Adverse effects of polychemotherapy for leprosy in 13 years of follow-up at a university hospital

Abstract Leprosy is one of the neglected diseases in the world and Brazil is the second country with more cases. A retrospective study was conducted based on the medical records of 196 leprosy patients diagnosed during the course of 13 years at a university hospital. The aim was to describe the adverse effects of polychemotherapy, as well the most prevalent and most vulnerable populations. In the study, dapsone was the most implicated drug, especially in women, and the risk increased with age. The authors conclude that with this patient profile, greater vigilance should be taken regarding possible adverse effects, especially anemia.

The interference of polypharmacy and the importance of clinical pharmacy advice in the treatment of leprosy: a case-control study

Abstract INTRODUCTION: Although supervised doses are essential for reducing leprosy treatment failure, the impact of specific drug interactions has rarely been assessed. This study aimed to estimate the risk of leprosy treatment suspension in patients receiving polypharmacy. METHODS We performed this case-control study in which the primary outcome was defined as the need to discontinue multibacillary leprosy treatment for at least one supervised dose, and the main risk factor was the detection of polypharmacy. Multivariate analysis by logistic regression was used for calculating odds ratio (OR). RESULTS: This study included 103 patients, of whom 43 needed to discontinue leprosy treatment (hemolysis = 26, hepatitis = 2, hemolysis associated with hepatitis = 6, and suspected treatment resistance = 9) and the rest did not. The severity of drug interactions had no effect on treatment discontinuation. Patients who used five or more drugs in addition to leprosy treatment had almost a 4-fold greater risk of treatment suspension (OR, 3.88; 95% confidence interval: 1.79-9.12; p < 0.001). The number of drugs used also positively influenced the occurrence of hemolysis (p < 0.001). No patient presented evidence of molecular resistance to rifampicin, dapsone, or ofloxacin treatment, as evidenced by genetic sequencing detection of rpoB, folp1, and gyrA mutations. CONCLUSIONS: Polypharmacy has deleterious effects on the already difficult-to-adhere-to treatment of leprosy and polypharmacy induces hemolysis. Additional measures must be taken to avoid the undesirable effects of inadequate polypharmacy.

Adverse events in patients with leprosy on treatment with thalidomide

Abstract INTRODUCTION: Thalidomide, used to treat erythema nodosum leprosum (ENL), is associated with severe adverse events (AEs) and is highly teratogenic. METHODS: A cross-sectional study was conducted on thalidomide-treated patients with ENL. AEs and selected variables were investigated through interviews and assessment of medical records. Odds ratios with 95% confidence intervals were estimated via logistic regression. RESULTS: Peripheral neuropathy symptoms and deep vein thrombosis (DVT) were the most common AEs reported. Although women of reproductive age used contraceptives, <50% of patients reported using condoms. Polypharmacy was associated with all endpoints, except DVT. CONCLUSIONS: Pharmacovigilance is crucial to prevent harmful thalidomide-associated AEs.

Clinical trial for uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): adverse effects approach

Abstract: BACKGROUND: The Clinical Trial for Uniform Multidrug Therapy for Leprosy Patients in Brazil (U-MDT/CT-BR), designed to evaluate the effectiveness of a six-months regimen, assessed the adverse effects caused by the drugs. OBJECTIVE: Describe adverse effects due to MDT in U-MDT/CT-BR, comparing the uniform regimen (U-MDT) to the current WHO regimen (R-MDT). Patients and methods: After operational classification, patients were randomly allocated to the study groups. U-MDT PB and U-MDT MB groups, received the U-MDT regimen, six doses of MB-MDT (rifampicin, dapsone and clofazimine). R-MDT PB and R-MDT MB groups, received the WHO regimens: six doses (rifampicin and dapsone) for PB and 12 doses (rifampicin, dapsone and clofazimine) for MB. During treatment, patients returned monthly for clinical and laboratorial evaluation. Patients with single lesion were not included in this trial. RESULTS: Skin pigmentation (21.7%) and xerosis (16.9%) were the most frequent complaints among 753 patients. Laboratory exams showed hemoglobin concentration lower than 10g/dL in 23.3% of the patients, glutamic oxaloacetic transaminase (GOT) above 40U/L in 29.5% and glutamic pyruvic transaminase (GPT) above 40U/L in 28.5%. Twenty-four patients (3.2%) stopped dapsone intake due to adverse effects, of whom 16.6% due to severe anemia. One case of sulfone syndrome was reported. STUDY LIMITATIONS: Loss of some monthly laboratory sample collection. CONCLUSIONS: There was no statistical difference regarding adverse effects in the R-MDT and U-MDT groups but anemia was greater in patients from R-MDT/MB group, therefore adverse effects do not represent a constraint to recommend the six-month uniform regimen of treatment for all leprosy patients.

Reacción lepromatosa tipo I, a propósito de un caso / Type I lepra reaction: a case report

La lepra es una infección crónica, granulomatosa, producida por Mycobacterium leprae, que afecta piel y nervios periféricos. Se describen dos tipos de reacciones leprosas: tipo I y tipo II, las que corresponden a cuadros agudos que exacerban la enfermedad. Estas leproreacciones pueden ocurrir antes, durante o después del tratamiento. Se presenta el caso de un paciente masculino que acude a consultar con lesiones cutáneas y resultado de biopsia de piel con diagnóstico de lepra. Se inicia tratamiento multidroga OMS-MB1. Posteriormente presenta una leproreacción tipo I, por lo que se le realiza tratamiento con prednisona.

Leprosy is a chronic granulomatous infection of the skin and peripheral nervous system produced by Mycobacterium leprae. Two types of acute leprosy reactions have been described: type I and type II. These reactions can occur before, during or after treatment. We present the case of an adult male patient presenting with skin lesions and skin biopsy diagnostic for leprosy. A multidrug WHO-MB 1 treatment was initiated, after which he presents with type I lepra reaction requiring corticosteroids.

Number of leprosy reactions during treatment: clinical correlations and laboratory diagnosis

Abstract INTRODUCTION: The occurrence of leprosy reactions, a common event during treatment, may be mostly related to the action of multidrug therapy on Mycobacterium leprae. The clinical and laboratory monitoring of patients with reactions is important, since collecting data that assists in predicting the risk of reactions may help to prevent disability. METHODS: This was a sectional study, in order to correlate clinical and laboratory diagnosis with the number of reactions during treatment. Spearman's correlation was used to verify the degree of association between the assessed variables. RESULTS: This study was conducted with 211 patients with leprosy reactions during treatment of M. leprae. The borderline tuberculoid group was the most prevalent clinical form (74/211; 35.1%) and the type one reaction showed the highest frequency (136/211; 64.5%). It was observed that 73.5% (155/211) of reactions occurred within 3 months of the initiation of multidrug therapy. The diagnostic values, including the bacterial indices (BIs) of dermal smears (r = 0.21, p < 0.05) and skin biopsies (r = 0.20; p < 0.05), showed a positive correlation with the number of reactions during treatment. CONCLUSIONS: This research showed a positive correlation between bacillary load markers and the number of leprosy reactions. This study provided scientific support to future research aiming to elucidate the influence of antigenic load on the number of leprosy reactions during treatment.

Identification of clinical, epidemiological and laboratory risk factors for leprosy reactions during and after multidrug therapy

This cross-sectional retrospective study evaluated 440 leprosy patients; 57% (251/440) had leprosy reactions during and/or after multidrug therapy, 80.5% (202/251) of whom presented with multibacillary leprosy. At diagnosis, positive bacterial index (BI) [odds ratio (OR) = 6.39; 95% confidence interval (CI): 4.1-10.1)] or polymerase chain reaction (PCR) (OR = 9.15; 95% CI: 5.4-15.5) in skin smears, anti-phenolic glycolipid-1 (anti-PGL-1) ELISA (OR = 4.77; 95% CI: 2.9-7.9), leucocytosis (OR = 9.97; 95% CI: 3.9-25.7), thrombocytopenia (OR = 5.72; 95% CI: 2.3-14.0) and elevated lactate dehydrogenase (OR = 2.38; 95% CI: 1.4-4.0) were potential markers for the development of reactions during treatment. After treatment, positive BI (OR = 8.47; 95% CI: 4.7-15.3) and PCR (OR = 6.46; 95% CI: 3.4-12.3) in skin smears, anti-PGL-1 ELISA (OR = 2.25; 95% CI: 1.3-3.9), anaemia (OR = 2.36; 95% CI: 1.2-4.5), leucocytosis (OR = 4.14; 95% CI: 1.5-11.6) and thrombocytopenia (OR = 3.70; 95% CI: 1.3-2.2) were risk factors for the occurrence of reactions during the study period. The identification of groups with an increased risk for developing reactions will allow for the timely development of a treatment plan to prevent nerve damage and, therefore, the appearance of the disabling sequelae associated with the stigma of leprosy.

Incapacidades físicas em pessoas acometidas pela hanseníase no período pós-alta da poliquimioterapia em um município no Norte do Brasil / Physical disabilities in leprosy patients after discharge from multidrug therapy in Northern Brazil / Incapacidades físicas en personas afectadas por la hanseniasis en el período post alta de la poliquimioterapia en un municipio en el norte de Brasil

Chronic sequelae and disabilities are one of the main problems in leprosy. The current study aimed to estimate the prevalence of disabilities in leprosy patients after successfully completing multidrug therapy in Araguaína, Tocantins State, Brazil. This was a cross-sectional study including 282 cases diagnosed from 2004 to 2009. The degrees of disability at diagnosis and at discharge from treatment were collected from medical records and the National Information System for Notifiable Diseases (SINAN). A simplified neurological workup was performed after discharge from treatment. The prevalence of disabilities at diagnosis was 29.4%, and 8.9% of then was grade II. Between diagnosis and discharge, the degree of physical disability worsened in 25% of cases. At diagnosis, the proportion of deformities was significantly higher in men (RR = 1.7; 95%CI: 1.23-2.37). There was a significant association between disability and multibacillary disease (p < 0.001) and occurrence of reactions (p < 0.001). The data show that after discharge from multidrug therapy, in order to prevent chronic sequelae and functional limitations, continuous monitoring is still needed for individuals that have been recorded as cured and thus deleted from the records.

Danos neurais contribuem para a incapacidade física na hanseníase. O objetivo foi estimar a prevalência de indivíduos com incapacidade física após a alta de poliquimioterapia da hanseníase em Araguaína, Tocantins, Brasil. Estudo transversal com 282 casos novos de 2004 a 2009. O grau de incapacidade no diagnóstico e na cura foi coletado de prontuários e do Sistema de Informação de Agravos de Notificação. No pós-alta usou-se o formulário de avaliação neurológica simplificada. A prevalência de incapacidade foi de 29,4%, sendo 8,9% grau 2. Houve associação entre incapacidades físicas com multibacilares (p < 0,001) e com episódios reacionais (p < 0,001). No diagnóstico, a ocorrência de deformidades foi 1,7 vez maior nos homens (IC95%: 1,23-2,37). Entre o diagnóstico e a alta houve piora do grau de incapacidade e esta piora foi maior após a alta: 25%. A piora do grau de incapacidade foi mais expressiva após a alta, apresentando associação com multibacilares e episódios reacionais. É preciso monitoramento contínuo de casos em alta, para prevenir sequelas e limitação funcional.

Daños neurales contribuyen a la incapacidad física en la hanseniasis. El objetivo fue estimar la prevalencia de individuos con incapacidad física, tras el alta de poliquimioterapia de la hanseniasis en Araguaína, Tocantins, Brasil. Estudio transversal con 282 casos nuevos de 2004 a 2009. El grado de incapacidad en el diagnóstico y en la cura se recogió de historiales médicos y del sistema de información de quejas por notificación. En el post alta se usó el formulario de evaluación neurológica simplificada. La prevalencia de incapacidad fue de un 29,4%, siendo un 8,9% grado 2. Hubo asociación entre incapacidades físicas con multibacilares (p < 0,001) y con episodios reaccionales (p < 0,001). En el diagnóstico, la ocurrencia de deformidades fue un 1,7 veces mayor en los hombres (IC95%: 1,23-2,37). Entre el diagnóstico y el alta hubo un empeoramiento del grado de incapacidad y ese empeoramiento fue mayor tras el alta: un 25%. El empeoramiento del grado de incapacidad fue más expresivo tras el alta, presentando asociación con multibacilares y episodios reaccionales. Es preciso el monitoreo continuo de casos en alta, para prevenir secuelas y limitación funcional.

Brazilian clinical trial of uniform multidrug therapy for leprosy patients: the correlation between clinical disease types and adverse effects

This study sought to verify the correlation between leprosy types and the adverse effects of treatment drugs. This quantitative, prospective, nested study was developed at the Dona Libânia Dermatology Centre in Fortaleza, Brazil. Data were collected from November 2007-November 2008. During this period, 818 leprosy patients were diagnosed and began treatment. Forty patients with tuberculoid leprosy (TT) were selected. Twenty patients followed a standard therapy of dapsone and rifampicin and 20 were administered dapsone, rifampicin and clofazimine (U-MDT). Twenty patients with borderline lepromatous (BL) and lepromatous leprosy (LL) were also selected and treated with U-MDT. All of the subjects received six doses. With the exception of haemolytic anaemia, there was a low incidence of adverse effects in all the groups. We did not observe any differences in the incidence of haemolytic anaemia or other side effects across groups of patients with TT, BL or LL treated with U-MDT.

Reações hansênicas em pacientes em alta por cura pela poliquimioterapia / Leprosy reactions in discharged patients following cure by multidrug therapy

INTRODUÇÃO: Reações hansênicas são a principal causa de lesões dos nervos e incapacidades provocadas pela hanseníase. MÉTODOS: Estudo retrospectivo com objetivo de verificar a frequência de reações hansênicas em pacientes com alta por cura pela poliquimioterapia (PQT). RESULTADOS: Pacientes que apresentaram reações durante o tratamento, 35,5 por cento continuaram pós-PQT; aqueles que não apresentaram no tratamento, somente 12,7 por cento tiveram pós-PQT; 63,4 por cento multibacilares apresentaram durante e 31,7 por cento após; paucibacilares 27,7 por cento durante e 8,3 por cento após. CONCLUSÕES: Existe relação diretamente proporcional entre presença de reações durante e após o tratamento. Formas clínicas multibacilares apresentam maior frequência de reações durante e após a cura.

INTRODUCTION: Reactional states are the main cause of nerve lesions and incapacities provoked by leprosy. METHODS: Retrospective study aimed at verifying the frequency of leprosy reactions in discharged patients following cure by multidrug therapy (MDT). RESULTS: Among patients who presented reactions during treatment, 35.5 percent continued after MDT; of those that did not present during treatment, only 12.7 percent presented after discharge; 63.4 percent multibacillary patients presented during and 31.7 percent after; 27.7 percent paucibacillary patients presented during and 8.3 percent after. CONCLUSIONS: A direct proportional relation exists between the presence of reactions during and after treatment. Multibacillary clinical forms present a greater frequency of reactions during and after cure.

Methemoglobinemia and dapsone levels in patients with leprosy

The objective of this work was to determine the methemoglobinemia and correlate with dapsone levels in multibacillary leprosy patients under leprosy multi-drug therapy. Thirty patients with laboratory and clinical diagnosis of multibacillary leprosy were enrolled. Dapsone was analyzed by high performance liquid chromatography and methemoglobinemia by spectrophotometry. The mean dapsone concentrations in male was 1.42 g/mL and in female was 2.42 g/mL. The mean methemoglobin levels in male was 3.09 µg/mL; 191 percent, and in female was 2.84 ± 1.67 percent. No correlations were seen between dapsone levels and methemoglobin in male and female patients. Our results demonstrated that the dosage of dapsone in leprosy treatment does not promote a significant methemoglobinemia.

Talidomida usada por pacientes com eritema nodoso hansênico / Thalidomide used by patients with erythema nodosum leprosum

INTRODUÇÃO: A talidomida é um fármaco utilizado atualmente no tratamento do eritema nodoso hansênico no Brasil. MÉTODOS: Estudo prospectivo para acompanhar a evolução clínica, registrar os eventos adversos e determinar as concentrações plasmáticas de talidomida em dose diária de 100mg/dia, em 20 pacientes com manifestações clínicas de eritema nodoso hansênico, divididos em dois grupos: após ou em curso da poliquimioterapia para hanseníase. RESULTADOS: Não foram observadas diferenças significativas nos grupos no decorrer do estudo, tanto na evolução clínica favorável dos pacientes, de 70 por cento e 90 por cento, quanto nos eventos adversos registrados que foram tontura e sonolência. Os teores plasmáticos de talidomida em D7 e D14 foram de 0,82±0,4μg/mL e 0,79±0,3μg/mL no grupo 1 e de 0,82±0,4 e 1,55±1,0 no grupo 2, respectivamente. CONCLUSÕES: Na amostra estudada, a poliquimioterapia não interferiu na evolução clínica, na incidência dos efeitos adversos e nos níveis plasmáticos de talidomida.

INTRODUCTION: Thalidomide is a drug currently used in Brazil for treating erythema nodosum leprosum. METHODS: This was a prospective study to follow up clinical evolution, record adverse events and determine plasma thalidomide levels from a dose of 100 mg/day, among 20 patients with clinical manifestations of erythema nodosum leprosum, divided into two groups: during or after leprosy multidrug therapy. RESULTS: No significant differences between the groups were seen during the study, either in relation to favorable clinical evolution among the patients (70 percent and 90 percent), or in relation to the adverse events recorded, which were dizziness and somnolence. The plasma thalidomide levels on D7 and D14 were 0.82 ± 0.4μg/ml and 0.79 ± 0.3 μg/ml in group 1 and 0.82 ± 0.4 and 1.55 ± 1.0 in group 2, respectively. CONCLUSIONS: In this sample, the multidrug therapy had no effect on the clinical evolution, incidence of adverse events and plasma thalidomide levels.

Agranulocytosis induced by multidrug therapy in leprosy treatment: a case report

Multidrug therapy (WHO/MDT) in multibacillary leprosy consists of treatment with rifampicin, dapsone andclofazimine. However, adverse effects can cause the patient to abandon treatment. We report on a patient whopresented agranulocytosis and hemolytic anemia associated with this treatment regime. We also examined theimportance of laboratory exams for diagnosis and follow-up of the patient, and for early detection of adverse effects, with a view to improving adhesion to treatment and contributing to the eradication of Hansen’s disease as a public health issue.

Características da reação tipo 1 e associação com vírus B e C da hepatite na hanseníase / Type 1 reaction in leprosy: characteristics and association with hepatitis B and C viruses

O episódio reacional tipo 1 ou reação reversa é ocorrência inflamatória aguda que atinge a pele e nervos periféricos, encontrada em até 30 por cento dos pacientes com hanseníase, sendo causa comum de incapacidade física. Fatores de risco associados incluem uso de poliquimioterapia e infecções virais. Neste estudo, foram avaliados 620 pacientes com hanseníase. Reação reversa foi diagnosticada em 121 (19,5 por cento) casos, sendo mais freqüente nos indivíduos borderlines (48 por cento). Início da poliquimioterapia foi considerado fator de risco para reação reversa, com 52 por cento dos casos apresentando o primeiro episódio neste momento. Neurite foi documentada em 73 por cento dos casos. A presença de vírus B ou C da hepatite foi documentada em 9 por cento de 55 pacientes com reação reversa e em nenhum dos 57 pacientes sem reação (p = 0, 026; teste exato de Fisher), sugerindo possível papel destes agentes como fatores de risco para desenvolvimento de reação reversa na hanseníase.

Type 1 reaction or reversal reaction is an acute inflammatory episode in the skin and peripheral nerves that is found in up to 30 percent of leprosy patients and commonly causes physical disabilities. Multidrug chemotherapy and viral infections are associated risk factors. In this study, 620 leprosy patients were evaluated. Reversal reactions were diagnosed in 121 cases (19.5 percent) and were most frequently found in borderline patients (48 percent). Starting on multidrug chemotherapy was considered to be a risk factor for reversal reaction: 52 percent of the cases presented their first episode at this time. Neuritis was found in 73 percent of the cases. The presence of hepatitis B or C virus was documented in 9 percent of the 55 patients with reversal reaction, while it was not detected in any of the 57 patients without reaction (p = 0.026, Fisher’s exact test). This suggests that these agents may have a role as risk factors for developing reversal reactions.

Vasculonecrotic reactions in leprosy

Multibacillary, lepromatous or borderline leprosy patients may present two types of vasculonecrotic reactions: Lucio phenomenon and that associated with erythema nodosum leprosum. Despite they can be distinguished through clinical and histological characteristics; both are often used as synonyms. It is said that leprosy reaction should be properly classified for therapeutic reasons, since it is well known that in Lucio phenomenon there is not a good response to thalidomide. The authors reported two cases of vasculonecrotic phenomena in lepromatous leprosy sharing clinical and histopathological characteristics of both reaction subtypes. The findings may indicate the spectral nature of the reaction phenomena in leprosy and emphasize the importance of the clinic-pathological correlation for proper classification. Our findings may contribute to the understanding of leprosy reactions pathogenesis, broaden the knowledge about their outcome with standard treatment, and provide the scientific background to design better therapeutic strategies for these complications.

Double-blind trial of the efficacy of pentoxifylline vs thalidomide for the treatment of type II reaction in leprosy

Type II reaction in leprosy, or erythema nodosum leprosum (ENL), is often characterized by severe clinical symptoms together with nerve function impairment leading to permanent disabilities. Thalidomide has been shown to be a highly effective drug for the treatment of ENL. It is, however, contraindicated for women of childbearing age due to its teratogenicity. On the other hand, pentoxifylline, used to treat hypercoagulable states, is not teratogenic and, like thalidomide, can inhibit the synthesis of tumor necrosis factor-a and other cytokines. In the present randomized double-blind clinical study we compared the effectiveness of orally administered pentoxifylline vs thalidomide in treating type II reaction in 44 patients. Daily doses of 300 mg thalidomide or 1.2 g pentoxifylline were administered for 30 days to multibacillary leprosy patients undergoing type II reaction. Randomly chosen patients were included in the study before, during, and after specific multidrug therapy. Clinical evaluations were performed on the 1st, 7th, 14th, 21st, and 30th days of treatment and laboratory tests were carried out on the 1st and 30th days. As expected, overall, thalidomide proved to be more effective in the treatment of type II leprosy reaction. Nevertheless, continuous treatment with pentoxifylline was effective in relieving the clinical signs of ENL, especially limb edema and systemic symptoms, in 62.5 percent of the patients.

Estudio retrospectivo a 10 años (1996-2005) de enfermos con lepra - Hospital F. J. Muñiz / Retrospective study to 10 years (1996-2005) of patients with leprosy - Hospital F. J. Muñiz

Antecedentes. La lepra es, en nuestro país, una enfermedad de baja endemia. Sin embargo, en los grandes centros poblacionales, como nuestra ciudad, se suelen concentrar gran cantidad de pacientes. Objetivos. Caracterizar el perfil epidemiológico de la población de enfermos de lepra que ha acudido al hospital. Determinar la distribución de los enfermos por sexo, edad al momento de la consulta, foma clínica, episodios reaccionales, talidomido-dependencia, complicaciones y cantidad de casos nuevos por año. Diseño. Estudio observacional-descriptivo, retrospectivo, de 10 años. Método. Se incluyeron 276 pacientes, sólo aquellos que iniciaron tratamiento durante el período comprendido entre enero de 1996 y diciembre de 2005. Se realizó el análisis estadístico de las variables estudiadas con intervalos de confianza del 95%. Resultados y conclusiones. La población estudiada fue de adultos, mayoritariamente multibacilares, con predominio del sexo masculino (relación 1,8 a 1) y edad media de 48 años. Solo el 3.26% se presentó con una forma de inicio, lo que evidencia el diagnóstico tardio de la enfermedad. El 39,85% de los pacientes desarrolló episodios reaccionales, que fueron más frecuentes en los enfermeros lepromatosos. En estos pacientes, el eritema nudoso (94,19%) fue el más común de los episodios reaccionales tipo 2. La talidomido-dependencia se constató en el 54.22% de estos pacientes. Hay una leve tendencia declinante en los casos nuevos detectados cada año.