Study design

This is an observational analytic non-concurrent secondary data study. Data of the national government database of leprosy cases diagnosed in Brazil (2001–2013) were used for the epidemiological trend evaluation of MB cases. The database is generated in all Brazilian States that have diverse capacities and expertise for leprosy diagnosis and classification. Therefore, to have a homogeneous group classified under the same standards, we included an analysis of bacillary loads obtained from a database at a leprosy referral center. At Souza Araújo Outpatient Clinic (Ambulatório Souza Araújo, ASA/Fiocruz, Rio de Janeiro, Brazil), slit skin smears are collected and read under standard protocols and only cases with positive bacilloscopy are classified as multibacillary. For this analysis we chose a different period of time (1990 to 2014) to include the largest possible number of cases.

Source of data

Brazil monitors mandatory notifiable conditions using SINAN (National Notifiable Diseases Information System). For each new case, a report form is generated at local health units, and sent to the central health services where data are checked, digitized and transferred from municipalities to States, and to the national database [13]. Until mid-2015 de-identified information in the national databases was freely accessible through the Informatics Department of the Public Health Care System (DATASUS).

All data were obtained from DATASUS on June 2, 2015. New cases, defined by the Ministry of Health as cases of leprosy with no previous treatment [7], were included. Sex, age group and operational classification were used as classifying variables. Cases with missing information regarding one of these variables were excluded. Physical disabilities caused by leprosy were classified as grade zero when patients had no problem in eyes, hands or feet; grade one when there was anesthesia in hands, feet or eyes; and grade two when there were visible deformities in hands, feet or eyes, or severe visual impairment [14]. As disability grade is an indirect indicator of diagnosis delay [9], rates were calculated independently for patients without physical impairment (disability grade 0) to reduce the influence of late diagnosis in progression to MB leprosy. Given that detection rates for MB leprosy have been related to leprosy endemicity, which is variable in Brazil, we looked for the relation of sex, age groups and MB rates by state.

To evaluate bacillary load variations, all new cases treated at ASA/Fiocruz (1990 to 2014) were analyzed using de-identified data on sex, age, disability grade and bacillary index (BI) at diagnosis. BI is calculated using Ridley’s logarithmic scale for number of acid-fast bacilli per microscopic field in smears collected from ear lobes, elbows, and leprosy skin lesions. In this scale, each additional unit indicates a 10-fold increase in the number of bacilli and is scored from 0 to 6+, ranging from no bacilli per 100 microscopic fields to 1,000 or more bacilli per microscopic field. Final BI results are calculated as the arithmetic mean of skin sites collected in each patient [15]. In ASA/Fiocruz, four or six sites are examined, generally two ear lobes, one elbow and a cutaneous lesion. Cases classified as indeterminate or pure neural leprosy, which present higher probabilities for misdiagnosis, and those with missing information regarding any variable were excluded.

Calculation of epidemiological indicators

National data on leprosy were categorized by year of diagnosis, sex and age group. Population data were obtained from the IBGE (Brazilian Institute of Geography and Statistics) [16]. Age was assigned with DATASUS age group definitions: 0–4, 5–9, 10–14, 15–19, 20–39, 40–59, 60–64, 65–69, 70–79, and 80 or more years of age.

New case detection rate (NCDR) is the number of new cases per 100,000 people, per year. Sex ratio is the quotient of NCDR in men to NCDR in women. Mean NCDRs were calculated as the arithmetic mean of annual new cases from 2001–2013, divided by the population in mid-2007. Mean NCDRs were calculated by sex and by age group using arithmetic mean of cases (2001–2013) and corresponding population at mid-2007. Mean NCDRs were also calculated by operational classification.

Mean NCDRs by age groups were calculated separately for three time periods: 2002–2005; 2006–2009 and 2010–2013, to ascertain whether there were changes in age distribution related to reduction in NCDRs.

Statistical analysis

Data were exported to Microsoft Excel worksheets (version 14.0.4760.1.000/2010). Statistical analysis was performed in Openepi (version 3.03a, CDC, Atlanta, Georgia, USA, available at http://www.openepi.com) and SPSS (version 22, IBM Corp, Armonk, NY, USA) using chi (χ)² test (Pearson) to compare rates between selected groups. Annual coefficient means were compared between men and women for all age groups using analyses of variance (ANOVA). Linear regression was used to test gender differences for the NCDR curves over time. BI was compared among study groups using Kruskal Wallis test. Confidence interval was established at 95%, thus a p-value less than 0.05 was considered to be statistically significant.

Ethical considerations

The protocol for this study was reviewed and approved by the Universidade Federal do Rio Grande do Norte Ethical Committee (CAA 06189612.9.0000.5537).

Leprosy and sex

Male predominance in leprosy is reported in different parts of the world [1,25–27]. This association could be related to greater exposure of men to the M. leprae bacillus or by the lack of women undergoing a full physical examination in some cultures [26]. There are also reports of more MB leprosy in men [18,25–27]. In Brazil, this has been documented, and hypothesized to be related to men being less attentive to their health, contributing to later diagnoses with progression to MB leprosy [28]. However, our results show that rates of MB leprosy were higher in men than in women in leprosy per se as well as in early diagnosed cases. This association was observed in different states within Brazil regardless of background NCDR of leprosy.

A recent study using random-effects models to evaluate the outcome of infection with ten major human pathogens, including M. leprae, concluded that differences in response to infection were more associated with physiologic than with behavioral risk factors [29]. Interestingly, in our study sex ratio for leprosy was similar in people less than 20 years of age and then became progressively larger with age, a finding reported by other authors [18,26]. This may be related to a greater exposure of men to the bacillus after childhood, but could be also related to physiologic changes at adolescence, such as estrogen and testosterone levels.

Studies in experimental models of other intracellular pathogens, such as Leishmania sp [30], Paracoccidioides brasiliensis [31], Mycobacterium marinum [32], M. avium [33] and M. tuberculosis [34], demonstrated that while estrogen stimulates cellular immune response to these pathogens, with increase in antigen-specific CD4 T cells and IFN-γ secretion, testosterone stimulates production of anti-inflammatory cytokines associated with Th2 response, such as IL-10 and IL-4, and increase in antibody levels. In all experimental models tested more serious lesions and higher parasite burdens were observed in males or in females previously treated with testosterone [30–34].

Our study with data from the ASA/Fiocruz reference center showed that BI was higher in males, even when considering only patients without disability at diagnosis. This suggests that factors other than decreased opportunities for diagnosis may be involved in the development of MB leprosy and higher BI in men. This study found higher BI in men from the age of 20, with significantly higher bacterial load in men 20–59 years of age. A possible explanation for this finding is that testosterone which change during adolescence may be involved in creating an environment that could facilitate M. leprae growth and yields a higher bacillary load in men. Additional research on sex hormones and leprosy are very important to better discuss these findings.

Leprosy and age

In Norway, the peak of leprosy NCDR moved from 15–29 years of age in mid 1800’s to people older than 50 years in early 1900s [17], paralleling the overall decrease in the incidence of the disease. At the same time, there was an increase in the percentage of MB cases among the elderly. This is explained by less exposure to M. leprae among younger people and by a longer incubation period for MB leprosy. Thus, only the previously infected individuals developed especially this type of disease at later ages. This was also observed in other areas where leprosy declined [17–19,27,35], but we found a significant association between MB leprosy and elderly patients in all Brazilian States, including hyperendemic areas from the North and Center-West Regions, indicating that reduced exposure to infection may not be enough to explain this pattern of leprosy.

In addition, it is meaningful to observe that life expectancy in Europe which used to be only 36.3 years in 1850 [36], increased to 50 years of age in Norway at the end of the 1800s [37]. Leprosy incidence peaked in adults in Congo [38] and in children and adolescents in the Philippines [39] when life expectancy in those countries was under 41 years of age [36,40]. Our results in Brazil showed a higher NCDR in elderly in all 3 time periods studied (2002–2005, 2006–2009 and 2010–2013), where life expectancy has been above 70 years of age since the 2000’s [40]. Similar results were observed more recently in Japan [19], Mexico [27] and Korea [41]. These findings may suggest that differences of leprosy NCDR by age could be related to overall life expectancy of the population.

Usually the association between leprosy and the elderly is discussed only as it relates to decreased leprosy transmission and longer incubation period for MB disease, but other potential contributing factors could include age-related immune changes and increased susceptibility to infectious diseases [42]. For example, the elderly can have impaired monocyte and neutrophil function, decrease in CD28 co-stimulatory molecule expression [43], reduction in phagocytic capacity, decreased antigen presentation and a change in cytokine profile from Th1 to Th2 [42]. Thus, key steps required for defense against M. leprae are potentially compromised with aging, and may be involved in the higher incidence of leprosy in older age groups.

Integration of active MB case finding in leprosy control programs

As MB patients transmit M. leprae, we advise targeting specific case detection strategies to men and elderly people to further reduce transmission of leprosy, in addition to preventing disability with early diagnosis and treatment.

In Brazil, the National Health System is based on family health teams, who are responsible for leprosy control among other health issues. These teams are multidisciplinary and usually composed of doctors, nurses and community health workers. The team visits household units for general medical care [44]. This opportunity should be considered an important means to exam elderly people, who sometimes have less access to health services due to decreased mobility and independence [45]. In addition, this knowledge can be useful for active search of the source of infection for leprosy cases under 15 years of age among the elderly men in the households.

Rapid serological tests with high sensitivity to detect MB leprosy are currently available [46, 47]. They are rapid immunochromatographic flow tests that detect IgM antibodies against specific M. leprae antigens and could be performed as point-of-care serologic evaluations during leprosy active search activities. Although they are not diagnostic tests because they can be positive in healthy people who may never develop leprosy, sera and blood from MB leprosy cases show strongly positive results. Thus, they can be used as an adjunctive tool in diagnostic campaigns, especially for specific population groups where MB leprosy is more frequent.

These strategies can be employed to improve MB leprosy detection and to accelerate the reduction of this important public health problem in Brazil.

Final comments

This study utilized data generated and entered by hundreds of different people, which needs to be considered in interpretation of the results. An analysis of the leprosy database in Brazil (SINAN) has identified problems linked to updating of data after case notification to the system, such as the date of completion of leprosy therapy; however, no problems where observed related to the software or data transfer [13]. Considering that we used secondary data produced in different settings nationwide, it is important to keep in mind that leprosy classification methodology may vary according to the diagnostic capacity of the center. In primary care settings, diagnosis and operational classification are mainly based on clinical findings, while in references centers, confirmatory and complementary tests, such as skin biopsy and slit-skin smear, can be performed. Nevertheless, during the study period, there were no major changes in the National Program’s recommended diagnosis and classification criteria. Although this may be considered as a limitation, the large number of cases included in the analysis should reduce the impact of differences in classification criteria between centers.