce an auto-immune reaction against the host's own antigens, which could explain the immune reaction in tuberculod leprosy and during a "reversal reaction" when M. leprae is not observed in the host tissues, but extensive granuloma formation occurs