Trend analysis of leprosy indicators in a hyperendemic Brazilian state, 2001–2015

ABSTRACT OBJECTIVE To analyze the temporal trend of leprosy indicators in a hyperendemic state of Brazil, from 2001–2015. METHODS This is a time-series study of leprosy indicators in the state of Maranhão, Northeastern region of Brazil. The study used data from the Brazilian National System of Reportable Diseases, for the period between 2001 and 2015. The following indicators were evaluated: (i) detection coefficient in the general population; (ii) detection coefficient in people under 15 years old; (iii) rate of cases with grade 2 physical disability in the diagnosis; (iv) rate of examined contacts, and (v) proportion of healing . The Prais-Winsten regression model was used for trend analysis. Analyses were performed for the state and by each health region. RESULTS 77,697 leprosy cases were analyzed in the general population and 7,599 in individuals under 15 years old. The detection coefficient in the general population ranged from 80.7/100 thousand inhabitants in 2001 to 51.2/100 thousand inhabitants in 2015. The coefficient in the general population presented a downward trend (annual percentage variation [APV] = -2.98; 95%CI -4.15– -1.79). For the population under 15 years old, the rate was 24.9/100 thousand inhabitants in 2001, and 19.9/100 thousand inhabitants in 2015, with downward trend (APV = -3.07; 95%CI -4.95– -1.15). It was observed upward trend in rate of contacts examined (APV = 2.35; 95%CI 0.58–4.15) and rate of cases with grade 2 disability (APV = 2.19; 95%CI 0.23–4.19). Stationary trend was observed in the proportion of healing (APV = -0.10; 95%CI -0.50–0.30). Regional differences were found in the performance of the indicators. CONCLUSIONS A downward trend for the detection coefficients in the general population and in individuals under 15 years old was found in Maranhão. Despite this result, the rates are still very high, demanding efforts from all spheres of public administration and health professionals to reduce the burden of the disease in the state.


INTRODUCTION
Leprosy is a chronic infectious disease caused by the Mycobacterium leprae bacillus 1 . This disease is characterized by dermatological and neurological effects and, although curable and despite the efforts made by government agencies in recent years through public policies, leprosy still represents a major problem for public health worldwide and in Brazil 2,3 . This bacterium presents high infectivity and low pathogenicity, since it can infect large numbers of individuals, but very few grow sick 2 .
Leprosy transmission occurs via the prolonged and intimate contact between susceptible or genetically predisposed individuals; untreated multibacillary patients; inhalation of microorganisms eliminated by superior airways; and to a lesser extent, direct contact. The nasal mucosa is the bacillus' main entrance way 2,4 . The best form of prevention and control of leprosy is through the detection and diagnosis of the infection, screening of family members, and early treatment 5 .
Mycobacterium leprae infection still present high levels in many regions. In 2015, 210,758 leprosy cases were reported worldwide, and 136 countries reported cases of this infection 3 . Of the total cases, 60.0% occurred in India (127,326), 13.0% in Brazil (26,395), and 8.0% in Indonesia (17,202). Thus, these countries comprised 81.0% of the new cases reported worldwide 3 . The American continent has the second largest rate of cases globally. In 2015, 28,806 cases were reported in the Americas (13.0% of total cases). Of these cases, almost all were reported in Brazil (26,395; 91.6%), making it the country with the highest concentration of leprosy cases in the Americas 3 .
In Brazil, leprosy still presents high morbidity and magnitude, causing disabilities and deformities which lead to further impairments in the clinical outcome due to the social stigma, loss of productivity and high costs for health services 3,6 . In 2015, Brazil presented a general detection coefficient, a detection coefficient for people under 15 years old, and the detection coefficient with grade 2 disability of 14.06 cases, 4.28 cases and 0.91 cases/100 thousand inhabitants, respectively. Moreover, a 78.23% ratio of examined contacts, and a proportion of healing of 83.44%. Macro-region analyses found the highest detection coefficient for the general population in the Northern region (29.59/100 thousand inhabitants), and the lowest in the Southern region (3.49/100 thousand inhabitants) in 2015 7 .
Three states have the highest detection coefficients in the general population of Brazil: Mato Grosso, Tocantins and Maranhão 7 . In particular, 3,540 new cases were detected in Maranhão in 2015, corresponding to 13.40% of the cases in Brazil 8 . In absolute numbers, Maranhão recorded more cases than eight of the 14 countries of the world with the highest rates of the disease. The detection coefficient in Maranhão was 51.27/100 thousand inhabitants in 2015 8 . In the population under 15 years old, 375 cases were reported in 2015, representing a 17.5/100 thousand inhabitants detection rate. According to the standards set by the Brazilian Ministry of Health, Maranhão is considered hyperendemic place for leprosy in both indicators 8 . The analyses of the indicators show that this state must be prioritized in the reduction of the burden of leprosy in Brazil.
Epidemiological indicators related to leprosy -such as the detection coefficient in the general population and in people under 15 years old, the ratio of new cases with grade 2 disability in the diagnosis, the ratio of contacts examined and the proportion of healingallow the reach of the goal set by the World Health Organization (WHO) to be monitored, which is to reduce the burden of leprosy globally and locally 9 . The systematic analysis of these indicators enables the evaluation of geographical and temporal variations of leprosy, contributing to the prevention and subsidizing the planning, administration and analysis of leprosy control interventions and policies, especially in Brazilian states with high leprosy rates, like Maranhão. In addition, there is a deficit of studies that evaluated the behavior, magnitude and trend of leprosy in Maranhão, which can subsidize the intensification of control actions of this infection 10 . Given this context, this study sought to analyze the temporal trend of leprosy indicators in a hyperendemic state of Brazil, between 2001-2015.

Study Design and Area
This is a time-series ecological study 11  Regarding the characterization of access and care from health services, by the end of 2015, the coverage of primary health care in the state was 85.9%, and 83.7% in the Family Health Strategy. In Maranhão, 1,006 basic health units (BHU) were enabled for fully providing leprosy care in 2015, i.e., those health units were capable of diagnosing and treating leprosy and conducting intra-household monitoring. This number corresponds to 62.5% of the total number of BHU registered in the state of Maranhão. Regarding reporting units by SINAN, there were 1,012 units, corresponding to 62.8% of the state total in the same period. Maranhão has two specialized units for the treatment of leprosy classified as grade 2, and one for grade 3, which perform preventive and corrective surgeries. These units are in the state capital.

Data Source and Variables
This study analyzed the time-series of leprosy indicators of Maranhão, stratified by the 19 health regions in the period from 2001 to 2015, aiming to viewing the trend of leprosy and the monitoring of the state's epidemiological and operational indicators. The data for the estimation of indicators were obtained from the SINAN database and population data from the Brazilian Institute of Geography and Statistics (Instituto Brasileiro de Geografia e Estatistica -IBGE). Data from SINAN originate from compulsory notifications records, which consist of standardized forms with socio-demographic and clinical information, filled by health professionals 10 .
The interest variables analyzed in this study were the indicators that represent the burden of morbidity and the magnitude of leprosy (leprosy detection rate in the general population and in people under 15 years old) and the quality of care services and prevention actions provided to patients (rate of intra-household contacts of new leprosy cases examined, the rate of cases with grade 2 in diagnosis and cure rate) 12 .   This indicator examines the capacity of health services in monitoring intra-household contacts of new leprosy cases, allowing the timely detection and the increase in the detection rate of infections.
(v) Proportion of healing in the cohort period Numerator: New paucibacillary and multibacillary cases cured in the cohort years.
Denominator: New paucibacillary and multibacillary cases in the cohort years.
This indicator allows viewing the measures adopted to conduct the treatment in the planned period, measuring the quality of care offered to patients with leprosy.

Statistical Analysis
Data were analyzed with the statistical program SPSS version 14.0. To describe the studied population, descriptive analysis was performed for all variables. Thus, the reported cases of leprosy were described by absolute and relative frequency by sex, age group, clinical form, operational classification and grade of disability.
The Prais-Winsten linear regression model was used for the time trend analysis 13 . Initially, the logarithmic transformation of natural indicators was performed, which can reduce the heterogeneity of variance of the residuals from regression analysis. Following, the regression analysis was performed, considering the dependent variables "Y", the analyzed indicators and the independent variable "x", corresponding to the year of the study.
Thus, the linear regression equation can be described as: β 0 is the constant or intercept; Log(Yt), matches the value; β 1 is the linear trend coefficient; x is the residual term.
After calculating the β coefficient and standard error (SE) in the regression analysis, the annual percentage variation and its 95% confidence interval (95%CI) were calculated using the following formulae: Trends were thus considered as upward, downward or stationary. The results were considered statistically significant when p < 0.05.

Descriptive Analysis of Cases
In the period from 2001 to 2015, 77,679 new leprosy cases were recorded in the state of Maranhão. Regarding the characteristics of the cases, most patients were male (57.7%) and had multibacillary operational classification (63.7%). Regarding the age groups, 9.8%, 35.8%, 42.1% and 12.3% of the cases occurred in individuals aged < 15 years, 15-34 years, 35-64 years and ≥ 65 years, respectively. Of the total cases, 19.2% and 6.3% presented grade 1 and 2 disability, respectively, at the time of diagnosis. The rate of cases in which disability grade was not assessed was 16.8%.

General detection rate
The detection rate of leprosy in the general population of the state of Maranhão decreased from 88.  Table 1 shows the trend analysis of the analyzed indicators by health region. Maranhão presented a significant downward trend in the annual percentage variation (APV): -3.5% (95%CI -4.82--2.15). Results stratified by health region also showed downward trend for the general detection rate in 11 (63.15%) health regions: Açailândia, Bacabal, Barra do Corda, Chapadinha, Imperatriz, Itapecuru Mirim, Pedreiras, Presidente Dutra, Santa Inês, Timon and Zé Doca. The other regions showed stability trend of this indicator (p > 0.05) ( Table 1). Red lines indicate increase in the ranking; black lines, maintenance; and blue lines, decrease.

Rate of contacts examined
During the analysis period, Maranhão showed an upward trend in the rate of contacts examined (APV = 2.8%; 95%CI 0.75-4.83). Among all regions, 14 (73.68%) presented stationary trend (p > 0.05). The study found an upward trend in the rate of contacts examined in only four (21.05%) health regions: Açailândia, Codó, Imperatriz and Pedreiras. Balsas presented a downward trend for this indicator ( Table 4).

Proportion of healing
Maranhão presented a stationary trend in the proportion of healing of leprosy during the analyzed period (VPA = -0.12%; 95%CI -0.58-0.34). Fourteen (73.7%) health regions presented stability trend (p < 0.05) in the proportion of healing between 2001 and 2015. Balsas, Imperatriz and Pedreiras presented upward trend, and Itapecuru Mirim and Pinheiros presented downward trend (Table 5). The results of this study also showed a downward trend for the general detection coefficient, suggesting a decrease in strength of leprosy in Maranhão 8 . However, the state still presents a hyperendemic pattern, a severe public health problem. Moreover, we found significant differences in the detection coefficient in the general population among health regions.

DISCUSSION
Of the 19 regions of the Maranhão, most (n = 11) presented downward trend for the general coefficient, four stability trends and no downward trend of this indicator. The health regions that presented the highest downward trends for this coefficient were Açailândia and Imperatriz.
To consider the strength of morbidity, represented by the magnitude and trend of leprosy found in the population of children and adolescents, is crucial for the planning of infection control actions 17 . The detection of new cases in individuals under 15 years suggests successive transmission, persistence or active circulation of Mycobacterium leprae, and the lack of effective control measures for leprosy 18,19 . For this indicator, this study showed a stationary trend in most health regions and downward trend in eight of them, corroborating another study in Brazil 18 . However, this indicator remains very high in Maranhão and hyperendemic in almost all regions, indicating the need for increasing control measures among this population.
The differences between the results of the indicators mentioned in health regions suggest the need for the assessment of economic and risk factors, and of the actions in each health region; thus, seeking to reduce the burden of leprosy in Maranhão. This will allow the discrepancies in the results found to be better explained and could contribute to the intensification of control and prevention actions that consider regional particularities. The risk of a healthy individual contracting leprosy increases ninefold with prolonged contact at home 20,21 . Therefore, conducting examinations of intra-household contacts of all new diagnosed cases is crucial for the prevention and control of leprosy, as it allows the early diagnosis and contributes to the prevention of subsequent deformities and disabilities 18,20,22 . In Brazil, Decree 3,125 from October 27, 2010, of the Ministry of Health considers as intra-household contact any individual who lives or used to live with an individual diagnosed with leprosy in the past five years 23 . In recent years, the Ministry of Health reworked the concept and began to consider household contact as any individual who lives or used to live with a leprosy patient, and social contact as any individual who has contact or used to have contact in a close and prolonged manner, regardless of being a family relationship or not 12 . Social contacts such as neighbors, work or school colleagues, must be investigated according to the degree and type of contact (i.e., if they had very close and prolonged contact with the untreated patient). However, the evaluation focus must be on patient's relatives contacts (parents, siblings, grandparents, uncles and aunts, among others), or other individuals with prolonged contact 12 . Regarding the ratio of examined contacts indicator, most regions presented stationary trend, and only four showed an upward trend. Balsas presented a downward trend for this indicator (Table 4). Stationary or upward trends of this indicator imply improvements in actions and activities of epidemiological monitoring 17 . Therefore, these results show the need for further efforts in all health regions of Maranhão to increase the rate of examined contacts, consequently improving this indicator in the state.
The most effective way to prevent the physical disabilities arising from the leprosy is the early diagnosis combined with the treatment of the disease and its reactions 24, 25 . The WHO estimates that the diagnosis and early treatment of leprosy infections led to the prevention of physical disability in approximately four million people worldwide 24 . In this study, we observed an upward trend in the rate of grade 2 disability at the time of diagnosis in Maranhão, and most regions presented stability trends; thus, corroborating other studies conducted in Brazil 8,14 . Only three regions showed upward trend for this indicator. The stationary trend in the rate of grade 2 physical disability indicates the late diagnosis of cases and failures in preventing physical disabilities 8,14 . Similarly, the upward trend in some health regions indicates late identification, contributing to the persistence of hidden prevalence (undiagnosed cases) and the consequent increase of transmissibility 26 . On the other hand, a stationary trend or increase in this indicator may suggest improvements in the evaluation of disabilities by health professionals. Given this context, increasing the control and intensifying prevention strategies of grade 2 disability of leprosy are required for reducing the disease burden in the state 14 . Mass campaigns for the diagnosis of leprosy must be intensified in all health regions of Maranhão, integrating them with other health programs for disease control, and establishing the decrease in the grade of disability at the time of the diagnosis as the objective 27 .
The effectiveness of leprosy treatment is evaluated by the proportion of healing of the patients in the years of the cohort 12 . It corresponds to an indicator for evaluating the quality of patient care and operation of the leprosy control program 23 . Since 1985, the multidrug therapy (MDT) against leprosy has been made available free of charge worldwide, which significantly reduced the disease's burden 24, 28 . Leprosy therapy, in Brazil, is conducted in an outpatient manner, using standardized therapeutic schemes according to the operational classification of the infection. The results found in this study show a stationary trend for the proportion of healing in Maranhão and most of its regions, in addition to an upward trend in three regions, suggesting the efficacy of MDT. However, two regions (Itapecuru Mirim and Pinheiros) showed downward trend for this indicator. This finding suggests the need for reorganization of the care services for leprosy patients in these regions, seeking to reduce the abandonment of therapy and ensure discharge for cure.
Our study presents some limitations. First, we used secondary data for the analysis, which suffer bias in the quality and quantity of information 16 . Thus, underreporting of cases during the analyzed period may have occurred due to the lack of completion of notification forms or errors during while transferring the information 29 . Nevertheless, this study showed the epidemiological scenario of the leprosy indicators in Maranhão. Moreover, we made advances when compared to previous studies, since we analyzed the trends and the performance of the indicators by health region of the state. These analyses allow a study focused on regionalities of Maranhão. Studies conducted in other states of Brazil did not analyze the trend by region, failing to obtain important data to subsidize specific control actions.
In conclusion, despite the reduction of detection coefficients in the general population and in individuals under 15 years old in Maranhão, these indicators remain high in many regions, which still assigns the state a hyperendemic character for this infection. The rate of grade 2 physical disability at the time of diagnosis is also high in almost all regions. The results of this study suggest the need for the intensification of efforts and actions to eliminate this disease, especially in regions with high magnitude for leprosy. Our results also suggest the expansion of leprosy control measures in the state, including the increase in the rate of contacts examined, the promotion of the early detection of leprosy cases through active search and detection campaigns of cases in schools and vulnerable regions, ensuring the onset and adherence to treatment to increase the proportion of healing and decrease of transmissibility rates, improvements in the prevention of physical disabilities, among others. Finally, subsequent studies must be conducted to verify the quality of leprosy control actions in the regions to better understand the regional differences of indicators.