Systematic Review of Survival Analysis in Leprosy Studies-Including the Following Outcomes: Relapse, Impairment of Nerve Function, Reactions and Physical Disability.

Leprosy is a public health problem in South American, African and Oceanian countries. National programs need to be evaluated, and the survival analysis model can aid in the construction of new indicators. The aim of this study was to assess the period of time until the outcomes of interest for patients with or exposed to leprosy by means of survival analysis surveys. This review researched articles using the databases of PubMed, Science Direct, Scopus, Scielo and BVS published in English and Portuguese. Twenty-eight articles from Brazil, India, Bangladesh, the Philippines and Indonesia were included. The Kaplan-Meier method, which derives the log-rank test, and Cox's proportional hazards regression, which obtains the hazard ratio, were applied. The mean follow-up until the following outcomes were: (I) leprosy (2.3 years) in the population who were exposed to it, (II) relapse (5.9 years), (III) clinical manifestations before, during and after treatment-nerve function impairment (5.2 years), leprosy reactions (4.9 years) and physical disability (8.3 years) in the population of patients with leprosy. Therefore, the use of survival analysis will enable the evaluation of national leprosy programs and assist in the decision-making process to face public health problems.

Leprosy and cutaneous leishmaniasis affecting the same individuals: A retrospective cohort analysis in a hyperendemic area in Brazil.

BACKGROUND: Leprosy and cutaneous leishmaniasis (CL) are neglected tropical diseases (NTDs) affecting the skin. Their control is challenging but the integration of skin NTDs control programs is recommended to improve timely detection and treatment. However, little is known about the occurrence of leprosy and CL in the same individuals, and what are the characteristics of such patients. This study aimed to identify and characterize patients diagnosed with both leprosy and CL (i.e., outcome) in the hyperendemic state of Mato Grosso, Brazil. Also, we investigated the demographic risk factors associated with the period between the diagnosis of both diseases. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective cohort study was conducted with patients diagnosed between 2008 and 2017. From the leprosy (n = 28,204) and CL (n = 24,771) databases of the national reporting system, 414 (0.8%; 414/52,561) patients presenting both diseases were identified through a probabilistic linkage procedure. This observed number was much higher than the number of patients that would be expected by chance alone (n = 22). The spatial distribution of patients presenting the outcome was concentrated in the North and Northeast mesoregions of the state. Through survival analysis, we detected that the probability of a patient developing both diseases increased over time from 0.2% in the first year to 1.0% within seven years. Further, using a Cox model we identified male sex (HR: 2.3; 95% CI: 1.7-2.9) and low schooling level (HR: 1.5; 95% CI: 1.2-1.9) as positively associated with the outcome. Furthermore, the hazard of developing the outcome was higher among individuals aged 40-55 years. CONCLUSIONS/SIGNIFICANCE: Leprosy and CL are affecting the same individuals in the area. Integration of control policies for both diseases will help to efficiently cover such patients. Measures should be focused on timely diagnosis by following-up patients diagnosed with CL, active case detection, and training of health professionals.

[Factors associated with timing of lepra reactions in a cohort from 2008 to 2016 in Rondônia, Amazon Region, Brazil]. / Fatores associados ao tempo de ocorrência das reações hansênicas numa coorte de 2008 a 2016 em Rondônia, Região Amazônica, Brasil.

The clinical management of leprosy patients poses a specific challenge, namely lepra reactions. This non-concurrent cohort study aimed to analyze the timing of the first lepra reaction during and after polychemotherapy (PCT) and associated factors. A total of 1,621 patients were assessed (PB = 8.9% and MB = 91.1%) from 2008 to 2016, reported to the System of Reaction States in Leprosy (SisReação/RO) database. Reactions occurred predominantly during PCT (997; 61.5%) and less frequently only after PCT (624; 38.5%). Earliness of the reaction after diagnosis was analyzed with Kaplan-Meier survival curves, with comparison between the PB and MB groups using the Mantel-Cox log-rank test. Univariate and multivariate Cox regression models were constructed to identify factors associated with occurrence of lepra reactions (hazard ratio) and the corresponding 95%CI. The multivariate model included variables with p-values < 0.20 in the univariate analysis. PB patients developed reactions earlier than MB patients. Other characteristics were associated with earlier reactions: female gender and negative smear microscopy. In the aggregate period (during and after PCT), PB presented 24% higher risk of lepra reaction than MB patients, and negative smear microscopy increased this risk by 40% compared to positive smear microscopy. During and after PCT, PB presented 1.3 and 1.6 times the risk, respectively, of reactions when compared to MB patients. We thus recommend prioritizing surveillance of lepra reactions during and after PCT as measures to prevent physical disabilities and to improve quality of life for persons with leprosy.

O manejo clínico de pacientes com hanseníase apresenta um desafio particular que são as reações. O objetivo deste estudo de coorte não concorrente foi analisar o tempo e fatores associados à ocorrência da primeira reação durante e após o tratamento da poliquimioterapia (PQT). Avaliou-se 1.621 pacientes paucibacilares (PB = 8,9%) e multibacilares (MB = 91,1%) de 2008 a 2016 notificados no Sistema de Estados Reacionais em Hanseníase/Rondônia (SisReação/RO). Prevaleceu a ocorrência durante o tratamento da PQT = 997 (61,5%), e 624 (38,5%) somente após o PQT. A precocidade da reação, a partir do diagnóstico, foi analisada por meio de curvas de sobrevida de Kaplan-Meier e comparadas entre os grupos PB e MB, usando o teste de log-rank de Mantel-Cox; e foram construídos modelos de regressão de Cox univariada e multivariada para identificar os fatores associados à ocorrência da reação (hazard ratio) e os correspondentes IC95%. No modelo multivariado foram incluídas variáveis com valores de p < 0,2 na análise univariada. Os PB desenvolveram reação de forma mais precoce do que os MB. Outras características associaram-se à reação em menor tempo: sexo feminino e baciloscopia negativa. No período agregado (durante e após a PQT), os pacientes PB apresentaram risco 24% maior de reação do que os MB e aqueles com baciloscopia negativa aumentaram este risco em 40% comparado à baciloscopia positiva. Durante e após a PQT, os PB apresentaram 1,3 e 1,6 vezes maior risco de ocorrência da reação dos pacientes MB. Dessa forma, recomendamos priorizar ações de vigilância para reações hansênicas durante e após a PQT como medidas de prevenção de incapacidades físicas e de melhoria na qualidade de vida das pessoas acometidas pela hanseníase.

La gestión clínica de pacientes con hanseniasis presenta un desafío particular que son las reacciones. El objetivo de este estudio de cohorte no concurrente fue analizar el tiempo y factores asociados a la ocurrencia de la primera reacción durante y tras el tratamiento de la poliquimioterapia (PQT). Se evaluó a 1621 pacientes (PB = 8,9% y MB = 91,1%) de 2008 a 2016, notificados en el Sistema de Estados Reaccionarios en Lepra (SisReação/RO). Prevaleció la ocurrencia durante la PQT = 997 (61,5%), y 624 (38,5%) solamente tras la PQT. La precocidad de la reacción a partir del diagnóstico se analizó mediante curvas de supervivencia de Kaplan-Meier y se compararon entre los grupos PB y MB, usando el test de log-rank de Mantel-Cox; asimismo, se construyeron modelos de regresión univariada y multivariada de Cox para identificar los factores asociados con la ocurrencia de la reacción (cociente de riesgos) y los correspondientes IC95%. En el modelo multivariado se incluyeron las variables con valores de p < 0,2 en el análisis univariado. Los PB desarrollaron una reacción de forma más precoz que los MB. Otras características se asociaron a la reacción en menor tiempo: sexo femenino y baciloscopia negativa. En el período agregado (durante y tras PQT), los PB presentaron un riesgo un 24% mayor de reacción que los multibacilares y la baciloscopia negativa aumentó este riesgo en un 40%, comparado con la baciloscopia positiva. Durante y tras el tratamiento PQT, los PB presentaron 1,3 y 1,6 veces el riesgo de ocurrencia de la reacción de los pacientes MB. De esa forma, recomendamos priorizar acciones de vigilancia para reacciones hansénicas durante y tras PQT, como medidas de prevención de discapacidades físicas, así como de mejoría en la calidad de vida de personas afectadas por la hanseniasis.

Fatores associados ao tempo de ocorrência das reações hansênicas numa coorte de 2008 a 2016 em Rondônia, Região Amazônica, Brasil / Factors associated with timing of lepra reactions in a cohort from 2008 to 2016 in Rondônia, Amazon Region, Brazil / Factores asociados al tiempo de ocurrencia de las reacciones hansénicas en una cohorte de 2008 a 2016 en Rondonia, Región Amazónica, Brasil

O manejo clínico de pacientes com hanseníase apresenta um desafio particular que são as reações. O objetivo deste estudo de coorte não concorrente foi analisar o tempo e fatores associados à ocorrência da primeira reação durante e após o tratamento da poliquimioterapia (PQT). Avaliou-se 1.621 pacientes paucibacilares (PB = 8,9%) e multibacilares (MB = 91,1%) de 2008 a 2016 notificados no Sistema de Estados Reacionais em Hanseníase/Rondônia (SisReação/RO). Prevaleceu a ocorrência durante o tratamento da PQT = 997 (61,5%), e 624 (38,5%) somente após o PQT. A precocidade da reação, a partir do diagnóstico, foi analisada por meio de curvas de sobrevida de Kaplan-Meier e comparadas entre os grupos PB e MB, usando o teste de log-rank de Mantel-Cox; e foram construídos modelos de regressão de Cox univariada e multivariada para identificar os fatores associados à ocorrência da reação (hazard ratio) e os correspondentes IC95%. No modelo multivariado foram incluídas variáveis com valores de p < 0,2 na análise univariada. Os PB desenvolveram reação de forma mais precoce do que os MB. Outras características associaram-se à reação em menor tempo: sexo feminino e baciloscopia negativa. No período agregado (durante e após a PQT), os pacientes PB apresentaram risco 24% maior de reação do que os MB e aqueles com baciloscopia negativa aumentaram este risco em 40% comparado à baciloscopia positiva. Durante e após a PQT, os PB apresentaram 1,3 e 1,6 vezes maior risco de ocorrência da reação dos pacientes MB. Dessa forma, recomendamos priorizar ações de vigilância para reações hansênicas durante e após a PQT como medidas de prevenção de incapacidades físicas e de melhoria na qualidade de vida das pessoas acometidas pela hanseníase.

The clinical management of leprosy patients poses a specific challenge, namely lepra reactions. This non-concurrent cohort study aimed to analyze the timing of the first lepra reaction during and after polychemotherapy (PCT) and associated factors. A total of 1,621 patients were assessed (PB = 8.9% and MB = 91.1%) from 2008 to 2016, reported to the System of Reaction States in Leprosy (SisReação/RO) database. Reactions occurred predominantly during PCT (997; 61.5%) and less frequently only after PCT (624; 38.5%). Earliness of the reaction after diagnosis was analyzed with Kaplan-Meier survival curves, with comparison between the PB and MB groups using the Mantel-Cox log-rank test. Univariate and multivariate Cox regression models were constructed to identify factors associated with occurrence of lepra reactions (hazard ratio) and the corresponding 95%CI. The multivariate model included variables with p-values < 0.20 in the univariate analysis. PB patients developed reactions earlier than MB patients. Other characteristics were associated with earlier reactions: female gender and negative smear microscopy. In the aggregate period (during and after PCT), PB presented 24% higher risk of lepra reaction than MB patients, and negative smear microscopy increased this risk by 40% compared to positive smear microscopy. During and after PCT, PB presented 1.3 and 1.6 times the risk, respectively, of reactions when compared to MB patients. We thus recommend prioritizing surveillance of lepra reactions during and after PCT as measures to prevent physical disabilities and to improve quality of life for persons with leprosy.

La gestión clínica de pacientes con hanseniasis presenta un desafío particular que son las reacciones. El objetivo de este estudio de cohorte no concurrente fue analizar el tiempo y factores asociados a la ocurrencia de la primera reacción durante y tras el tratamiento de la poliquimioterapia (PQT). Se evaluó a 1621 pacientes (PB = 8,9% y MB = 91,1%) de 2008 a 2016, notificados en el Sistema de Estados Reaccionarios en Lepra (SisReação/RO). Prevaleció la ocurrencia durante la PQT = 997 (61,5%), y 624 (38,5%) solamente tras la PQT. La precocidad de la reacción a partir del diagnóstico se analizó mediante curvas de supervivencia de Kaplan-Meier y se compararon entre los grupos PB y MB, usando el test de log-rank de Mantel-Cox; asimismo, se construyeron modelos de regresión univariada y multivariada de Cox para identificar los factores asociados con la ocurrencia de la reacción (cociente de riesgos) y los correspondientes IC95%. En el modelo multivariado se incluyeron las variables con valores de p < 0,2 en el análisis univariado. Los PB desarrollaron una reacción de forma más precoz que los MB. Otras características se asociaron a la reacción en menor tiempo: sexo femenino y baciloscopia negativa. En el período agregado (durante y tras PQT), los PB presentaron un riesgo un 24% mayor de reacción que los multibacilares y la baciloscopia negativa aumentó este riesgo en un 40%, comparado con la baciloscopia positiva. Durante y tras el tratamiento PQT, los PB presentaron 1,3 y 1,6 veces el riesgo de ocurrencia de la reacción de los pacientes MB. De esa forma, recomendamos priorizar acciones de vigilancia para reacciones hansénicas durante y tras PQT, como medidas de prevención de discapacidades físicas, así como de mejoría en la calidad de vida de personas afectadas por la hanseniasis.

Disability progression among leprosy patients released from treatment: a survival analysis.

BACKGROUND: Leprosy can be cured, but physical disability (PD) as a result of the infection can progress in the post-release from treatment phase. This study evaluated the likelihood of, and factors associated with, the progression of the PD grade post-release from treatment among leprosy patients treated in Cáceres-MT, Brazil in the period 2000 to 2017. METHODS: A retrospective cohort study and survival analysis were performed in the hyperendemic municipality of Cáceres in the state of Mato Grosso. The study population consisted of newly diagnosed leprosy patients released from treatment between January 1, 2000 and December 31, 2017. The main outcome was the progression of the PD grade with regard to probability and time; and the evaluated covariates included clinical, operational and demographic variables. The Cox proportional risk model was used to estimate the risk ratio (Hazard Ratios) of the covariates. Both an univariate and a multivariate analysis were implemented, with 95% confidence intervals. RESULTS: The mean time for progression of the PD grade was 162 months for PB and 151 months for MB leprosy patients. The survival curve showed that 15 years after the release from treatment, the probability of PD grade progression was 35%, with no difference between PB and MB or age groups. Leprosy reactions and registered medical complaints of any kind during treatment were identified as risk factors with Hazard Ratios of 1.6 and 1.8 respectively. CONCLUSIONS: People released from treatment as cured of leprosy are susceptible to worsening of the PD, especially those who have had complications during multi-drug therapy treatment. This indicates that leprosy patients should be periodically monitored, even after the successful completion of multidrug therapy.

The bidirectional association between type 2 diabetes and psoriasis: Two retrospective cohort studies.

BACKGROUND: Inflammation plays a crucial role in both type 2 diabetes mellitus (T2DM) and psoriasis pathogenesis; thus, a bidirectional association between them is likely suspected. AIMS: We investigated the possible bidirectional association between T2DM and psoriasis. METHODS: Using the Taiwan National Health Insurance Research Database, we conducted two retrospective cohort studies. The analysis of psoriasis onset in relation to T2DM status included 31,697 patients with diabetes and 126,788 nondiabetic control subjects (Analysis 1). The analysis of T2DM onset in relation to psoriasis status included 1,947 psoriatic patients and 7,788 nonpsoriatic control subjects (Analysis 2). The follow-up period was from 2000 to the date of the outcome of interest, date of death, or December 31, 2013. Cox proportional models were used to estimate the relative hazards. RESULTS: In Analysis 1, Kaplan-Meier (KM)-based cumulative incidence of psoriasis was higher in the T2DM cohort than that in the non-T2DM cohort (1.2% vs. 0.7%). The covariate-adjusted hazard ratio (HR) was 1.40 [95% confidence interval (CI), 1.20-1.63] for patients with T2DM. Analysis 2 revealed KM-based cumulative T2DM incidences of 18.7% and 13.1% in psoriatic and nonpsoriatic subjects, respectively. The adjusted HR for incident T2DM was higher in patients with psoriasis (1.38; 95% CI, 1.20-1.58). LIMITATION: This article may not represent the population worldwide and patient selection bias may exist. CONCLUSION: Our results provide evidence for a bidirectional T2DM-psoriasis association. T2DM and psoriasis are common worldwide; thus, our findings have public health implications for the early identification and management of these comorbid diseases.

Assisted reproductive technology treatment and risk of ovarian cancer-a nationwide population-based cohort study.

STUDY QUESTION: Does hormone stimulation during assisted reproductive technology (ART) treatment increase the risk of ovarian cancer? SUMMARY ANSWER: No increased risk of ovarian cancer was found among ART-treated women, with the exception of ART-treated women with endometriosis. WHAT IS KNOWN ALREADY: Previous studies on the association between ovarian stimulation during ART and ovarian cancer have shown conflicting results. The risk of ovarian cancer varies according to the cause of infertility, and only a few studies on ART treatment and risk of ovarian cancer have had sufficient data to address this issue. Endometriosis has been linked to an increased risk of ovarian cancer. STUDY DESIGN, SIZE, DURATION: Women undergoing ART treatment during 1994-2015 were registered in the Danish IVF register. Data were linked with data from the Danish Cancer Register and socio-demographic population registers using an individual person identification number assigned to people residing in Denmark. PARTICIPANTS/MATERIALS, SETTING, METHODS: All women undergoing ART treatment were age-matched with a random sample of the female background population and followed for up to 22 years. After relevant exclusions, the population consisted of 58 472 ART-treated women and 625 330 untreated women, all with no previous malignancies. Ovarian cancer risk was assessed using multivariable cox regression analyses with adjustment for educational level, marital status, parity and treatment year. Results are shown as hazard ratios (HRs) with corresponding CIs. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 393 (0.06%) women were diagnosed with ovarian cancer during follow-up (mean 9.7 years). Women treated with ART had an increased risk of ovarian cancer (HR 1.20, 95% CI 1.10-1.31), which diminished over time. The increased risk was apparent among women with female factor infertility (HR 1.36, 95% CI 1.25-1.48), whereas no female factor infertility was associated with a lower risk (HR 0.87, 95% CI 0.76-1.00). The risk was increased among women with endometriosis (HR 3.78, 95% CI 2.45-5.84), whereas no increased risk was found among ART-treated women with polycystic ovary syndrome, other female causes of infertility and unexplained infertility. LIMITATIONS, REASONS FOR CAUTION: The association between ART treatment and ovarian cancer is likely influenced by increased detection due to multiple ultrasound scans during ART treatment. WIDER IMPLICATIONS OF THE FINDINGS: Undergoing ART treatment without the presence of endometriosis was not associated with an increased risk of ovarian cancer, which is reassuring. Whether ART treatment increases the risk of ovarian cancer among women with endometriosis needs further investigation. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a PhD grant to D.V. from the Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Funding for establishing the Danish National ART-couple II cohort was achieved from Ebba Rosa Hansen Foundation. The funders had no influence on data collection, analyses or results presented. The authors have no conflicts of interest to declare.

BCG vaccine and leprosy household contacts: Protective effect and probability to becoming sick during follow-up.

BACKGROUND: Immunoprophylaxis with Bacillus Calmette-Guérin (BCG) vaccine is still the most effective intervention in the prevention of leprosy among household contacts (HHCs) of leprosy patients. METHODS: A retrospective cohort study using data of 5.061 HHCs for a period of 16 years (follow-up of 7 years per leprosy HHCs), evaluating the occurrence of disease as the main outcome and the presence or absence of BCG scars verified at the first evaluation. Statistical analyzes were performed using the relative risk, hazard ratio and survival curves by Kaplan-Meier test. RESULTS: A total of 92 contacts sickened, of which 41.3% (38/92) in the first year and 58.7% (54/92) in the course of the other years of follow-up. Of those who became sick, 62% (57/92) developed borderline tuberculoid (BT). The additional protective effect occurred for those who had 2 BCG scars at the first follow-up assessment (Relative Risk: 0.41; p = 0.007) when compared to those not previously exposed to the vaccine. The number of BCG scars examined at the first assessment (t0 = time zero) affected the occurrence of the outcome evidenced by the difference in survival curves throughout the follow-up (Log Rank, p = 0.041; Breslow, p = 0.012; Tarone-Ware, p = 0.020). Leprosy HHCs with 0 BCG scar at time zero (t0) have a shorter survival time (average time of 22 months between t0 and outcome) when compared to those with 2 BCG scars (average time of 36 months between t0 and outcome). CONCLUSIONS: Vaccination of healthy individuals without signs and symptoms of leprosy is extremely important because BCG vaccine has an additional protective effect in those cases with 2 BCG scars throughout follow-up. Reducing the risk of leprosy HHCs becoming sick depends on preventive actions such as immunoprophylaxis and index cases treatment.

Determining the best percent-predicted equation for estimated VO2 peak by a 1-km moderate perceptually-regulated treadmill walk to predict mortality in outpatients with cardiovascular disease.

OBJECTIVES: To determine the prognostic ability of established percent-predicted equations of peak oxygen consumption (%PRED) estimated by a moderate submaximal walking test in a large cohort of outpatients with cardiovascular disease (CVD). DESIGN: Population-based prospective study. METHODS: A total of 1442 male patients aged 25-85 years at baseline, underwent a moderate perceptually-regulated (11-13 on the 6-20 Borg scale) treadmill walk (1k-TWT) for peak oxygen consumption estimation (VO2 peak). %PRED was derived from ACSM, Ades et al, Morris et al, and the Wasserman/Hansen equations, and their prognostic performance was assessed. Overall mortality was the end point. Participants were divided into quartiles of %PRED, and mortality risk was estimated using a Cox regression model. RESULTS: During a median 8.2year follow-up, 167 all-cause deaths occurred. The Wasserman/Hansen equation provided the highest prognostic value. Mortality rate was lower across increasing quartiles of %PRED. Compared to the first quartile, after adjustment for confounders, the mortality risk decreased for the second, third, and fourth quartiles, with HRs of 0.75 (95% CI 0.44-1.29, p=0.29), 0.67 (95% CI 0.38-1.18, p=0.17), and 0.37 (95% CI 0.10-0.78, p=0.009), respectively (p for trend <0.0001). Each 1% increase in %PRED conferred a 4% improvement in survival. CONCLUSIONS: The percent-predicted VO2 peak determined by Wasserman/Hansen equations applied to the 1k-TWT is inversely and significantly related to survival in cardiac outpatients. The 1k-TWT is a simple and useful tool for stratifying mortality risk in patients participating in secondary prevention programs.

High mortality associated with retreatment of tuberculosis in a clinic in Kampala, Uganda: a retrospective study.

The World Health Organization recommends for tuberculosis retreatment a regimen of isoniazid (H), rifampicin (R), ethambutol (E), pyrazinamide (Z), and streptomycin (S) for 2 months, followed by H, R, E, and Z for 1 month and H, R, and E for 5 months. Using data from the National Tuberculosis and Leprosy Program registry, this study determined the long-term outcome under programmatic conditions of patients who were prescribed the retreatment regimen in Kampala, Uganda, between 1997 and 2003. Patients were traced to determine their vital status; 62% (234/377) patients were found dead. Having ≤ 2 treatment courses and not completing retreatment were associated with mortality in adjusted analyses.

Progression of leprosy disability after discharge: is multidrug therapy enough?

OBJECTIVE: To evaluate the risk factors related to worsening of physical disabilities after treatment discharge among patients with leprosy administered 12 consecutive monthly doses of multidrug therapy (MDT/WHO). METHODS: Cohort study was carried out at the Leprosy Laboratory in Rio de Janeiro, Brazil. We evaluated patients with multibacillary leprosy treated (MDT/WHO) between 1997 and 2007. The Cox proportional hazards model was used to estimate the relationship between the onset of physical disabilities after release from treatment and epidemiological and clinical characteristics. RESULTS: The total observation time period for the 368 patients was 1 570 person-years (PY), averaging 4.3 years per patient. The overall incidence rate of worsening of disability was 6.5/100 PY. Among those who began treatment with no disability, the incidence rate of physical disability was 4.5/100 PY. Among those who started treatment with Grade 1 or 2 disabilities, the incidence rate of deterioration was 10.5/100 PY. The survival analysis evidenced that when disability grade was 1, the risk was 1.61 (95% CI: 1.02-2.56), when disability was 2, the risk was 2.37 (95% CI 1.35-4.16), and when the number of skin lesions was 15 or more, an HR = 1.97 (95% CI: 1.07-3.63). Patients with neuritis showed a 65% increased risk of worsening of disability (HR = 1.65 [95% CI: 1.08-2.52]). CONCLUSION: Impairment at diagnosis was the main risk factor for neurological worsening after treatment/MDT. Early diagnosis and prompt treatment of reactional episodes remain the main means of preventing physical disabilities.

Preventing nerve function impairment in leprosy: validation and updating of a prediction rule.

BACKGROUND: To validate and update a prediction rule for estimating the risk of leprosy-related nerve function impairment (NFI). METHODOLOGY/PRINCIPAL FINDINGS: Prospective cohort using routinely collected data, in which we determined the discriminative ability of a previously published rule and an updated rule with a concordance statistic (c). Additional risk factors were analyzed with a Cox proportional hazards regression model. The population consisted of 1,037 leprosy patients newly diagnosed between 2002 and 2003 in the health care facilities of the Rural Health Program in Nilphamari and Rangpur districts in northwest Bangladesh. The primary outcome was the time until the start of treatment. An NFI event was defined as the decision to treat NFI with corticosteroids after diagnosis. NFI occurred in 115 patients (13%; 95% confidence interval 11%-16%). The original prediction rule had adequate discriminative ability (c = 0.79), but could be improved by substituting one predicting variable: 'long-standing nerve function impairment at diagnosis' by 'anti-PGL-I antibodies'. The adjusted prediction rule was slightly better (c = 0.81) and identified more patients with NFI (80%) than the original prediction rule (72%). CONCLUSIONS/SIGNIFICANCE: NFI can well be predicted by using the risk variables 'leprosy classification' and 'anti-PGL-I antibodies'. The use of these two variables that do not include NFI offer the possibility of predicting NFI, even before it occurs for the first time. Surveillance beyond the treatment period can be targeted to those most likely to benefit from preventing permanent disabilities.

HIV-M. leprae interaction: can HAART modify the course of leprosy?

It has been speculated that, as seen in tuberculosis, human immunodeficiency virus (HIV) and Mycobacterium leprae (M. leprae) co-infection may exacerbate the pathogenesis of leprosy lesions and/or lead to increased susceptibility to leprosy. However, to date, HIV infection has not appeared to increase susceptibility to leprosy. In contrast, initiation of antiretroviral treatment (ART) has been reported to be associated with anecdotal activation of M. leprae infection and exacerbation of existing leprosy lesions. To determine whether ART is associated with worsening of the manifestations of leprosy, a cohort of leprosy patients recruited between 1996 and 2006 at the Oswaldo Cruz Foundation (FIOCRUZ) Leprosy Outpatient Clinic in Rio de Janeiro, Brazil, was studied longitudinally. ART treatment of HIV/leprosy co-infection was associated with the tuberculoid type, paucibacillary disease, and lower bacillary loads. CD4 lymphocyte counts were higher among HIV/leprosy patients at the time of leprosy diagnosis, while viral loads were lower compared with the time of HIV diagnosis. The conclusion was that ART and immune reconstitution were critical factors driving the development and/or clinical appearance of leprosy lesions.

Age is an important risk factor for onset and sequelae of reversal reactions in Vietnamese patients with leprosy.

BACKGROUND: Reversal, or type 1, leprosy reactions (T1Rs) are acute immune episodes that occur in skin and/or nerves and are the leading cause of neurological impairment in patients with leprosy. T1Rs occur mainly in patients with borderline or multibacillary leprosy, but little is known about additional risk factors. METHODS: We enrolled 337 Vietnamese patients with leprosy in our study, including 169 subjects who presented with T1Rs and 168 subjects with no history of T1Rs. A multivariate analysis was used to determine risk factors for T1R occurrence, time to T1R onset after leprosy diagnosis, and T1R sequelae after treatment. RESULTS: Prevalence of T1Rs was estimated to be 29.1%. Multivariate analysis identified 3 clinical features of leprosy associated with T1R occurrence. Borderline leprosy subtype (odds ratio, 6.3 [95% confidence interval, 2.9-13.7] vs. polar subtypes) was the major risk factor; 2 other risk factors were positive bacillary index and presence of > 5 skin lesions. In addition, age at leprosy diagnosis was a strong independent risk factor for T1Rs (odds ratio, 2.4 [95% confidence interval, 1.3-4.4] for patients aged > or = 15 years old vs. < 15 years old). We observed that T1Rs with neuritis occurred significantly earlier than pure skin-related T1Rs. Sequelae were present in 45.1% of patients who experienced T1Rs after treatment. The presence of a motor or sensory deficit at T1R onset was an independent risk factor for sequelae, as was the age at diagnosis of leprosy (odds ratio, 4.4 [95% confidence interval, 1.7-11.6] for patients > or = 20 years old vs. < 20 years old). CONCLUSION: In addition to specific clinical features of leprosy, age is an important risk factor for both T1R occurrence and sequelae after treatment for T1Rs.

Risk factors for developing leprosy--a population-based cohort study in Indonesia.

We identified risk factors associated with increased yearly incidence rates of leprosy in five island populations. Age, sex, household size and Mycobacterium leprae-specific antibodies as well as contact factors were studied. Of 94 index patients (patients diagnosed in 2000), 43 (46%) were classified as multibacillary (MB), 17 (19%) were seropositive for PGL-1 [corrected] antibodies and 6 (7%) had M. leprae DNA in nasal swabs as determined by polymerase chain reaction (PCR) testing. All PCR positive patients were also seropositive. Forty-four of 4903 initially symptom free persons developed leprosy within 4 years, giving an incidence rate of 298 per 1000 person-years. Men had a 22 times higher risk [95% confidence interval (CI): 1.2-4.1] of developing leprosy than women. People living in households with more than 7 members had a 3.1 times higher risk (95% CI: 1.3-7.3) than households of 1-4 members. Persons who were seropositive in 2000 had a 3.8 times higher risk (95% CI: 1.1-12.6) than seronegative persons. Household contacts of MB patients had an adjusted hazard ratio (aHR) of 4.6 (95% CI: 1.6-12.9) and household contacts of PCR positive patients an aHR of 9.36 (95% CI: 2.5-34.9) compared with non-contacts. Patients with PCR positive nasal swabs, suggesting nasal excretion of M. leprae, are probably the patients with the highest transmission potential. Since all index patients who were PCR positive were also seropositive, serology seems an adequate tool to identify these patients. Preventing seropositive persons from becoming seropositive and infectious patients might break the chain of transmission.

Incidence of ocular morbidity among multibacillary leprosy patients during a 2 year course of multidrug therapy.

AIM: To evaluate the incidence of and risk factors for ocular complications in multibacillary (MB) leprosy patients during their 2 year, fixed duration, multidrug therapy (MDT). METHODS: Periodic eye examinations were conducted prospectively on a cohort of 301 consecutive newly diagnosed MB patients every 6 months during their 2 year course of MDT. Incidence of ocular pathology was calculated as the number of events per person year of event free follow up of patients who did not have the specific finding at baseline. RESULTS: 292 (97%) patients had one or more follow up visits. The incidence of lagophthalmos was 1.2%/patient year (95% CI 0.5% to 2.8%); corneal opacity was 7.4%/patient year (95% CI 5.1% to 10.6%); uveal involvement was 5.1%/patient year (95% CI 3.3% to 7.8%), and cataract that reduced vision to 6/18 or less was seen in 4.3%/patient year (95% CI 2.7% to 6.9%) of patients. Overall, 23 individuals (5.8%/patient year, 95% CI 3.9 to 8.8) developed leprosy related potentially blinding pathology during the 2 years of MDT. CONCLUSIONS: Approximately 20% of patients with MB leprosy can be expected to develop ocular complications of leprosy during a 2 year course of MDT, many (11%) of which are potentially vision threatening. Ophthalmological monitoring to detect and treat ocular complications at defined intervals during MDT is indicated.

Outcome and prognostic factors in non-ambulatory Hansen Type I intervertebral disc extrusions: 308 cases.

Thoracolumbar intervertebral disc disease is the most common cause of caudal paresis in dogs. Whilst the pathogenesis of the extrusion has been widely studied, treatment protocols and prognostic factors relating to outcome remain controversial. Recent studies have examined a multitude of factors relating to time to regain ambulation after decompressive surgery. Most intervertebral disc herniations occur in the thoracolumbar region, causing upper motor neuron signs in the rear limbs, which are thought to have a more favourable prognosis compared to the lower motor neuron signs created by herniation of an intervertebral disc in the caudal lumbar region. Due to the potential disruption of the lumbar intumescence, lower motor neuron signs have been reported as having a less favourable prognosis. The purpose of this study was to evaluate the intervertebral disc space as a prognostic factor relating to ambulatory outcome and time to ambulation after decompressive surgery. Hansen Type I intervertebral disc extrusions were studied in 308 non-ambulatory dogs. Preoperative and postoperative neurological status, corticosteroid use, signalment, intervertebral disc space, postoperative physical rehabilitation, previous hemilaminectomy surgery, disc fenestration, return to ambulation, and time to ambulation were reviewed.

A clinical prediction rule for nerve function impairment in leprosy patients-revisited after 5 years of follow-up.

Nerve function impairment (NFI) commonly occurs during or after chemotherapy in leprosy. We previously described a clinical prediction rule to estimate the risk of NFI occurring within 2 years of diagnosis, based on 2510 patients who are followed up in the Bangladesh Acute Nerve Damage Study (BANDS). This prediction rule assigns new leprosy patients to one of three risk groups based on leprosy group and the presence or absence of NFI at registration. Updated data with up to 5 years of follow-up showed that 95% of all NFI occurred within 2 years. This study confirms the validity of the rule and supports the conclusion that there is little value for the detection of NFI in extending follow-up beyond 2 years.

Delay in presentation, an indicator for nerve function status at registration and for treatment outcome--the experience of the Bangladesh Acute Nerve Damage Study cohort.

The objective of our research was to relate delay in presentation in the Bangladesh Acute Nerve Damage Study cohort to intake status and to treatment outcome. The Bangladesh Acute Nerve Damage Study (BANDS) is a prospective cohort study of 2664 consecutive newly registered patients at clinics run by the Danish-Bangladesh Mission Leprosy (DBLM) project in Nilphamari, northern Bangladesh. The 1-year intake began in April 1995. Three-year follow-up for PB cases and 5 years for MB cases was completed in 2001. Delay in presentation in the BANDS cohort is associated with increased signs of nerve function impairment at registration. Individuals presenting with no nerve impairment and maintaining nerve function to the end of follow-up had the shortest mean delays. Individuals presenting with impairment that did not improve during follow-up had the longest mean delays. Discussion focuses on the value of setting a threshold value defining early presentation. Since the WHO Grade 2 disability rate effectively sanctions lengthy delays where there is no impairment, an indicator relating directly to delay is preferred as an indicator for good practice in leprosy control.

Estimating the relative recurrence risk ratio using a global cross-ratio model

The relative recurrence risk ratio lambdaR (and particularly the sibling recurrence risk ratio, lambdaS) is often of interest to those wanting to quantify the genetic contribution towards risk of disease or to discriminate between different genetic models. However, estimating lambdaR for complex diseases for which genetic and environmental risk factors are both involved is not straightforward. Ignoring environmental factors may lead to inflated estimates of lambdaR. We present a marginal model which uses a copula function to model the association in cumulative incidence rates between pairs of relatives. This model is applicable to present-state data and allows estimation of risk of disease in a pair of relatives (and hence lambdaR), given measured environmental covariates. We apply the model to leprosy among sibling pairs from the Karonga district, Malawi. If risk factors are ignored, the apparent lambdaS in this population is over 3. Accounting for known nongenetic risk factors reduces it to just under 2.