Relapsed Cases of Leprosy in a Hyperendemic City in Northeast Brazil

Results: Three hundred and six cases were reported; 42.5% were registered in Basic Health Units (BHUs) and 57.5%, in Reference Units (RUs). There was predominance of multibacillary forms of leprosy. The typo of health unit reporting the case was associated with the clinical form of the disease (p < 0.01) and the number of affected nerves (p < 0.05). Records without specification of the clinical form were more frequent in BHUs than in RUs, and the dimorphic form was more frequently reported in RUs.


Introduction
Leprosy is a low-pathogenic and highly infectious chronic disease caused by Mycobacterium leprae.Household environments are the main spaces where transmission takes place.Unfavorable housing and sanitation conditions and high number of coinhabitants favor the spread of this disease [1,2].
The decrease of the number of leprosy cases in Brazil in recent decades is associated with the introduction of multidrug therapy (MDT) in 1986.However, despite technical and scientific advances and economic and political changes in the Brazilian society, these factors have not detectably affected the transmission of leprosy and the control of this disease has proven difficult [3].
A decrease of 68% has been observed in the prevalence rate of leprosy in Brazil, a drop from 4.52 patients per 10,000 inhabitants in 2003 to 1.42 in 2013, precisely.Notwithstanding these statistics, the epidemiological situation is not homogeneous in the country, and different prevalence trends and control strategies in each region.The North and Northeast regions have the highest transmission risk rates, with over 80% of all diagnosed cases [4].
The state of Piauí still has highly endemic areas for leprosy.Some cities have considerably high risk of transmissibility.In 2014, the detection rate in Piauí was 33.74 patients per 100,000 inhabitants, and the capital, Teresina, is a typically hyperendemic city with 49.73 patients per 100,000 inhabitants and the leader in the number of cases reported in the state [5,6].
In this context, the study of indicators of the quality of leprosy services is essential for evaluating the effectiveness of the leprosy control program based on the new guidelines of the Ministry of Health (MOH).One of the indicators is the proportion of relapsed cases reported in the year, since it is still difficult for health services to confirm relapses, especially among paucibacillary cases, due to the need to differentiate leprosy reactions.It is noteworthy that only in 2016 proportion of relapsed cases was included in the list of indicators [7].
Leprosy relapse consists in cases where the patient was regularly treated with official standardized regimens and correctly discharged for healing and returned afterwards with new clinical signs and symptoms of active infectious disease, such as increased number/size of lesions and thickening of nerves.Leprosy relapse generally happens in a period of more than five years after cure.The indicator consists in identifying municipalities reporting relapsed cases for monitoring of therapeutic failure, since the increasing number of cases may be related to relapses [8,9].
Between 2004 and 2009, the worldwide number of relapsed cases of leprosy stayed relatively constant; between 2,000 and 3,000 cases.In Teresina, 56 relapsed cases were diagnosed from 2001 to 2008, and some nerves were observed to be already affected in 18% (n = 10) of these cases [10,9].
Conducting the follow-up of healed or discharged patients is essential because this makes it possible to detect relapses, reactions and infections, thus providing a reliable support for decision-making related to the needs of patients.Thus, studies on leprosy relapse favor the delineation of the clinical-epidemiological profile of the affected population and contribute to reducing the social stigma and especially the physical disabilities that affect these patients.Thus, the aim of the present study was to evaluate relapsed cases of leprosy in the period from 2001 to 2014 in the capital city of Piauí.

Study design
Cross-sectional and analytical study that is part of a larger Operational research project entitled: IN-TEGRAHANS PIAUÍ: integrated approach to clinical, epidemiological (space-time), operational and psychosocial aspects of leprosy in Piauí cities with high endemicity.

Population and Sample
All relapsed cases of leprosy in people living in the city of Teresina from 2001 to 2014.This information was obtained from the Information System for Notifiable Diseases (SINAN) of the state.
Inclusion criteria: case classified in the SINAN (at the moment of entry) as relapsed case in the period 2001-2014; with Teresina-PI as the city of notification.
Exclusion criteria: relapsed case recorded by misdiagnosis, duplication or transfer to another city.
The number of relapsed cases reported during the study period was 355.After applying the inclusion and exclusion criteria, 306 diagnosed cases remained.

Procedures for data collection
Data from the official online database of the Information System for Notifiable Diseases (SINAN) of the State Department of Health of Piauí (SESAPI) were analyzed.The variables selected for analysis were: gender, age, race, level of education, occupation, number of lesions, affected nerves, clinical form, operational classification, degree of disability assessed at the beginning of treatment, bacilloscopy in the relapse diagnosis and type of discharge.

Procedures for data analysis
The calculation of the percentage indicator of relapsed leprosy consists in the ratio between the number of relapses that took place in the years studied and the number of all cases registered in the same year for treatment of leprosy, multiplied by 100.This reflects the quality of the health service from the perspective of monitoring treatment failure [7].Categorical variables are presented in proportions.Association tests (chi-square or Fisher's exact test) were applied, with 95% of confidence interval between the variable "unit of notification", i.e., basic health unit (BHU) or secondary/tertiary reference unit (RU).The level of significance adopted was p <0.05.

Ethical aspects
The study complied with the formal requirements of national and international regulatory standards for research involving human beings and was approved by the Ethics Committee of the Federal University of Piauí under Opinion nº: 1115818.

Results
Table 1 describes the associations between the percentage of relapsed cases at the moment of entry in BHUs and in RUs and the variables gender, age, level of education and race.Most relapsed cases (59%, n = 181) were male patients aged 45.21 years on average (SD = 17.26, minimum 6, maximum 86).Among the patients, ten were younger than 15 years with similar distribution in the BHUs and RUs.As for schooling, more than 50% of the patients had primary education and there was a statistically significant difference only between the reporting health units and the level of education of patients.Most of the patients (71.9%) self-declared to be brown-skinned.
The average relapse rate was 21.9 cases per year, with a minimum of 8 cases in 2014 and a maximum of 43 in 2008.The highest rate (6.6%) was observed in 2009, and the lowest in 2002 (1.7%) and in 2014 (1.9%) (Figure 1).
One hundred and thirty relapsed cases of leprosy were reported in BHUs (42.5%) and 176 (57.5%) cases in secondary and tertiary RUs.Figures 2 and  3 show that multibacillary (MB) cases were more frequent than paucibacillary (PB) cases in the period studied in both, BHUs and RUs.Relapsed cases reported in 2008, 2012, 2013 and 2014 in BHUs were exclusively MB, as well as were the cases reported in 2014 in RUs.
There was an association between the clinical form of the disease (p < 0.01), number of affected nerves (p < 0.05) and the type of health unit that reported the case.Records where the clinical form was ignored were more frequent in BHUs than in RUs, and the record of the dimorphic form was more frequent in RUs.The dimorphic form (42.2%; n = 129) was more frequent among all relapsed cases, followed by the Virchowian form (23.2%; n = 71).Absence of record on assessment of affected nerves was proportionally higher in BHUs.The mean number of affected nerves was 0.7 (SD = 1.2; minimum 0 and maximum 6).
The prevalence of the MB form in the operational classification was observed in both BHUs and RUs (> 70%, n = 224).Among patients 93 (30.4%) presented some physical impairment at the moment of diagnosis and only 85 (27.8%) performed smear microscopy, which were mostly positive, reinforcing the bacillary persistence.Cure rate was slightly higher than 80% and the number of ignored discharges reached 22 (7.2%).(Table 2)

Discussion
Several aspects contribute to the occurrence of relapses.These may be related to intrinsic factors of the bacillus, such as reinfection of the patient due to irregular treatment adherence by patients, or to extrinsic factors such as difficult distinction between leprosy reaction and relapse in health services [2,7].
In 2013, an average of 3,196 relapsed cases were reported in a survey conducted in 96 countries, while in 2014, 1312 cases reported, excluding Brazil.However, a decreased of more than 100 cases was observed in the country between 2013 and 2012 [2,11].Thus, following the global strategy of the World Health Organization (WHO), the MOH has adopted the assessment of cases in 2016 as an indicator to identify municipalities that notify relapsed cases in order to monitor treatment failure.It is noteworthy that, because this measure has only recently been implemented, there are no parameters to guide the classification of cases.
The drop in the number of relapses can be related to the consistent conduct of health services based on the differential diagnosis between reaction and relapse through association of clinical and laboratory tests.At the same time, this drop may also reflect the underreporting of cases, hindering accurate estimates of the number of relapses.
The findings of this study revealed that the majority of the 306 patients who entered in basic health units and reference units for relapsed leprosy from 2001 to 2014 were male individuals and adults.Research studies have indicated the males predominate in new cases and in relapsed cases of leprosy; men are between 0.21 and 0.81 times more likely to have a relapse when compared to women.This may be related to the persistent behavior of low search for health services in the case of men [12,13,14,15,16].
The mean age was 45.21 years.This age is close to data found in studies conducted in the North (49 years) [17], Midwest (46.3 years) [13] and Northeast of Brazil (42.3 years) [10].The predominance of adults in leprosy relapse cases is also common in India and Colombia where the predominant age groups are 15-35 years and average of 39 years, respectively [14,18].An adult is five times more likely to experience a relapse than a child, provided the other variables are kept the same [12].
It was noted that level of education had a significant effect on the incidence of relapses.The number of patients with higher education was greater in RUs while and the number of ignored cases was greater in BHUs.This shows that people with higher levels of education prefer seeking specialized centers and that collection of data for characterization of patients is frequently ignored in basic health units.
As for ethnic group, the majority of patients seeking health services for relapsed leprosy was brown-skinned (71.9%).In fact, the majority (71%) of people in the Brazilian population declare themselves black or brown-skinned, according to the last census held in Brazil [19].A study conducted in Mato Grosso presented the brown ethnicity as a protective factor against leprosy relapse [13].
Considering the Primary Health Care as the main gateway to assistance, it was observed that the multibacillary form of leprosy prevails in the cases reported each year.This suggests late diagnosis or endemism in the exposed population and lack of skill from the part of professionals when it comes to dealing with this disease.This weakens the service and the quality of care offered to people living with leprosy [12,20].
Reference Units (Secondary or Tertiary) are prepared to address cases of difficult diagnosis, clinical complications, adverse reactions to treatment, leprosy reactions, relapses and need for surgical rehabilitation or when there is suspicion of multidrug therapy failure, as this type of treatment may cause drug resistance.Therefore, patients may need to be referred for appropriate follow-up [9].
It was found that the diagnosis of relapses occurs predominantly in Reference Units.These environments have specific criteria favoring the identification of leprosy for proper management.This opposes to the fact [21] that the highest percentage of diagnosed relapses was found in BHUs in the present study, most of which were confirmed even despite the negative result for bacilloscopy.This suggests that the health care network has difficulties to accurately diagnose cases of relapse.
The multibacillary form of the disease was predominant in the present survey.This indicates that patients are referred to assistance in serious states and that the professionals have difficulty that to diagnose leprosy in early stages.In a specialized Reference Unit in northern Pará, the multibacillary form was present in 96.3% (n = 27) of all patients [22].
The operational classification has significant influence on cases of leprosy relapse; the multibacillary form is four times more likely to induce a relapse than the paucibacillary form [10].Such information becomes even more alarming when considering the inconsistencies in the system, since there is no congruence between the operational classification, the number of nerves affected and the number of injuries that can be related to the permanent and continuous education of the professionals involved in the care.
With regard to clinical forms, the most frequent was the dimorphic, corresponding to 42.2% (n = 129) of cases identified in BHUs (36.2%) and RUs (46.6%), followed by the Virchowian form with 23.2 % of the relapses.Both are multibacillary forms of the disease.The predominance of this form reflects the preponderance of late diagnosis and, consequently, increased risk of onset of physical disabilities.The same was observed in another study [18].This translates the persistence of the transmission chain and reinforces the need for attention from the part of professionals to ensure adherence to treatment and active search for contacts [9,18,22].
It is worth mentioning that the percentage of information ignored in SINAN is still high, such as the type of discharge, which would allow to know the outcome of the cases in the health units.Still, the majority of the patients were cured, and 22 (7.2%) were ignored, that is, the teams did not know the actual situation of the patient, hindering the more accurate evaluation of relapse-related aspects.
Thus, the recommendation of following-up leprosy patients and leprosy complications is relevant for comprehensive care.Services that make up the leprosy care network must arrange and organize the reference and counter-reference system, invest in well-trained professionals who are experience in the diagnosis of relapses, due to the high prevalence of the disease in the capital, establishing the flows to ensure proper management of relapses in all levels of attention.

Conclusion
The evaluation of relapsed cases of leprosy in Teresina showed that the profile of cases is similar to that found in national and international studies on the theme.Because this is a study carried out with se-condary data, the incompleteness and inconsistency of some variables represent a limitation, bringing some difficulties to the process of data analysis.
It is believed that instances of relapses are under--reported in the studied site.Thus, it is imperative to pay greater attention to the diagnostic confirmation of relapses, especially in multibacillary cases, as this is the infecting and disabling form, as well as to the neurological and dermatological evaluation of all patients for timely diagnosis and prevention of physical disabilities.Therefore, the training of health professionals is a key to achieving qualified information on epidemiological surveillance of relapsed cases.This will aid the survey of a most reliable profile of the evaluated population.
It is worth noting that the deficiency in the health services network in recognizing cases of relapse, along with a lack of reliable, complete and accurate information, especially the lack of constant evaluation and the lack of information available to recognize the factors associated with relapses, make it difficult to plan and strengthen actions in the health care network.

Figure 1 :
Figure 1: Percentage of relapsed cases of leprosy according to year of diagnosis, from 2001 to 2014.Teresina, PI, Brazil.

Figure 2 :
Figure 2: Percentage of relapsed cases of leprosy in Basic Health Units according to the operational classification and the year of diagnosis 2001-2014.Teresina, PI, Brazil, 2016.

Figure 3 :
Figure 3: Percentage of relapsed cases of leprosy in Reference Units according to the operational classification and the year of diagnosis 2001-2014.Teresina, PI, Brazil, 2016.

Table 2 .
Association between entries for relapsed leprosy in basic health units and reference units and clinical variables.Teresina, PI, Brazil.