Clinical variables associated with leprosy reactions and persistence of physical impairment

INTRODUCTION

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 treated³. 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 thalidomide⁴.

Assessment of physical impairment in leprosy is employed as an epidemiological indicator to evaluate leprosy programs, determine early or late diagnosis, and monitor patient follow-up in health care center over the course of treatment⁵. The World Health Organization’s (WHO) global strategy (2011 to 2015) aims to reduce the rate of new cases of grade 2 physical impairment⁴. Additionally, early detection of new cases of leprosy and corticosteroid treatment for severe reactional episodes may prevent future cases of irreversible nerve damage⁶.

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 Notificação (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 epidemiological and clinical factors associated with physical impairment⁷. 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.

METHODS

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 finish the specific treatment, were transferred during the first 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 classification 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 classification: 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 defined the type 1 reaction as an episode characterized by acute inflammation in skin lesions or nerves^8 , 9and the type 2 reaction as the appearance of inflamed cutaneous nodules with or without neuritis⁹.

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 monofilament test, or when any motor impairment is observed. However, for this analysis, we only considered the objective scale of physical impairment as defined 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 , 11or the occurrence of reactional episodes¹².Thus, we investigated the association of the demographic and clinical data with these two variables as well as with physical impairment.

RESULTS

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 to 2011. We found similar percentages of PB forms (50.8%; 251/494, 95% CI [46.8 to 55.1]) and MB forms (49.2%; 243/494, 95% CI [44.9 to 53.2]). However, men presented a higher frequency of MB forms. Of the 268 men, 162 (60.4%) were affected by MB forms compared with 81 (35.8%) of the 226 women (p< 0.001). Physical impairment was evaluated and recorded in 396 (80.2%) of the 494 patients at diagnosis (200 men and 196 women). Men presented twice as much grade 2 physical impairment at diagnosis [12% (24/200)] as women [6.1% (12/196); p = 0.04], and reactional episodes were more frequently observed in MB forms [57.2% (139/243); p < 0.0001] and in men [45.1% (121/268)] than in women [33.6% (76/226); p = 0.009] ( Table 1 ).

Ages were registered for 488 patients and ranged from 3 to 85 years (mean ± SD, 41 ± 18.2). Eight percent of the patients (39/488) were children aged younger than 15 years. Clinical forms were registered in 424 patients. The predominant clinical form of leprosy was tuberculoid (TT) [40.1% (170/424)], followed by borderline (BB) [20.1% (85/424)], indeterminate (IL) [18.4% (78/424)], lepromatous (LL) [17.2% (73/424)], and pure neural (PN) [4.2% (18/424)].

Reactional episodes were detected in 40% (197/494; 95%CI [35.6 to 44.1]) of the patients and were more frequently observed in MB forms [57.2% (139/243); p < 0.0001]. The RR, or the type 1 reaction, was the most common [75.1% (148/197)] and more frequent during treatment for leprosy.

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.

FIGURE 1 Number of leprosy patients with recorded neurological examinations and any grade of physical impairment detected at diagnosis and at the end of treatment attended in the two major leprosy centers in Sergipe, Brazil, from 2005 to 2011. 

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.

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.

DISCUSSION

The morbidity associated with leprosy is related to multiple skin lesions observed in MB forms¹¹, leprosy reactions¹², and physical impairment¹³, 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 leprosy⁷, leprosy reactions¹⁵, and physical impairment⁷. 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 leprosy².

Interestingly, in leishmaniasis, which is another disease caused by an intracellular organism, epidemiological data and experimental animal studies also suggest higher susceptibility in males¹⁶. A study using an experimental model of infection by Paracoccidioides braziliensis demonstrated the influence of sex hormones on the immune response, revealing that testosterone promotes an increased production of interleukin–10 (IL–10), and less protection against this infection¹⁷. 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 2010⁴. The number of thickened nerves is significantly 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 impairment¹⁸.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 reflect 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 impairments¹⁹

Leprosy reactions are associated with the development of physical impairments. Early identification 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 events²¹but also to reduce swelling and prevent further physical impairment¹⁸.

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 reactions¹⁹. However, in this study, patients were treated with smaller doses of steroids over a shorter period. This approach may be insufficient 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 leprosy-related reactions and associated impairment of nerve function by prophylactic oral corticosteroids for 4 months in MB patients. However, this significant effect was not sustained after one year²². A clinical trial using oral corticosteroids for neuropathy demonstrated that during the first month higher doses of steroids produced better results. However, earlier treatment with lower doses was also effective²³. The administration of the correct dose of prednisone improved the clinical and electrophysiological condition of PN patients, contributing to the prevention of further neurological damage²⁴.

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 strategies that emphasize the importance of performing the neurological examination and the adequate treatment of leprosy reactions to prevent physical impairment after treatment.