Clinical variables associated with leprosy reactions and persistence of physical impairment

Introduction: Leprosy is a chronic disease that affects skin and peripheral nerves. Disease complications include reactional episodes and physical impairment. One World Health Organization (WHO) goal of leprosy programs is to decrease the number of grade 2 impairment diagnoses by 2015. This study aims to evaluate clinical factors associated with the occurrence of leprosy reactions and physical impairment in leprosy patients. Methods: We conducted a retrospective study of data from medical records of patients followed in two important centers for the treatment of leprosy in Aracaju, Sergipe, Brazil, from 2005 to 2011. We used the chi-square test to analyze associations between the following categorical variables: gender, age, operational classifi cation, clinical forms, leprosy reactions, corticosteroid treatment, and physical impairment at the diagnosis and after cure. Clinical variables associated with multibacillary leprosy and/or reactional episodes and the presence of any grade of physical impairment after cure were evaluated using the logistic regression model. Results: We found that men were more affected by multibacillary forms, reactional episodes, and grade 2 physical impairment at diagnosis. Leprosy reactions were detected in a total of 40% of patients and all were treated with corticosteroids. However, physical impairment was observed in 29.8% of the patients analyzed at the end of the treatment and our multivariate analysis associated a low dose and short period of corticosteroid treatment with persistence of physical impairments. Conclusions: Physical impairment should receive an increased attention before and after treatment, and adequate treatment should be emphasized.

Leprosy is a chronic disease caused by infection with Mycobacterium leprae.The bacillus affects the skin and Schwann cells of the peripheral nerves, resulting in cutaneous lesions and neuropathy.Loss of sensory, motor, and autonomic nerve function in the eyes, hands, and feet can result in secondary complications, such as deformity, impairment, psychological disturbances, and social exclusion 1,2 .
Periods of acute immunologic hypersensitivity known as reactional episodes can occur before the diagnosis and during or after treatment and cause nerve injury if not appropriately treated 3 .There are two primary types of hypersensitivity reaction: type 1 reactions, also referred to as reversal reactions (RR) (exacerbation of cellular immunity), and type 2 reactions, or erythema nodosum leprosum (exacerbation of humoral immunity) 3 .There is a clear recommendation for corticosteroid treatment of severe type 1 reactional episodes by the Brazilian Ministry of Health: 1 to 2mg/kg of body weight for at least 12 weeks.For severe type 2 reactions, the Brazilian Ministry of Health recommends the same dose of corticosteroid plus thalidomide 4 .
Assessment of physical impairment in leprosy is employed as an epidemiological indicator to evaluate leprosy programs, determine early or late diagnosis, and monitor patient followup in health care center over the course of treatment 5 .The World Health Organization's (WHO) global strategy (2011 to 2015) aims to reduce the rate of new cases of grade 2 physical impairment 4 .Additionally, early detection of new cases of leprosy and corticosteroid treatment for severe reactional episodes may prevent future cases of irreversible nerve damage 6 .
The State of Sergipe is located in northeastern Brazil and is a priority for the national leprosy control program.In the last seven years, 3,039 patients were registered in the Brazilian Information Health System of the Sistema de Informação de Agravos de Notifi cação (SINAN), and the percentage of grade 2 impairments at diagnosis increased between 2005 and 2010 (from 4.8% to 8.7%).These numbers call attention to the need to perform studies evaluating epidemi ological and clinical

METHODS
factors associated with physical impairment 7 .This study aims to evaluate clinical factors associated with the occurrence of physical impairment in leprosy patients from two centers for the treatment of leprosy patients in Sergipe.
We conducted a retrospective study of data from the medical records of patients followed in two centers for the treatment of leprosy located in the City of Aracaju, State of Sergipe, Brazil, from 2005 to 2011.From a total of 545 records of patients diagnosed with leprosy, 51 patients were excluded because they did not fi nish the specifi c treatment, were transferred during the fi rst two months of treatment, or the records did not contain the necessary information.A total of 494 patient records were analyzed.The analyzed variables were: gender, age (≥ 15 years and < 15 years), the classifi cation of physical impairment at diagnosis and after treatment (grade 0, 1 and 2) based on the WHO and the Brazilian Ministry of Health standard examination, operational classifi cation: paucibacillary (PB) and multibacillary (MB), clinical forms (indeterminate leprosy, tuberculoid leprosy, borderline leprosy, lepromatous leprosy, and pure neural leprosy), reactional episodes, and treatment with corticosteroids.We defi ned the type 1 reaction as an episode characterized by acute infl ammation in skin lesions or nerves 8,9 and the type 2 reaction as the appearance of infl amed cutaneous nodules with or without neuritis 9 .
Nerve involvement in leprosy is considered to occur when there are signs of pain or nerve thickening on palpation of the nerves, when there is loss of sensitivity according to the monofi lament test, or when any motor impairment is observed.However, for this analysis, we only considered the objective scale of physical impairment as defi ned by the WHO.This scale ranksphysical impairment in leprosy as follows: grade 0 (no anesthesia and no visible impairment to the eyes, hands, or feet), grade 1 (anesthesia but no visible deformities to the eyes, hands, or feet), and grade 2 (hand ulcers, absorption or contractures of the digits, plantar ulcers, callosities, foot drop, or claw).This assessment should be conducted at the beginning and the end of treatment or at any time during treatment if the patient has a complaint.
The severity of the disease is associated with clinical forms with high bacilli loads (MB forms) 10,11 or the occurrence of reactional episodes 12 .Thus, we investigated the association of the demographic and clinical data with these two variables as well as with physical impairment.

Statistical analysis
We created a database in Statistical Package for the Social Sciences (SPSS) statistical program version 17.0.0.Categorical variables are presented as simple or frequency count sand percentages and quantitative variables as means and standard deviations.To analyze the associations between categorical variables we used thechi-square test.To assess the factors associated with MB leprosy and reactional episodes, we used a logistic regression model in which MB leprosy and/or reactional episode was considered the dependent variable, where as gender and physical impairment at diagnosis were the independent variables.In addition, the logistic regression model was used to evaluate the presence of any grade of physical impairment after treatment as the dependent variable and male gender, reactional episodes, and a corticosteroid dose lower than 20mg for a period less than 30 days as independent variables.We adopted α = 0.05 as the level of signifi cance.
We analyzed the medical records of 494 patients, 268 (54%) men and 226 (46%) women)of the two major centers for the treatment of leprosy patients in Sergipe from 2005  Figure 1 shows the frequency of recorded physical impairment examinations in the 494 patients included in this study before and after treatment and the frequency of any grade of physical impairment found in the examined patients.At diagnosis, 80.2% (396/494) of the patients were evaluated for physical impairment, and 36% (143/396) exhibited grade 1 [27% (107/396)] or grade 2 [9% (36/396)] physical impairments.After treatment, the assessment of physical impairment was recorded in only 37.4% (185/494) of patients, and 29.8% (55/185) of these patients exhibited physical impairments.
Based on the frequency of grade 1 and 2 of physical impairment found after treatment (30%) and considering that an examination to evaluate the grade of physical impairment was not recorded after treatment for a majority of patients [62.5% (309/494)], physical impairment might have been detected in 93 additional patients had they been examined.Of the 494 patients included in this study, 40% (197/494, 95%CI [35.6 to 44.1]) experienced reactional episodes, and all 197 received corticosteroid treatment.However, 162/197 (82.2%) patients received a dose below 20mg of prednisone for less than 30 days.After corticosteroid treatment of these 162 patients, only 54 underwent neurological assessment at the beginning and at the end of the treatment.Of these patients, the grade of physical impairment of 52% (28/54) remained the same or increased.For instance, of these 54 patients, 26 patients had grade 0 physical impairment before treatment.Of these 26 patients, 18 continued to exhibit no signs of nerve injury after treatment, however, 7 patients progressed to grade 1 and 1 patient to grade 2 physical impairment.Of 23 patients presenting with grade 1 physical impairment before treatment, 14 remained at grade 1, one patient progressed to grade 2, and only eight patients improved to grade 0 after treatment.Of 5 patients diagnosed with grade 2 physical impairment before treatment, four patients remained with grade 2, whereas one patient improved to grade 1 after treatment.

DISCUSSION
To assess the factors associated with MB leprosy and/or reactional episode, we used a logistic regression model in which MB leprosy and/or reactional episode was a dependent variable and gender and grade 1 and 2 of physical impairment at diagnosis were independent variables.Table 2 shows an independent association between MB leprosy and/or reactional episode and factors such as male gender (OR 2.42, 95%CI [1.49 to 3.95]; p<0.001) and grade 2 (OR 6.32, 95%CI [1.98 to 20.15]; p=0.002) or grade 1 (OR 2.72, 95%CI [1.50 to 4.92]; p=0.001) physical impairment at diagnosis.When the presence of any grade of physical impairment after cure was evaluated as a dependent variable with male gender, age, reactional episodes, and a corticosteroid dose lower than 20mg for a period less than 30 days as independent variables, we observed an independent association of the presence of any grade of physical impairment after cure with this treatment regimen (OR 4.94, 95%CI [2.49 to 9.82]; p<0.001).No associations with male gender, age, and leprosy reactions were detected.
The morbidity associated with leprosy is related to multiple skin lesions observed in MB forms 11 , leprosy reactions 12 , and physical impairment 13 , which are the disease's primary complications.It is important to identify the clinical characteristics that can predict these deleterious outcomes.In this study, we found independent associations of male gender with MB forms, leprosy reactions, and physical impairment.A higher prevalence of leprosy in men is reported by others 2,13,14 as well as associations between male gender and MB forms of leprosy 7 , leprosy reactions 15 , and physical impairment 7 .This frequency of complication among men might be related to socio-cultural issues, such as higher exposure as a result of more intense social or work activities, less pursuit of health care, and the fear of losing one's employment because of the stigma of leprosy 2 .Interestingly, in leishmaniasis, which is another disease caused by an intracellular organism, epidemiological data and experimental animal studies also suggest higher susceptibility in males 16 .A study using an experimental model of infection by Paracoccidioides braziliensis demonstrated the infl uence of sex hormones on the immune response, revealing that testosterone promotes an increased production of interleukin-10 (IL-10), and less protection against this infection 17 .There is no study on this issue in the context of leprosy.
The global strategy for the control of leprosy from 2011 to 2015 aims to reduce the rate of new cases with grade 2 physical impairment worldwide by more than 35% by the end of 2015, compared with the baseline at the end of 2010 4 .The number of thickened nerves is signifi cantly associated with increased risk for physical impairments 2,18 .Furthermore, physical impairment at diagnosis has been associated with a worse prognosis for deformities 19,20 .
The proportion of patients evaluated using a neurological examination and diagnosed with physical impairment facilitates an indirect assessment of the effectiveness of programs to prevent impairment 18 .The Brazilian Ministry of Health has established that the physical impairment evaluation should be performed in at least 90% of the leprosy patients at diagnosis and 75% after treatment.In the present study, we demonstrate that leprosy reactions and physical impairment are frequent in this population.However, a number of patients in these medical centers are not tested for impairment at diagnosis and a larger number of patients are not assessed at the end of treatment.These results may refl ect problems with professional training for the prevention of leprosy-related physical impairment.It is essential to develop strategies that emphasize the importance of the neurological examination to prevent physical impairments 19 .
Leprosy reactions are associated with the development of physical impairments.Early identifi cation combined with the proper treatment of leprosy reactions can be an effective strategy to prevent physical impairment in leprosy 13,14 .Prednisone is the drug of choice not only for the treatment of leprosy reactions and silent neuritis events 21 but also to reduce swelling and prevent further physical impairment 18 .
The Brazilian Ministry of Health guidelines suggest the administration of 1 to 2mg/kg of prednisone daily for at least 90 days to treat severe reactions 19 .However, in this study, patients were treated with smaller doses of steroids over a shorter period.This approach may be insuffi cient to reverse nerve damage, resulting in a high frequency of physical impairment after treatment.In fact, in the present study, we demonstrated an independent association between the persistence of physical impairment after treatment and treatment with corticosteroids in a dose lower than 20mg for a period less than 30 days.
Although there is a clear recommendation by the Brazilian Ministry of Health to treat leprosy reactions with corticosteroids, controversy remains regarding the dose and duration of corticosteroid treatment that is necessary to prevent physical impairment.A multicenter study in Bangladesh and Nepal demonstrated a decrease in primary outcome events of leprosyrelated reactions and associated impairment of nerve function by prophylactic oral corticosteroids for 4 months in MB patients.However, this signifi cant effect was not sustained after one year 22 .A clinical trial using oral corticosteroids for neuropathy demonstrated that during the fi rst month higher doses of steroids produced better results.However, earlier treatment with lower doses was also effective 23 .The administration of the correct dose of prednisone improved the clinical and electrophysiological condition of PN patients, contributing to the prevention of further neurological damage 24 .
In conclusion, our data suggest that increased attention should be paid to men by the leprosy control program because men present higher frequencies of MB forms and severe outcomes, including leprosy reactions and grade 2 physical impairment at diagnosis.Additionally, it is essential to develop that emphasize importance of performing the neurological examination and the adequate treatment of leprosy reactions to prevent physical impairment after treatment.

TABLE 1 -
Clinical characteristics according to gender of leprosy patients attended from 2005 to 2011 in Sergipe, Brazil.

TABLE 2 -
Logistic regression analysis of factors associated with multibacillary/leprosy reaction and physical impairment after treatment in leprosy patients attended from 2005 to 2011 in Sergipe, Brazil.Model: Logistic regression after adjustment of the model (Forward Stepwise); *Variables that were not associated independently with physical impairment after treatment: gender (p=0.44),age (p=0.17), and reactional episode (p=0.24).OR: odds ratio; CI: confi dence interval.