ABSTRACT

Objective:

To investigate the risk factors associated with leprosy in contacts of patients.

Method:

We carried out a systematic review and meta-analysis by searching the databases MEDLINE, Embase, Cochrane Library, CINAHL, LILACS, Scopus, and Web of Science until September 2019. Four reviewers carried out the selection, analysis, and evaluation of quality of studies. The random effects model was used to calculate the pooled relative risk (RR) and 95% confidence intervals (95% CI) when heterogeneity was greater than 50%.

Results:

The search resulted in 2,148 references and included 24 reports. Most of the studies had been conducted in Brazil and India, had a cohort design and included household, neighbors, and social contacts. The risk factors associated with illness due to leprosy in contacts were: illiteracy (RR = 1,48; 95%CI 1,22 - 1,79), living in the same house (RR = 2,41; 95%CI 1,87 - 3,10) of a case of leprosy with high bacillary load (RR = 2.40; 95%CI 1.69 - 3.41), seropositivity to the Mycobacterium leprae PGL-1 (phenolic glycolipid-1) antigen (RR = 3.54; 95%CI 2.21 - 5.67), presence of the bacillus in the bloodstream (RR = 10.61; 95%CI 4.74 - 23.77) and negative Mitsuda reaction (RR = 2,68; 95%CI 1,76 - 4,07). Immunization with BCG (bacillus Calmette-Guérin) vaccine had a protective effect against leprosy.

Conclusion:

Leprosy in contacts of patients involves social determination, individual susceptibility, and difficulties in access to disease control actions, but modifiable risk factors are the main determinants of illness in this population.

Keywords:
Leprosy; Risk factors; Social determinants of health; Epidemiological monitoring; Systematic review; Meta-analysis

INTRODUCTION

Leprosy is a chronic infectious disease caused by the bacillus Mycobacterium leprae (M. leprae). In 30 years of multidrug therapy, cases increased from more than 5 million annually to less than 200,000 in 2014¹1. World Health Organization. Global leprosy update, 2014: need for early case detection. Wkly Epidemiol Rec 2015; 90(36): 461-76.. This goal of less than one case per 10,000 inhabitants was reached by most countries in 2005; however, even nowadays, the elimination of leprosy remains a challenge in several countries²2. World Health Organization. Global leprosy update, 2013: reducing disease burden. Wkly Epidemiol Rec 2014; 89(36): 389-400..

In 2017, 210,671 new cases of leprosy were diagnosed globally³3. World Health Organization. Global leprosy update, 2017: reducing the disease burden due to leprosy. Wkly Epidemiol Rec 2018; 93(35): 445-56.. As control strategies, the treatment of patients, early diagnosis and surveillance of contacts contributed to the decrease in incidence⁴4. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância das Doenças Transmissíveis. Diretrizes para a vigilância, atenção e eliminação da hanseníase como problema de saúde pública: manual técnico-operacional. Brasília: Ministério da Saúde; 2016. 58 p.. However, there was an increase in prevalence across the world in 2017 compared to the previous year, with 20,765 more cases³3. World Health Organization. Global leprosy update, 2017: reducing the disease burden due to leprosy. Wkly Epidemiol Rec 2018; 93(35): 445-56.. The challenges of leprosy control include continued transmission of the bacillus, difficulties in surveillance of contacts, and limited knowledge about transmission⁵5. World Health Organization. Global leprosy strategy: accelerating towards a leprosy-free world. Nova Délhi: World Health Organization, Regional Office for South-East Asia; 2016. 34 p.. The prevention of leprosy requires interventions with emphasis on patient contacts⁶6. Moet FJ, Meima A, Oskam L, Richardus JH. Risk factors for the development of clinical leprosy among contacts, and their relevance for targeted interventions. Lepr Rev 2004; 75(4): 310-26. since contact is the main determinant for the lingering of incidence levels⁷7. van Beers SM, Hatta M, Klatser PR. Patient contact is the major determinant in incident leprosy: implications for future control. Int J Lepr Other Mycobact Dis 1999; 67(2): 119-28..

Studies have shown different dimensions of risk for the illness of people who got in contact with leprosy cases, enabling the monitoring of the effects of predictive variables⁸8. Moet FJ, Meima A, Oskam L, Richardus JH. Risk factors for the development of clinical leprosy among contacts, and their relevance for targeted interventions. Lepr Rev 2004; 75(4): 310-26. https://doi.org/10.47276/lr.75.4.310
https://doi.org/https://doi.org/10.47276... ^,99. Araújo S, Lobato J, Reis EM, Souza DOB, Gonçalves MA, Costa AV, et al. Unveiling healthy carriers and subclinical infections among household contacts of leprosy patients who play potential roles in the disease chain of transmission. Mem Inst Oswaldo Cruz 2012; 107(Supl. 1): 55-9. https://doi.org/10.1590/S0074-02762012000900010
https://doi.org/https://doi.org/10.1590/... . Systematic reviews on this theme are scarce and mostly address subclinical infection markers and the use of chemoprophylaxis to prevent the disease¹⁰10. Penna ML, Penna GO, Iglesias PC, Natal S, Rodrigues LC. Anti-PGL-1 Positivity as a Risk marker for the development of leprosy among contacts of leprosy cases: systematic review and meta-analysis. PLoS Negl Trop Dis 2016; 10(5): e0004703. https://doi.org/10.1371/journal.pntd.0004703
https://doi.org/https://doi.org/10.1371/... ^,1111. Ferreira SMB, Yonekura T, Ignotti E, Oliveira LB, Takahashi J, Soares CB. Effectiveness of rifampicin chemoprophylaxis in preventing leprosy in patient contacts: a systematic review of quantitative and qualitative evidence. JBI Database System Rev Implement Rep 2017; 15(10): 2555-84. https://doi.org/10.11124/JBISRIR-2016-003301
https://doi.org/https://doi.org/10.11124... . This study, therefore, intends to advance the discussion of the dimensions of risk for leprosy by incorporating current findings and contributing to establishing the profile of the individual, social and epidemiological characteristics that make contact groups vulnerable to this disease.

Leprosy-control policies reinforce the need for the systematic detection of contacts to identify those at higher risk of becoming ill⁵5. World Health Organization. Global leprosy strategy: accelerating towards a leprosy-free world. Nova Délhi: World Health Organization, Regional Office for South-East Asia; 2016. 34 p.. A more comprehensive understanding of factors that lead to individual vulnerability is needed. Thus, the aim of this study was to investigate the risk factors associated with the development of leprosy among contacts of patients.

METHODS

The protocol of this systematic review and meta-analysis was registered in the platform International Prospective Register of Systematic Reviews (PROSPERO) under the code CRD42019148528, and the report followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The following databases were searched between August and September 2019: Medical Literature Analysis and Retrieval System Online (MEDLINE), via PubMed, Embase, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Latino- American and Caribbean Health Sciences (LILACS), via the Virtual Health Library (VHL), Scopus and Web of Science.

The outcome investigated was clinical diagnosis of leprosy performed by a specialized professional in reference services or another health unit. “Contacts” were defined as individuals who lived with a person affected by leprosy in the same household or social environment at the time of diagnosis or in a previous period. In order to define the search terms, the controlled vocabularies Health Sciences Descriptors (DeCS), Medical Subject Headings (MeSH), and Embase Subject Headings (EMTREE) were consulted. Significant free terms were also included (Supplementary Material 1). No language or publication date/period filters were applied.

Studies published in full text, with a cohort, case-control, or cross-sectional design that included leprosy as an outcome and the use of measures of effect were included. Gray-literature productions were excluded, except for theses and dissertations, duplicates, qualitative review studies or meta-analyses, case reports, clinical trials, experimental studies, ecological studies, exclusively descriptive studies, and studies with no “contact” in the sample.

DATA COLLECTION AND ANALYSIS

The results were added up and duplicates were removed. The screening was performed by reading the title and abstract, followed by confirmation of eligibility by reading the full text by a pair of reviewers (ENAN and ICB; EOA and APMC) and independently. The information obtained was compared and any disagreements were resolved by consensus or a third reviewer. The Kappa statistical test identified significant agreement in the decision-making process of the pair of reviewers (kappa = 0.39; p = 0.005 and kappa = 0.74; p < 0.0001, respectively). The programs Rayyan QCRI (Qatar Computing Research Institute) and Mendeley were used to manage the references.

The following information was extracted from the eligible studies and added to a standardized table: authors, year of publication, journal, location and period of study, design, sample, contact characteristic, comparison group (if any), outcome, risk factors, and measures of effect, recorded with a 95% confidence interval (95%CI) and p-value, when available. For the systematic review, information was aggregated to allow descriptive synthesis and categorization of variables into three dimensions of risk factors: social determinants, genetic susceptibility, and characteristics of exposure to M. leprae.

For the meta-analysis, only cohort studies were included. A random-effects model was used in the presence of heterogeneity (I² ≥ 50%) and a fixed-effects model for heterogeneity below 50%. In studies that evaluated chemoprophylaxis, data from the placebo group were used. Surveys with overlapping samples, lack of stratified information, or categories that made comparisons impossible were excluded. In these cases, the results were presented in the systematic review.

We present the relative risks (RR) and 95%CI, using the Mantel-Haenszel method and assuming a p-value < 0.05 as significant. The results were grouped in a forest plot. Publication bias was assessed using a funnel plot. Heterogeneity between studies was assessed using the I² statistic analysis, defining values ​​< 25% as low heterogeneity, 25-50% as acceptable, and > 50% as high heterogeneity. Sensitivity analyses were based on the RR variation. The meta-analysis was conducted in the software Review Manager, version 5.4.1. The quality of work and the risk of bias were assessed using the Newcastle - Ottawa Quality Assessment Scale (NOS)¹²12. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa: University of Ottawa; 2014., specific for the evaluation of non-randomized studies. The instrument has three categories: selection, comparability, and exposure, totaling eight questions. Among possible answers, a star can be assigned to the one that defines the least possibility of bias. In the end, the responses with nine stars at most are added up. Studies with ≥ 7 stars are considered to have a low risk of bias and those with < 7 stars, a high risk of bias.

RESULTS

A total of 2,148 references were screened, 103 papers were selected for full reading and 23 were considered eligible. Additionally, we included a study present in the Theses Repository of Universidade Federal de Minas Gerais, Brazil. Figure 1 shows the selection process.

Of the 24 publications, 23 were cohort studies and one was a cross-sectional study. The follow-up period ranged from one to twenty years (Supplementary Material 2), the publication covered the period from 1991 to 2019 and the most frequent language was English, followed by Portuguese. Brazil and India were the most represented countries. The sample ranged from 68 to 28,092 participants. The contact categories were household, intra-household, neighbors, relatives, and social. The incidence of leprosy in contacts ranged from 0.21 to 21.7%, being lower in Venezuela and higher in Brazil. Risk factors are described in Supplementary Material 3. The excluded studies are presented in Supplementary Material 4.

The scores of study quality and risk of bias ranged from six to nine stars. Nineteen cohorts (79%) scored ≥ 7, indicating a low risk of bias. Sources of bias were associated with loss to follow-up and difficulties in comparisons between groups due to non-matching or lack of adjustment for confounding variables. The cross-sectional study was not evaluated due to the absence of a standardized questionnaire in the NOS instrument.

DOMAIN 1: SOCIAL DETERMINANTS

This domain included: sex, age, housing, income, and education. Sex and age were evaluated in seven cohort studies¹³13. Feenstra SG, Pahan D, Moet FJ, Oskam L, Richardus JH. Patient-related factors predicting the effectiveness of rifampicin chemoprophylaxis in contacts: 6 year follow up of the COLEP cohort in Bangladesh. Lepr Rev 2012; 83(3): 292-304.^,1414. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy-a population-based cohort study in Indonesia. Lepr Rev 2006; 77(1): 48-61.^,1515. Moet FJ, Pahan D, Schuring RP, Oskam L, Richardus JH. Physical distance, genetic relationship, age, and leprosy classification are independent risk factors for leprosy in contacts of patients with leprosy. J Infect Dis 2006; 193(3): 346-53. https://doi.org/10.1086/499278
https://doi.org/https://doi.org/10.1086/... ^,1616. Sales AM, Ponce de Leon A, Düppre NC, Hacker MA, Nery JA, Sarno EN, et al. Leprosy among patient contacts: a multilevel study of risk factors. PLoS Negl Trop Dis 2011; 5(8): e101371. https://doi.org/10.1371/journal.pntd.0001013
https://doi.org/https://doi.org/10.1371/... ^,1717. Fine PEM, Stern JAC, Pönnighaus JM, Bliss L, Saul J, Chihana A, et al. Household and dwelling contact as risk factors for leprosy in Northern Malawi. Am J Epidemiol 1997; 146(1): 91-102. https://doi.org/10.1093/oxfordjournals.aje.a009195
https://doi.org/https://doi.org/10.1093/... ^,1818. Düppre NC, Camacho LA, Sales AM, Illarramendi X, Nery JA, Sampaio EP, et al. Impact of PGL-I seropositivity on the protective effect of BCG vaccination among leprosy contacts: a cohort study. PLoS Negl Trop Dis 2012; 6(6): e1711. https://doi.org/10.1371/journal.pntd.0001711
https://doi.org/https://doi.org/10.1371/... ^,1919. Douglas JT, Cellona RV, Fajardo Jr. TT, Abalos RM, Balagon MV, Klatser PR. Prospective study of serological conversion as a risk factor for development of leprosy among household contacts. Clin Diagn Lab Immunol 2004; 11(5): 897-900. https://doi.org/10.1128/CDLI.11.5.897-900.2004
https://doi.org/https://doi.org/10.1128/... . Two studies reported a lower incidence of leprosy in children under five years of age¹³13. Feenstra SG, Pahan D, Moet FJ, Oskam L, Richardus JH. Patient-related factors predicting the effectiveness of rifampicin chemoprophylaxis in contacts: 6 year follow up of the COLEP cohort in Bangladesh. Lepr Rev 2012; 83(3): 292-304.^,1414. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy-a population-based cohort study in Indonesia. Lepr Rev 2006; 77(1): 48-61.. Ages from 15 to 19 years old and over 30 years old were associated with leprosy¹⁵15. Moet FJ, Pahan D, Schuring RP, Oskam L, Richardus JH. Physical distance, genetic relationship, age, and leprosy classification are independent risk factors for leprosy in contacts of patients with leprosy. J Infect Dis 2006; 193(3): 346-53. https://doi.org/10.1086/499278
https://doi.org/https://doi.org/10.1086/... . The association of sex with the disease showed conflicting results¹³13. Feenstra SG, Pahan D, Moet FJ, Oskam L, Richardus JH. Patient-related factors predicting the effectiveness of rifampicin chemoprophylaxis in contacts: 6 year follow up of the COLEP cohort in Bangladesh. Lepr Rev 2012; 83(3): 292-304.^,1414. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy-a population-based cohort study in Indonesia. Lepr Rev 2006; 77(1): 48-61.^,1515. Moet FJ, Pahan D, Schuring RP, Oskam L, Richardus JH. Physical distance, genetic relationship, age, and leprosy classification are independent risk factors for leprosy in contacts of patients with leprosy. J Infect Dis 2006; 193(3): 346-53. https://doi.org/10.1086/499278
https://doi.org/https://doi.org/10.1086/... ^,1616. Sales AM, Ponce de Leon A, Düppre NC, Hacker MA, Nery JA, Sarno EN, et al. Leprosy among patient contacts: a multilevel study of risk factors. PLoS Negl Trop Dis 2011; 5(8): e101371. https://doi.org/10.1371/journal.pntd.0001013
https://doi.org/https://doi.org/10.1371/... ^,1717. Fine PEM, Stern JAC, Pönnighaus JM, Bliss L, Saul J, Chihana A, et al. Household and dwelling contact as risk factors for leprosy in Northern Malawi. Am J Epidemiol 1997; 146(1): 91-102. https://doi.org/10.1093/oxfordjournals.aje.a009195
https://doi.org/https://doi.org/10.1093/... . The meta-analysis did not find a statistically significant association of these variables with the condition, with significant heterogeneity in studies that assessed gender (I² = 92%) (Figures 2A and 2B).

The relationship between family size and leprosy was investigated in two studies; one of them compared groups of contacts, finding no association¹³13. Feenstra SG, Pahan D, Moet FJ, Oskam L, Richardus JH. Patient-related factors predicting the effectiveness of rifampicin chemoprophylaxis in contacts: 6 year follow up of the COLEP cohort in Bangladesh. Lepr Rev 2012; 83(3): 292-304.; the other compared contacts and non-contacts and reported a higher risk between contacts living in environments with a greater number of people (hazard ratio = 3.47; p = 0.003)¹⁴14. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy-a population-based cohort study in Indonesia. Lepr Rev 2006; 77(1): 48-61.. Lower-income was not associated with the development of leprosy in contacts in an Indian study¹³13. Feenstra SG, Pahan D, Moet FJ, Oskam L, Richardus JH. Patient-related factors predicting the effectiveness of rifampicin chemoprophylaxis in contacts: 6 year follow up of the COLEP cohort in Bangladesh. Lepr Rev 2012; 83(3): 292-304.. On the other hand, in Brazil, contacts with a monthly income of less than three minimum wages had a greater chance of becoming ill, even when the family income of the leprosy case was analyzed¹⁶16. Sales AM, Ponce de Leon A, Düppre NC, Hacker MA, Nery JA, Sarno EN, et al. Leprosy among patient contacts: a multilevel study of risk factors. PLoS Negl Trop Dis 2011; 5(8): e101371. https://doi.org/10.1371/journal.pntd.0001013
https://doi.org/https://doi.org/10.1371/... . Two studies assessed schooling¹³13. Feenstra SG, Pahan D, Moet FJ, Oskam L, Richardus JH. Patient-related factors predicting the effectiveness of rifampicin chemoprophylaxis in contacts: 6 year follow up of the COLEP cohort in Bangladesh. Lepr Rev 2012; 83(3): 292-304.^,1616. Sales AM, Ponce de Leon A, Düppre NC, Hacker MA, Nery JA, Sarno EN, et al. Leprosy among patient contacts: a multilevel study of risk factors. PLoS Negl Trop Dis 2011; 5(8): e101371. https://doi.org/10.1371/journal.pntd.0001013
https://doi.org/https://doi.org/10.1371/... ; only one reported a higher risk of leprosy among people with less education¹⁶16. Sales AM, Ponce de Leon A, Düppre NC, Hacker MA, Nery JA, Sarno EN, et al. Leprosy among patient contacts: a multilevel study of risk factors. PLoS Negl Trop Dis 2011; 5(8): e101371. https://doi.org/10.1371/journal.pntd.0001013
https://doi.org/https://doi.org/10.1371/... . Differences in categorization made the meta-analysis of housing and income impossible. The meta-analysis of schooling showed a higher risk of leprosy in illiterate contacts (RR = 1.48; 95%CI 1.22 - 1.79; p < 0.0001) (Figure 2C).

DOMAIN 2: GENETIC SUSCEPTIBILITY

This domain included consanguinity, evaluated in four studies¹⁵15. Moet FJ, Pahan D, Schuring RP, Oskam L, Richardus JH. Physical distance, genetic relationship, age, and leprosy classification are independent risk factors for leprosy in contacts of patients with leprosy. J Infect Dis 2006; 193(3): 346-53. https://doi.org/10.1086/499278
https://doi.org/https://doi.org/10.1086/... ^,1616. Sales AM, Ponce de Leon A, Düppre NC, Hacker MA, Nery JA, Sarno EN, et al. Leprosy among patient contacts: a multilevel study of risk factors. PLoS Negl Trop Dis 2011; 5(8): e101371. https://doi.org/10.1371/journal.pntd.0001013
https://doi.org/https://doi.org/10.1371/... ^,2020. Durães SM, Guedes LS, Cunha MD, Magnanini MM, Oliveira ML. Epidemiologic study of 107 cases of families with leprosy in Duque de Caxias, Rio de Janeiro, Brazil. An Bras Dermatol 2010; 85(3): 339-45. http://dx.doi.org/10.1590/S0365-05962010000300007
https://doi.org/http://dx.doi.org/10.159... ^,2121. Durães SMB, Guedes LS, da Cunha MD, Cavaliere FAM, de Oliveira MLWDR. Estudo de 20 focos familiares de hanseníase no município de Duque de Caxias, Rio de Janeiro. An Bras Dermatol 2005; 80(Supl. 3): S295-300. http://dx.doi.org/10.1590/S0365-05962005001000006
https://doi.org/http://dx.doi.org/10.159... . All papers reported a significantly higher chance of leprosy in consanguineous contacts, especially first-degree relatives¹⁵15. Moet FJ, Pahan D, Schuring RP, Oskam L, Richardus JH. Physical distance, genetic relationship, age, and leprosy classification are independent risk factors for leprosy in contacts of patients with leprosy. J Infect Dis 2006; 193(3): 346-53. https://doi.org/10.1086/499278
https://doi.org/https://doi.org/10.1086/... ^,1616. Sales AM, Ponce de Leon A, Düppre NC, Hacker MA, Nery JA, Sarno EN, et al. Leprosy among patient contacts: a multilevel study of risk factors. PLoS Negl Trop Dis 2011; 5(8): e101371. https://doi.org/10.1371/journal.pntd.0001013
https://doi.org/https://doi.org/10.1371/... ^,2020. Durães SM, Guedes LS, Cunha MD, Magnanini MM, Oliveira ML. Epidemiologic study of 107 cases of families with leprosy in Duque de Caxias, Rio de Janeiro, Brazil. An Bras Dermatol 2010; 85(3): 339-45. http://dx.doi.org/10.1590/S0365-05962010000300007
https://doi.org/http://dx.doi.org/10.159... ^,2121. Durães SMB, Guedes LS, da Cunha MD, Cavaliere FAM, de Oliveira MLWDR. Estudo de 20 focos familiares de hanseníase no município de Duque de Caxias, Rio de Janeiro. An Bras Dermatol 2005; 80(Supl. 3): S295-300. http://dx.doi.org/10.1590/S0365-05962005001000006
https://doi.org/http://dx.doi.org/10.159... . This association remained significant in the adjusted analyses¹⁵15. Moet FJ, Pahan D, Schuring RP, Oskam L, Richardus JH. Physical distance, genetic relationship, age, and leprosy classification are independent risk factors for leprosy in contacts of patients with leprosy. J Infect Dis 2006; 193(3): 346-53. https://doi.org/10.1086/499278
https://doi.org/https://doi.org/10.1086/... ^,1616. Sales AM, Ponce de Leon A, Düppre NC, Hacker MA, Nery JA, Sarno EN, et al. Leprosy among patient contacts: a multilevel study of risk factors. PLoS Negl Trop Dis 2011; 5(8): e101371. https://doi.org/10.1371/journal.pntd.0001013
https://doi.org/https://doi.org/10.1371/... ^,2020. Durães SM, Guedes LS, Cunha MD, Magnanini MM, Oliveira ML. Epidemiologic study of 107 cases of families with leprosy in Duque de Caxias, Rio de Janeiro, Brazil. An Bras Dermatol 2010; 85(3): 339-45. http://dx.doi.org/10.1590/S0365-05962010000300007
https://doi.org/http://dx.doi.org/10.159... . Second-degree relative or other kinship was not associated with the development of leprosy; however, one study reported a higher risk among spouses (odds ratio = 3.29; 95%CI 1.56 - 6.96)¹⁵15. Moet FJ, Pahan D, Schuring RP, Oskam L, Richardus JH. Physical distance, genetic relationship, age, and leprosy classification are independent risk factors for leprosy in contacts of patients with leprosy. J Infect Dis 2006; 193(3): 346-53. https://doi.org/10.1086/499278
https://doi.org/https://doi.org/10.1086/... . Only two papers were included in the meta-analysis¹⁶16. Sales AM, Ponce de Leon A, Düppre NC, Hacker MA, Nery JA, Sarno EN, et al. Leprosy among patient contacts: a multilevel study of risk factors. PLoS Negl Trop Dis 2011; 5(8): e101371. https://doi.org/10.1371/journal.pntd.0001013
https://doi.org/https://doi.org/10.1371/... ^,2020. Durães SM, Guedes LS, Cunha MD, Magnanini MM, Oliveira ML. Epidemiologic study of 107 cases of families with leprosy in Duque de Caxias, Rio de Janeiro, Brazil. An Bras Dermatol 2010; 85(3): 339-45. http://dx.doi.org/10.1590/S0365-05962010000300007
https://doi.org/http://dx.doi.org/10.159... . There was a higher risk of leprosy development in consanguineous contacts, however, the association was borderline (RR = 1.32; 95%CI 0.98 - 1.78; p = 0.07) (Figure 2D).

DOMAIN 3: EXPOSURE TO MYCOBACTERIUM LEPRAE

This domain included aspects of living with the leprosy patient and immune responses triggered by exposure to the bacillus. Aspects of living with the patient included contact characteristics and clinical characteristics of the case. As for the characteristics of the contact, the most frequent variable was the type of contact included in nine studies¹⁴14. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy-a population-based cohort study in Indonesia. Lepr Rev 2006; 77(1): 48-61.^,1515. Moet FJ, Pahan D, Schuring RP, Oskam L, Richardus JH. Physical distance, genetic relationship, age, and leprosy classification are independent risk factors for leprosy in contacts of patients with leprosy. J Infect Dis 2006; 193(3): 346-53. https://doi.org/10.1086/499278
https://doi.org/https://doi.org/10.1086/... ^,1616. Sales AM, Ponce de Leon A, Düppre NC, Hacker MA, Nery JA, Sarno EN, et al. Leprosy among patient contacts: a multilevel study of risk factors. PLoS Negl Trop Dis 2011; 5(8): e101371. https://doi.org/10.1371/journal.pntd.0001013
https://doi.org/https://doi.org/10.1371/... ^,1717. Fine PEM, Stern JAC, Pönnighaus JM, Bliss L, Saul J, Chihana A, et al. Household and dwelling contact as risk factors for leprosy in Northern Malawi. Am J Epidemiol 1997; 146(1): 91-102. https://doi.org/10.1093/oxfordjournals.aje.a009195
https://doi.org/https://doi.org/10.1093/... ^,1818. Düppre NC, Camacho LA, Sales AM, Illarramendi X, Nery JA, Sampaio EP, et al. Impact of PGL-I seropositivity on the protective effect of BCG vaccination among leprosy contacts: a cohort study. PLoS Negl Trop Dis 2012; 6(6): e1711. https://doi.org/10.1371/journal.pntd.0001711
https://doi.org/https://doi.org/10.1371/... ^,2020. Durães SM, Guedes LS, Cunha MD, Magnanini MM, Oliveira ML. Epidemiologic study of 107 cases of families with leprosy in Duque de Caxias, Rio de Janeiro, Brazil. An Bras Dermatol 2010; 85(3): 339-45. http://dx.doi.org/10.1590/S0365-05962010000300007
https://doi.org/http://dx.doi.org/10.159... ^,2222. Brasil MTLRF, de Oliveira LR, Rímoli NS, Cavallari FS, Gonçalves OS, Lessa ZL, et al. Sorologia Anti PGL-1 e risco de ocorrência de hanseníase em área de alta endemicidade do Estado de São Paulo: quatro anos de seguimento. Rev Bras Epidemiol 2003; 6(3): 262-71. http://dx.doi.org/10.1590/S1415-790X2003000300010
https://doi.org/http://dx.doi.org/10.159... ^,2424. Ortuno-Gutierrez N, Baco A, Braet S, Younoussa A, Mzembaba A, Salim Z, et al. Clustering of leprosy beyond the household level in a highly endemic setting on the Comoros, an observational study. BMC Infect Dis 2019; 19(1): 501. https://doi.org/10.1186/s12879-019-4116-y
https://doi.org/https://doi.org/10.1186/... . Eight reported a higher risk of leprosy development in household contacts¹¹⁴14. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy-a population-based cohort study in Indonesia. Lepr Rev 2006; 77(1): 48-61.^,1616. Sales AM, Ponce de Leon A, Düppre NC, Hacker MA, Nery JA, Sarno EN, et al. Leprosy among patient contacts: a multilevel study of risk factors. PLoS Negl Trop Dis 2011; 5(8): e101371. https://doi.org/10.1371/journal.pntd.0001013
https://doi.org/https://doi.org/10.1371/... ^,1717. Fine PEM, Stern JAC, Pönnighaus JM, Bliss L, Saul J, Chihana A, et al. Household and dwelling contact as risk factors for leprosy in Northern Malawi. Am J Epidemiol 1997; 146(1): 91-102. https://doi.org/10.1093/oxfordjournals.aje.a009195
https://doi.org/https://doi.org/10.1093/... ^,1818. Düppre NC, Camacho LA, Sales AM, Illarramendi X, Nery JA, Sampaio EP, et al. Impact of PGL-I seropositivity on the protective effect of BCG vaccination among leprosy contacts: a cohort study. PLoS Negl Trop Dis 2012; 6(6): e1711. https://doi.org/10.1371/journal.pntd.0001711
https://doi.org/https://doi.org/10.1371/... ^,2020. Durães SM, Guedes LS, Cunha MD, Magnanini MM, Oliveira ML. Epidemiologic study of 107 cases of families with leprosy in Duque de Caxias, Rio de Janeiro, Brazil. An Bras Dermatol 2010; 85(3): 339-45. http://dx.doi.org/10.1590/S0365-05962010000300007
https://doi.org/http://dx.doi.org/10.159... ^,2222. Brasil MTLRF, de Oliveira LR, Rímoli NS, Cavallari FS, Gonçalves OS, Lessa ZL, et al. Sorologia Anti PGL-1 e risco de ocorrência de hanseníase em área de alta endemicidade do Estado de São Paulo: quatro anos de seguimento. Rev Bras Epidemiol 2003; 6(3): 262-71. http://dx.doi.org/10.1590/S1415-790X2003000300010
https://doi.org/http://dx.doi.org/10.159... ^,2323. Chanteau S, Glaziou P, Plichart C, Luquiaud P, Plichart R, Faucher JF, et al. Low predictive value of PGL-I serology for the early diagnosis of leprosy in family contacts: results of a 10-year prospective field study in French Polynesia. Int J Lepr Other Mycobact Dis 1993; 61(4): 533-41.^,2424. Ortuno-Gutierrez N, Baco A, Braet S, Younoussa A, Mzembaba A, Salim Z, et al. Clustering of leprosy beyond the household level in a highly endemic setting on the Comoros, an observational study. BMC Infect Dis 2019; 19(1): 501. https://doi.org/10.1186/s12879-019-4116-y
https://doi.org/https://doi.org/10.1186/... ^. In the meta-analysis, household contact was a risk factor for the disease when compared with individuals without contact (RR = 1.72; 95%CI 1.45 - 2.05; p < 0.00001) and also with neighbors of leprosy patients (RR = 2.41; 95%CI 1.87 - 3.10; p < 0.00001) (Figures 3A and 3B). The physical distance from a patient was evaluated in three investigations¹⁴14. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy-a population-based cohort study in Indonesia. Lepr Rev 2006; 77(1): 48-61.^,1515. Moet FJ, Pahan D, Schuring RP, Oskam L, Richardus JH. Physical distance, genetic relationship, age, and leprosy classification are independent risk factors for leprosy in contacts of patients with leprosy. J Infect Dis 2006; 193(3): 346-53. https://doi.org/10.1086/499278
https://doi.org/https://doi.org/10.1086/... ^,2424. Ortuno-Gutierrez N, Baco A, Braet S, Younoussa A, Mzembaba A, Salim Z, et al. Clustering of leprosy beyond the household level in a highly endemic setting on the Comoros, an observational study. BMC Infect Dis 2019; 19(1): 501. https://doi.org/10.1186/s12879-019-4116-y
https://doi.org/https://doi.org/10.1186/... . A physical distance ≤ 25 meters was related to a greater chance of leprosy development in studies in India¹⁵15. Moet FJ, Pahan D, Schuring RP, Oskam L, Richardus JH. Physical distance, genetic relationship, age, and leprosy classification are independent risk factors for leprosy in contacts of patients with leprosy. J Infect Dis 2006; 193(3): 346-53. https://doi.org/10.1086/499278
https://doi.org/https://doi.org/10.1086/... and Comoros²⁴24. Ortuno-Gutierrez N, Baco A, Braet S, Younoussa A, Mzembaba A, Salim Z, et al. Clustering of leprosy beyond the household level in a highly endemic setting on the Comoros, an observational study. BMC Infect Dis 2019; 19(1): 501. https://doi.org/10.1186/s12879-019-4116-y
https://doi.org/https://doi.org/10.1186/... , although in Indonesia no significant association was found¹⁴14. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy-a population-based cohort study in Indonesia. Lepr Rev 2006; 77(1): 48-61..

Living with leprosy cases for at least five years increased the chance of becoming ill by two times¹⁶16. Sales AM, Ponce de Leon A, Düppre NC, Hacker MA, Nery JA, Sarno EN, et al. Leprosy among patient contacts: a multilevel study of risk factors. PLoS Negl Trop Dis 2011; 5(8): e101371. https://doi.org/10.1371/journal.pntd.0001013
https://doi.org/https://doi.org/10.1371/... . A higher risk was also reported in unvaccinated contacts who lived with cases for a period equal to or greater than 21 years¹⁸18. Düppre NC, Camacho LA, Sales AM, Illarramendi X, Nery JA, Sampaio EP, et al. Impact of PGL-I seropositivity on the protective effect of BCG vaccination among leprosy contacts: a cohort study. PLoS Negl Trop Dis 2012; 6(6): e1711. https://doi.org/10.1371/journal.pntd.0001711
https://doi.org/https://doi.org/10.1371/... . Living with more than one patient increased the chance of becoming ill in contacts from two to six times¹³13. Feenstra SG, Pahan D, Moet FJ, Oskam L, Richardus JH. Patient-related factors predicting the effectiveness of rifampicin chemoprophylaxis in contacts: 6 year follow up of the COLEP cohort in Bangladesh. Lepr Rev 2012; 83(3): 292-304.^,1414. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy-a population-based cohort study in Indonesia. Lepr Rev 2006; 77(1): 48-61.^,2525. Barreto JG, Bisanzio D, Frade MA, Moraes TM, Gobbo AR, de Souza Guimarães L, et al. Spatial epidemiology and serologic cohorts increase the early detection of leprosy. BMC Infect Dis 2015; 15: 527. .https://doi.org/10.1186/s12879-015-1254-8
https://doi.org/https://doi.org/10.1186/... , even in those who received chemoprophylaxis with a dose of rifampicin¹³13. Feenstra SG, Pahan D, Moet FJ, Oskam L, Richardus JH. Patient-related factors predicting the effectiveness of rifampicin chemoprophylaxis in contacts: 6 year follow up of the COLEP cohort in Bangladesh. Lepr Rev 2012; 83(3): 292-304.. The clinical characteristics of the patients were evaluated in nine studies¹⁴14. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy-a population-based cohort study in Indonesia. Lepr Rev 2006; 77(1): 48-61.^,1515. Moet FJ, Pahan D, Schuring RP, Oskam L, Richardus JH. Physical distance, genetic relationship, age, and leprosy classification are independent risk factors for leprosy in contacts of patients with leprosy. J Infect Dis 2006; 193(3): 346-53. https://doi.org/10.1086/499278
https://doi.org/https://doi.org/10.1086/... ^,1616. Sales AM, Ponce de Leon A, Düppre NC, Hacker MA, Nery JA, Sarno EN, et al. Leprosy among patient contacts: a multilevel study of risk factors. PLoS Negl Trop Dis 2011; 5(8): e101371. https://doi.org/10.1371/journal.pntd.0001013
https://doi.org/https://doi.org/10.1371/... ^,1717. Fine PEM, Stern JAC, Pönnighaus JM, Bliss L, Saul J, Chihana A, et al. Household and dwelling contact as risk factors for leprosy in Northern Malawi. Am J Epidemiol 1997; 146(1): 91-102. https://doi.org/10.1093/oxfordjournals.aje.a009195
https://doi.org/https://doi.org/10.1093/... ^,1818. Düppre NC, Camacho LA, Sales AM, Illarramendi X, Nery JA, Sampaio EP, et al. Impact of PGL-I seropositivity on the protective effect of BCG vaccination among leprosy contacts: a cohort study. PLoS Negl Trop Dis 2012; 6(6): e1711. https://doi.org/10.1371/journal.pntd.0001711
https://doi.org/https://doi.org/10.1371/... ^,1919. Douglas JT, Cellona RV, Fajardo Jr. TT, Abalos RM, Balagon MV, Klatser PR. Prospective study of serological conversion as a risk factor for development of leprosy among household contacts. Clin Diagn Lab Immunol 2004; 11(5): 897-900. https://doi.org/10.1128/CDLI.11.5.897-900.2004
https://doi.org/https://doi.org/10.1128/... ^,2626. Matos HJ. Modelagem de dados epidemiológicos de contatos de hanseníase em uma coorte acompanhada na Fundação Oswaldo Cruz, Rio de Janeiro, entre 1987 a 1998 [dissertação]. Rio de Janeiro: Fundação Oswaldo Cruz; 2000. 116 p.^,2727. Goulart IM, Bernardes Souza DO, Marques CR, Pimenta VL, Gonçalves MA, Goulart LR. Risk and protective factors for leprosy development determined by epidemiological surveillance of household contacts. Clin Vaccine Immunol 2008; 15(1): 101-5. https://doi.org/10.1128/CVI.00372-07
https://doi.org/https://doi.org/10.1128/... ^,2929. Araujo S, Rezende MM, Sousa DC, Rosa MR, Santos DC, Goulart LR, et al. Risk-benefit assessment of Bacillus Calmette-Guérin vaccination, anti-phenolic glycolipid I serology, and Mitsuda test response: 10-year follow-up of household contacts of leprosy patients. Rev Soc Bras Med Trop 2015; 48(6): 739-45. https://doi.org/10.1590/0037-8682-0245-2015
https://doi.org/https://doi.org/10.1590/... . Of these, eight reported a higher risk of leprosy in contacts of patients with multibacillary forms (MB) ¹⁴14. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy-a population-based cohort study in Indonesia. Lepr Rev 2006; 77(1): 48-61.^,1515. Moet FJ, Pahan D, Schuring RP, Oskam L, Richardus JH. Physical distance, genetic relationship, age, and leprosy classification are independent risk factors for leprosy in contacts of patients with leprosy. J Infect Dis 2006; 193(3): 346-53. https://doi.org/10.1086/499278
https://doi.org/https://doi.org/10.1086/... ^,1717. Fine PEM, Stern JAC, Pönnighaus JM, Bliss L, Saul J, Chihana A, et al. Household and dwelling contact as risk factors for leprosy in Northern Malawi. Am J Epidemiol 1997; 146(1): 91-102. https://doi.org/10.1093/oxfordjournals.aje.a009195
https://doi.org/https://doi.org/10.1093/... ^,1919. Douglas JT, Cellona RV, Fajardo Jr. TT, Abalos RM, Balagon MV, Klatser PR. Prospective study of serological conversion as a risk factor for development of leprosy among household contacts. Clin Diagn Lab Immunol 2004; 11(5): 897-900. https://doi.org/10.1128/CDLI.11.5.897-900.2004
https://doi.org/https://doi.org/10.1128/... ^,2626. Matos HJ. Modelagem de dados epidemiológicos de contatos de hanseníase em uma coorte acompanhada na Fundação Oswaldo Cruz, Rio de Janeiro, entre 1987 a 1998 [dissertação]. Rio de Janeiro: Fundação Oswaldo Cruz; 2000. 116 p.^,2727. Goulart IM, Bernardes Souza DO, Marques CR, Pimenta VL, Gonçalves MA, Goulart LR. Risk and protective factors for leprosy development determined by epidemiological surveillance of household contacts. Clin Vaccine Immunol 2008; 15(1): 101-5. https://doi.org/10.1128/CVI.00372-07
https://doi.org/https://doi.org/10.1128/... ^,2828. Vijayakumaran P, Jesudasan K, Mozhi NM, Samuel JD. Does MDT arrest transmission of leprosy to household contacts? Int J Lepr Other Mycobact Dis 1998; 66(2): 125-30., especially household contacts younger than 15 years¹⁷17. Fine PEM, Stern JAC, Pönnighaus JM, Bliss L, Saul J, Chihana A, et al. Household and dwelling contact as risk factors for leprosy in Northern Malawi. Am J Epidemiol 1997; 146(1): 91-102. https://doi.org/10.1093/oxfordjournals.aje.a009195
https://doi.org/https://doi.org/10.1093/... . Two studies found a greater chance of leprosy among contacts of paucibacillary cases (PB)¹⁷17. Fine PEM, Stern JAC, Pönnighaus JM, Bliss L, Saul J, Chihana A, et al. Household and dwelling contact as risk factors for leprosy in Northern Malawi. Am J Epidemiol 1997; 146(1): 91-102. https://doi.org/10.1093/oxfordjournals.aje.a009195
https://doi.org/https://doi.org/10.1093/... ^,1919. Douglas JT, Cellona RV, Fajardo Jr. TT, Abalos RM, Balagon MV, Klatser PR. Prospective study of serological conversion as a risk factor for development of leprosy among household contacts. Clin Diagn Lab Immunol 2004; 11(5): 897-900. https://doi.org/10.1128/CDLI.11.5.897-900.2004
https://doi.org/https://doi.org/10.1128/... . The meta-analysis showed that there was a greater risk among contacts of MB cases compared to PB cases, but this association was not statistically significant (RR = 1.23; 95%CI 0.93 - 1.64) (Figure 3C).

Four studies reported a greater chance of leprosy in contacts of patients with positive bacilloscopic index (BI)¹⁴14. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy-a population-based cohort study in Indonesia. Lepr Rev 2006; 77(1): 48-61.^,1616. Sales AM, Ponce de Leon A, Düppre NC, Hacker MA, Nery JA, Sarno EN, et al. Leprosy among patient contacts: a multilevel study of risk factors. PLoS Negl Trop Dis 2011; 5(8): e101371. https://doi.org/10.1371/journal.pntd.0001013
https://doi.org/https://doi.org/10.1371/... ^,1818. Düppre NC, Camacho LA, Sales AM, Illarramendi X, Nery JA, Sampaio EP, et al. Impact of PGL-I seropositivity on the protective effect of BCG vaccination among leprosy contacts: a cohort study. PLoS Negl Trop Dis 2012; 6(6): e1711. https://doi.org/10.1371/journal.pntd.0001711
https://doi.org/https://doi.org/10.1371/... ^,2828. Vijayakumaran P, Jesudasan K, Mozhi NM, Samuel JD. Does MDT arrest transmission of leprosy to household contacts? Int J Lepr Other Mycobact Dis 1998; 66(2): 125-30.. Contacts of patients with BI > 2+ had three times the risk of becoming ill¹⁶16. Sales AM, Ponce de Leon A, Düppre NC, Hacker MA, Nery JA, Sarno EN, et al. Leprosy among patient contacts: a multilevel study of risk factors. PLoS Negl Trop Dis 2011; 5(8): e101371. https://doi.org/10.1371/journal.pntd.0001013
https://doi.org/https://doi.org/10.1371/... ^,2828. Vijayakumaran P, Jesudasan K, Mozhi NM, Samuel JD. Does MDT arrest transmission of leprosy to household contacts? Int J Lepr Other Mycobact Dis 1998; 66(2): 125-30.. This risk increased from four to seven times for contacts of patients with BI > 3+¹⁶16. Sales AM, Ponce de Leon A, Düppre NC, Hacker MA, Nery JA, Sarno EN, et al. Leprosy among patient contacts: a multilevel study of risk factors. PLoS Negl Trop Dis 2011; 5(8): e101371. https://doi.org/10.1371/journal.pntd.0001013
https://doi.org/https://doi.org/10.1371/... . Contacts of families whose sum of BI was > 3.6 also had a higher risk of developing the disease, regardless of immunization with bacillus Calmette-Guérin (BCG)¹⁸18. Düppre NC, Camacho LA, Sales AM, Illarramendi X, Nery JA, Sampaio EP, et al. Impact of PGL-I seropositivity on the protective effect of BCG vaccination among leprosy contacts: a cohort study. PLoS Negl Trop Dis 2012; 6(6): e1711. https://doi.org/10.1371/journal.pntd.0001711
https://doi.org/https://doi.org/10.1371/... . The meta-analysis showed that contacts of patients with BI > 3+ had a higher risk of becoming ill (RR = 2.40; 95%CI 1.69 - 3.41; p < 0.0001), however heterogeneity between studies was high (I² = 53%) (Figure 3D). Living with patients presenting physical disabilities increased the chance of leprosy in contacts by almost ten times¹⁴14. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy-a population-based cohort study in Indonesia. Lepr Rev 2006; 77(1): 48-61.^,1616. Sales AM, Ponce de Leon A, Düppre NC, Hacker MA, Nery JA, Sarno EN, et al. Leprosy among patient contacts: a multilevel study of risk factors. PLoS Negl Trop Dis 2011; 5(8): e101371. https://doi.org/10.1371/journal.pntd.0001013
https://doi.org/https://doi.org/10.1371/... .

Eight cohorts analyzed BCG vaccination as an interaction factor and in adjusted analyses,¹⁴14. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy-a population-based cohort study in Indonesia. Lepr Rev 2006; 77(1): 48-61.^,1515. Moet FJ, Pahan D, Schuring RP, Oskam L, Richardus JH. Physical distance, genetic relationship, age, and leprosy classification are independent risk factors for leprosy in contacts of patients with leprosy. J Infect Dis 2006; 193(3): 346-53. https://doi.org/10.1086/499278
https://doi.org/https://doi.org/10.1086/... ^,1616. Sales AM, Ponce de Leon A, Düppre NC, Hacker MA, Nery JA, Sarno EN, et al. Leprosy among patient contacts: a multilevel study of risk factors. PLoS Negl Trop Dis 2011; 5(8): e101371. https://doi.org/10.1371/journal.pntd.0001013
https://doi.org/https://doi.org/10.1371/... ^,1717. Fine PEM, Stern JAC, Pönnighaus JM, Bliss L, Saul J, Chihana A, et al. Household and dwelling contact as risk factors for leprosy in Northern Malawi. Am J Epidemiol 1997; 146(1): 91-102. https://doi.org/10.1093/oxfordjournals.aje.a009195
https://doi.org/https://doi.org/10.1093/... ^,1818. Düppre NC, Camacho LA, Sales AM, Illarramendi X, Nery JA, Sampaio EP, et al. Impact of PGL-I seropositivity on the protective effect of BCG vaccination among leprosy contacts: a cohort study. PLoS Negl Trop Dis 2012; 6(6): e1711. https://doi.org/10.1371/journal.pntd.0001711
https://doi.org/https://doi.org/10.1371/... ^,2626. Matos HJ. Modelagem de dados epidemiológicos de contatos de hanseníase em uma coorte acompanhada na Fundação Oswaldo Cruz, Rio de Janeiro, entre 1987 a 1998 [dissertação]. Rio de Janeiro: Fundação Oswaldo Cruz; 2000. 116 p.^,2727. Goulart IM, Bernardes Souza DO, Marques CR, Pimenta VL, Gonçalves MA, Goulart LR. Risk and protective factors for leprosy development determined by epidemiological surveillance of household contacts. Clin Vaccine Immunol 2008; 15(1): 101-5. https://doi.org/10.1128/CVI.00372-07
https://doi.org/https://doi.org/10.1128/... ^,2929. Araujo S, Rezende MM, Sousa DC, Rosa MR, Santos DC, Goulart LR, et al. Risk-benefit assessment of Bacillus Calmette-Guérin vaccination, anti-phenolic glycolipid I serology, and Mitsuda test response: 10-year follow-up of household contacts of leprosy patients. Rev Soc Bras Med Trop 2015; 48(6): 739-45. https://doi.org/10.1590/0037-8682-0245-2015
https://doi.org/https://doi.org/10.1590/... , but only Brazilian studies reported a significant reduction in the chance of developing the disease¹⁶16. Sales AM, Ponce de Leon A, Düppre NC, Hacker MA, Nery JA, Sarno EN, et al. Leprosy among patient contacts: a multilevel study of risk factors. PLoS Negl Trop Dis 2011; 5(8): e101371. https://doi.org/10.1371/journal.pntd.0001013
https://doi.org/https://doi.org/10.1371/... ^,2626. Matos HJ. Modelagem de dados epidemiológicos de contatos de hanseníase em uma coorte acompanhada na Fundação Oswaldo Cruz, Rio de Janeiro, entre 1987 a 1998 [dissertação]. Rio de Janeiro: Fundação Oswaldo Cruz; 2000. 116 p.^,2727. Goulart IM, Bernardes Souza DO, Marques CR, Pimenta VL, Gonçalves MA, Goulart LR. Risk and protective factors for leprosy development determined by epidemiological surveillance of household contacts. Clin Vaccine Immunol 2008; 15(1): 101-5. https://doi.org/10.1128/CVI.00372-07
https://doi.org/https://doi.org/10.1128/... ^,2929. Araujo S, Rezende MM, Sousa DC, Rosa MR, Santos DC, Goulart LR, et al. Risk-benefit assessment of Bacillus Calmette-Guérin vaccination, anti-phenolic glycolipid I serology, and Mitsuda test response: 10-year follow-up of household contacts of leprosy patients. Rev Soc Bras Med Trop 2015; 48(6): 739-45. https://doi.org/10.1590/0037-8682-0245-2015
https://doi.org/https://doi.org/10.1590/... . Studies conducted in Indonesia, India, Malawi, and some in Brazil did not report a significant association¹⁴14. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy-a population-based cohort study in Indonesia. Lepr Rev 2006; 77(1): 48-61.^,1515. Moet FJ, Pahan D, Schuring RP, Oskam L, Richardus JH. Physical distance, genetic relationship, age, and leprosy classification are independent risk factors for leprosy in contacts of patients with leprosy. J Infect Dis 2006; 193(3): 346-53. https://doi.org/10.1086/499278
https://doi.org/https://doi.org/10.1086/... ^,1717. Fine PEM, Stern JAC, Pönnighaus JM, Bliss L, Saul J, Chihana A, et al. Household and dwelling contact as risk factors for leprosy in Northern Malawi. Am J Epidemiol 1997; 146(1): 91-102. https://doi.org/10.1093/oxfordjournals.aje.a009195
https://doi.org/https://doi.org/10.1093/... ^,1818. Düppre NC, Camacho LA, Sales AM, Illarramendi X, Nery JA, Sampaio EP, et al. Impact of PGL-I seropositivity on the protective effect of BCG vaccination among leprosy contacts: a cohort study. PLoS Negl Trop Dis 2012; 6(6): e1711. https://doi.org/10.1371/journal.pntd.0001711
https://doi.org/https://doi.org/10.1371/... . In the meta-analysis, the presence of a vaccine scar was associated with protection against leprosy in contacts (OR = 0.52; 95%CI 0.34 - 0.78; p = 0.002) (Figure 4A). Selecting works from different countries resulted in a significant heterogeneity (I² = 78%). In the sensitivity analysis that included only Brazilian studies¹⁶16. Sales AM, Ponce de Leon A, Düppre NC, Hacker MA, Nery JA, Sarno EN, et al. Leprosy among patient contacts: a multilevel study of risk factors. PLoS Negl Trop Dis 2011; 5(8): e101371. https://doi.org/10.1371/journal.pntd.0001013
https://doi.org/https://doi.org/10.1371/... ^,2626. Matos HJ. Modelagem de dados epidemiológicos de contatos de hanseníase em uma coorte acompanhada na Fundação Oswaldo Cruz, Rio de Janeiro, entre 1987 a 1998 [dissertação]. Rio de Janeiro: Fundação Oswaldo Cruz; 2000. 116 p.^,2929. Araujo S, Rezende MM, Sousa DC, Rosa MR, Santos DC, Goulart LR, et al. Risk-benefit assessment of Bacillus Calmette-Guérin vaccination, anti-phenolic glycolipid I serology, and Mitsuda test response: 10-year follow-up of household contacts of leprosy patients. Rev Soc Bras Med Trop 2015; 48(6): 739-45. https://doi.org/10.1590/0037-8682-0245-2015
https://doi.org/https://doi.org/10.1590/... , the association remained significant (RR = 0.40; 95%CI 0.30 - 0.54), with high heterogeneity (I² = 57%).

Seropositivity to M. leprae antigens was addressed in 15 papers¹⁴14. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy-a population-based cohort study in Indonesia. Lepr Rev 2006; 77(1): 48-61.^,1818. Düppre NC, Camacho LA, Sales AM, Illarramendi X, Nery JA, Sampaio EP, et al. Impact of PGL-I seropositivity on the protective effect of BCG vaccination among leprosy contacts: a cohort study. PLoS Negl Trop Dis 2012; 6(6): e1711. https://doi.org/10.1371/journal.pntd.0001711
https://doi.org/https://doi.org/10.1371/... ^,1919. Douglas JT, Cellona RV, Fajardo Jr. TT, Abalos RM, Balagon MV, Klatser PR. Prospective study of serological conversion as a risk factor for development of leprosy among household contacts. Clin Diagn Lab Immunol 2004; 11(5): 897-900. https://doi.org/10.1128/CDLI.11.5.897-900.2004
https://doi.org/https://doi.org/10.1128/... ^,2222. Brasil MTLRF, de Oliveira LR, Rímoli NS, Cavallari FS, Gonçalves OS, Lessa ZL, et al. Sorologia Anti PGL-1 e risco de ocorrência de hanseníase em área de alta endemicidade do Estado de São Paulo: quatro anos de seguimento. Rev Bras Epidemiol 2003; 6(3): 262-71. http://dx.doi.org/10.1590/S1415-790X2003000300010
https://doi.org/http://dx.doi.org/10.159... ^,2323. Chanteau S, Glaziou P, Plichart C, Luquiaud P, Plichart R, Faucher JF, et al. Low predictive value of PGL-I serology for the early diagnosis of leprosy in family contacts: results of a 10-year prospective field study in French Polynesia. Int J Lepr Other Mycobact Dis 1993; 61(4): 533-41.^,2525. Barreto JG, Bisanzio D, Frade MA, Moraes TM, Gobbo AR, de Souza Guimarães L, et al. Spatial epidemiology and serologic cohorts increase the early detection of leprosy. BMC Infect Dis 2015; 15: 527. .https://doi.org/10.1186/s12879-015-1254-8
https://doi.org/https://doi.org/10.1186/... ^,2727. Goulart IM, Bernardes Souza DO, Marques CR, Pimenta VL, Gonçalves MA, Goulart LR. Risk and protective factors for leprosy development determined by epidemiological surveillance of household contacts. Clin Vaccine Immunol 2008; 15(1): 101-5. https://doi.org/10.1128/CVI.00372-07
https://doi.org/https://doi.org/10.1128/... ^,2929. Araujo S, Rezende MM, Sousa DC, Rosa MR, Santos DC, Goulart LR, et al. Risk-benefit assessment of Bacillus Calmette-Guérin vaccination, anti-phenolic glycolipid I serology, and Mitsuda test response: 10-year follow-up of household contacts of leprosy patients. Rev Soc Bras Med Trop 2015; 48(6): 739-45. https://doi.org/10.1590/0037-8682-0245-2015
https://doi.org/https://doi.org/10.1590/... ^,3030. Nagao-Dias AT, Casimiro de Macedo A, Rodrigues RO, Pedroza FHC, Albuquerque AA, Moreira FA, et al. Serum Anti-PGL-1 IgG, IgM, and IgA in a 3-Year Follow-up Study of 4-15-Year-old Leprosy Contacts. Pediatr Infect Dis J 2019; 38(9): e193-e198. https://doi.org/10.1097/INF.0000000000002337
https://doi.org/https://doi.org/10.1097/... ^,3131. Ulrich M, Smith PG, Sampson C, Zuniga M, Centeno M, Garcia V, et al. IgM antibodies to native phenolic glycolipid-I in contacts of leprosy patients in Venezuela: epidemiological observations and a prospective study of the risk of leprosy. Int J Lepr Other Mycobact Dis 1991; 59(3): 405-15.^,3232. Reis EM, Araújo S, Lobato J, Neves AF, Costa AV, Gonçalves MA, et al. Mycobacterium leprae DNA in peripheral blood may indicate a bacilli migration route and high-risk for leprosy onset. Clin Microbiol Infect 2014; 20(5): 447-52. https://doi.org/10.1111/1469-0691.12349
https://doi.org/https://doi.org/10.1111/... ^,3333. Araújo S, Freitas LO, Goulart LR, Goulart IM. Molecular evidence for the aerial route of infection of Mycobacterium leprae and the role of asymptomatic carriers in the persistence of leprosy. Clin Infect Dis 2016; 63(11): 1412-20. https://doi.org/10.1093/cid/ciw570
https://doi.org/https://doi.org/10.1093/... ^,3434. Andrade ARC. Incidência de hanseníase nos contatos submetidos ao teste sorológico ML Flow em municípios de Minas Gerais [dissertation]. Belo Horizonte: Universidade Federal de Minas Gerais; 2012. 120 p.^,3535. Richardus RA, van der Zwet K, van Hooij A, Wilson L, Oskam L, Faber R, et al. Longitudinal assessment of anti-PGL-I serology in contacts of leprosy patients in Bangladesh. PLoS Negl Trop Dis 2017; 11(12): e0006083. https://doi.org/10.1371/journal.pntd.0006083
https://doi.org/https://doi.org/10.1371/... ^,3636. Dayal R, Bharadwaj VP. Prevention and early detection of leprosy in children. J Trop Pediatr 1995; 41(3): 132-8. https://doi.org/10.1093/tropej/41.3.132
https://doi.org/https://doi.org/10.1093/... . Eleven studies reported a significant increase in the risk of leprosy in contacts with anti-PGL-1 (anti-phenolic glycolipid- 1) seropositivity¹⁴14. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy-a population-based cohort study in Indonesia. Lepr Rev 2006; 77(1): 48-61.^,1818. Düppre NC, Camacho LA, Sales AM, Illarramendi X, Nery JA, Sampaio EP, et al. Impact of PGL-I seropositivity on the protective effect of BCG vaccination among leprosy contacts: a cohort study. PLoS Negl Trop Dis 2012; 6(6): e1711. https://doi.org/10.1371/journal.pntd.0001711
https://doi.org/https://doi.org/10.1371/... ^,2222. Brasil MTLRF, de Oliveira LR, Rímoli NS, Cavallari FS, Gonçalves OS, Lessa ZL, et al. Sorologia Anti PGL-1 e risco de ocorrência de hanseníase em área de alta endemicidade do Estado de São Paulo: quatro anos de seguimento. Rev Bras Epidemiol 2003; 6(3): 262-71. http://dx.doi.org/10.1590/S1415-790X2003000300010
https://doi.org/http://dx.doi.org/10.159... ^,2525. Barreto JG, Bisanzio D, Frade MA, Moraes TM, Gobbo AR, de Souza Guimarães L, et al. Spatial epidemiology and serologic cohorts increase the early detection of leprosy. BMC Infect Dis 2015; 15: 527. .https://doi.org/10.1186/s12879-015-1254-8
https://doi.org/https://doi.org/10.1186/... ^,2727. Goulart IM, Bernardes Souza DO, Marques CR, Pimenta VL, Gonçalves MA, Goulart LR. Risk and protective factors for leprosy development determined by epidemiological surveillance of household contacts. Clin Vaccine Immunol 2008; 15(1): 101-5. https://doi.org/10.1128/CVI.00372-07
https://doi.org/https://doi.org/10.1128/... ^,2929. Araujo S, Rezende MM, Sousa DC, Rosa MR, Santos DC, Goulart LR, et al. Risk-benefit assessment of Bacillus Calmette-Guérin vaccination, anti-phenolic glycolipid I serology, and Mitsuda test response: 10-year follow-up of household contacts of leprosy patients. Rev Soc Bras Med Trop 2015; 48(6): 739-45. https://doi.org/10.1590/0037-8682-0245-2015
https://doi.org/https://doi.org/10.1590/... ^,3030. Nagao-Dias AT, Casimiro de Macedo A, Rodrigues RO, Pedroza FHC, Albuquerque AA, Moreira FA, et al. Serum Anti-PGL-1 IgG, IgM, and IgA in a 3-Year Follow-up Study of 4-15-Year-old Leprosy Contacts. Pediatr Infect Dis J 2019; 38(9): e193-e198. https://doi.org/10.1097/INF.0000000000002337
https://doi.org/https://doi.org/10.1097/... ^,3131. Ulrich M, Smith PG, Sampson C, Zuniga M, Centeno M, Garcia V, et al. IgM antibodies to native phenolic glycolipid-I in contacts of leprosy patients in Venezuela: epidemiological observations and a prospective study of the risk of leprosy. Int J Lepr Other Mycobact Dis 1991; 59(3): 405-15.^,3232. Reis EM, Araújo S, Lobato J, Neves AF, Costa AV, Gonçalves MA, et al. Mycobacterium leprae DNA in peripheral blood may indicate a bacilli migration route and high-risk for leprosy onset. Clin Microbiol Infect 2014; 20(5): 447-52. https://doi.org/10.1111/1469-0691.12349
https://doi.org/https://doi.org/10.1111/... ^,3333. Araújo S, Freitas LO, Goulart LR, Goulart IM. Molecular evidence for the aerial route of infection of Mycobacterium leprae and the role of asymptomatic carriers in the persistence of leprosy. Clin Infect Dis 2016; 63(11): 1412-20. https://doi.org/10.1093/cid/ciw570
https://doi.org/https://doi.org/10.1093/... ^,3434. Andrade ARC. Incidência de hanseníase nos contatos submetidos ao teste sorológico ML Flow em municípios de Minas Gerais [dissertation]. Belo Horizonte: Universidade Federal de Minas Gerais; 2012. 120 p., even in children under fifteen years of age³⁶36. Dayal R, Bharadwaj VP. Prevention and early detection of leprosy in children. J Trop Pediatr 1995; 41(3): 132-8. https://doi.org/10.1093/tropej/41.3.132
https://doi.org/https://doi.org/10.1093/... . The meta-analysis found that the risk of leprosy in contacts with positive anti-PGL-1 serology was significantly higher compared to contacts with negative serology (RR = 3.54; 95%CI 2.21 - 5.67; p < 0.0001) (Figure 4B). However, the analysis with all studies revealed significant heterogeneity (I² = 78%).

Due to the use of different serological analysis methods, it was decided to perform a sensitivity analysis that would restrict the meta-analysis to studies that used the Enzyme-Linked Immunosorbent Assay (ELISA) technique, with a cut-off point lower than 0.3. This resulted in five papers¹⁴14. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy-a population-based cohort study in Indonesia. Lepr Rev 2006; 77(1): 48-61.^,2323. Chanteau S, Glaziou P, Plichart C, Luquiaud P, Plichart R, Faucher JF, et al. Low predictive value of PGL-I serology for the early diagnosis of leprosy in family contacts: results of a 10-year prospective field study in French Polynesia. Int J Lepr Other Mycobact Dis 1993; 61(4): 533-41.^,2525. Barreto JG, Bisanzio D, Frade MA, Moraes TM, Gobbo AR, de Souza Guimarães L, et al. Spatial epidemiology and serologic cohorts increase the early detection of leprosy. BMC Infect Dis 2015; 15: 527. .https://doi.org/10.1186/s12879-015-1254-8
https://doi.org/https://doi.org/10.1186/... ^,3131. Ulrich M, Smith PG, Sampson C, Zuniga M, Centeno M, Garcia V, et al. IgM antibodies to native phenolic glycolipid-I in contacts of leprosy patients in Venezuela: epidemiological observations and a prospective study of the risk of leprosy. Int J Lepr Other Mycobact Dis 1991; 59(3): 405-15.^,3535. Richardus RA, van der Zwet K, van Hooij A, Wilson L, Oskam L, Faber R, et al. Longitudinal assessment of anti-PGL-I serology in contacts of leprosy patients in Bangladesh. PLoS Negl Trop Dis 2017; 11(12): e0006083. https://doi.org/10.1371/journal.pntd.0006083
https://doi.org/https://doi.org/10.1371/... . After adjustment, the association of anti-PGL-1 seropositivity with the illness of contacts remained significant (RR = 2.41; 95%CI 1.62 - 3.59) and with no heterogeneity (I² = 0%). A similar result was observed when studies that assessed serology using the ML Flow test were included²²22. Brasil MTLRF, de Oliveira LR, Rímoli NS, Cavallari FS, Gonçalves OS, Lessa ZL, et al. Sorologia Anti PGL-1 e risco de ocorrência de hanseníase em área de alta endemicidade do Estado de São Paulo: quatro anos de seguimento. Rev Bras Epidemiol 2003; 6(3): 262-71. http://dx.doi.org/10.1590/S1415-790X2003000300010
https://doi.org/http://dx.doi.org/10.159... ^.3434. Andrade ARC. Incidência de hanseníase nos contatos submetidos ao teste sorológico ML Flow em municípios de Minas Gerais [dissertation]. Belo Horizonte: Universidade Federal de Minas Gerais; 2012. 120 p. (RR = 2.06; 95%CI 1.44 - 2.95; I² = 0%).

Five studies analyzed the Mitsuda reaction in contacts²⁶26. Matos HJ. Modelagem de dados epidemiológicos de contatos de hanseníase em uma coorte acompanhada na Fundação Oswaldo Cruz, Rio de Janeiro, entre 1987 a 1998 [dissertação]. Rio de Janeiro: Fundação Oswaldo Cruz; 2000. 116 p.^,2727. Goulart IM, Bernardes Souza DO, Marques CR, Pimenta VL, Gonçalves MA, Goulart LR. Risk and protective factors for leprosy development determined by epidemiological surveillance of household contacts. Clin Vaccine Immunol 2008; 15(1): 101-5. https://doi.org/10.1128/CVI.00372-07
https://doi.org/https://doi.org/10.1128/... ^,2929. Araujo S, Rezende MM, Sousa DC, Rosa MR, Santos DC, Goulart LR, et al. Risk-benefit assessment of Bacillus Calmette-Guérin vaccination, anti-phenolic glycolipid I serology, and Mitsuda test response: 10-year follow-up of household contacts of leprosy patients. Rev Soc Bras Med Trop 2015; 48(6): 739-45. https://doi.org/10.1590/0037-8682-0245-2015
https://doi.org/https://doi.org/10.1590/... ^,3232. Reis EM, Araújo S, Lobato J, Neves AF, Costa AV, Gonçalves MA, et al. Mycobacterium leprae DNA in peripheral blood may indicate a bacilli migration route and high-risk for leprosy onset. Clin Microbiol Infect 2014; 20(5): 447-52. https://doi.org/10.1111/1469-0691.12349
https://doi.org/https://doi.org/10.1111/... ^,3333. Araújo S, Freitas LO, Goulart LR, Goulart IM. Molecular evidence for the aerial route of infection of Mycobacterium leprae and the role of asymptomatic carriers in the persistence of leprosy. Clin Infect Dis 2016; 63(11): 1412-20. https://doi.org/10.1093/cid/ciw570
https://doi.org/https://doi.org/10.1093/... . A positive reaction was associated with protection against the disease²⁷27. Goulart IM, Bernardes Souza DO, Marques CR, Pimenta VL, Gonçalves MA, Goulart LR. Risk and protective factors for leprosy development determined by epidemiological surveillance of household contacts. Clin Vaccine Immunol 2008; 15(1): 101-5. https://doi.org/10.1128/CVI.00372-07
https://doi.org/https://doi.org/10.1128/... ^,2929. Araujo S, Rezende MM, Sousa DC, Rosa MR, Santos DC, Goulart LR, et al. Risk-benefit assessment of Bacillus Calmette-Guérin vaccination, anti-phenolic glycolipid I serology, and Mitsuda test response: 10-year follow-up of household contacts of leprosy patients. Rev Soc Bras Med Trop 2015; 48(6): 739-45. https://doi.org/10.1590/0037-8682-0245-2015
https://doi.org/https://doi.org/10.1590/... ^,3232. Reis EM, Araújo S, Lobato J, Neves AF, Costa AV, Gonçalves MA, et al. Mycobacterium leprae DNA in peripheral blood may indicate a bacilli migration route and high-risk for leprosy onset. Clin Microbiol Infect 2014; 20(5): 447-52. https://doi.org/10.1111/1469-0691.12349
https://doi.org/https://doi.org/10.1111/... , and the reaction < 7 mm, along with anti-PGL-1 seropositivity, was proven to be a risk factor²⁶26. Matos HJ. Modelagem de dados epidemiológicos de contatos de hanseníase em uma coorte acompanhada na Fundação Oswaldo Cruz, Rio de Janeiro, entre 1987 a 1998 [dissertação]. Rio de Janeiro: Fundação Oswaldo Cruz; 2000. 116 p.^,2929. Araujo S, Rezende MM, Sousa DC, Rosa MR, Santos DC, Goulart LR, et al. Risk-benefit assessment of Bacillus Calmette-Guérin vaccination, anti-phenolic glycolipid I serology, and Mitsuda test response: 10-year follow-up of household contacts of leprosy patients. Rev Soc Bras Med Trop 2015; 48(6): 739-45. https://doi.org/10.1590/0037-8682-0245-2015
https://doi.org/https://doi.org/10.1590/... . The pooled estimates showed a higher risk of leprosy in contacts with a negative reaction (RR = 2.68; 95%CI 1.76 - 4.07; p < 0.0001) (Figure 4C).

The presence of bacillary deoxyribonucleic acid (DNA) in the nasal mucosa of contacts increased the risk of leprosy³³33. Araújo S, Freitas LO, Goulart LR, Goulart IM. Molecular evidence for the aerial route of infection of Mycobacterium leprae and the role of asymptomatic carriers in the persistence of leprosy. Clin Infect Dis 2016; 63(11): 1412-20. https://doi.org/10.1093/cid/ciw570
https://doi.org/https://doi.org/10.1093/... , being 14 times higher when present in the bloodstream³²32. Reis EM, Araújo S, Lobato J, Neves AF, Costa AV, Gonçalves MA, et al. Mycobacterium leprae DNA in peripheral blood may indicate a bacilli migration route and high-risk for leprosy onset. Clin Microbiol Infect 2014; 20(5): 447-52. https://doi.org/10.1111/1469-0691.12349
https://doi.org/https://doi.org/10.1111/... ^,3333. Araújo S, Freitas LO, Goulart LR, Goulart IM. Molecular evidence for the aerial route of infection of Mycobacterium leprae and the role of asymptomatic carriers in the persistence of leprosy. Clin Infect Dis 2016; 63(11): 1412-20. https://doi.org/10.1093/cid/ciw570
https://doi.org/https://doi.org/10.1093/... . Living with patients that presented bacillary DNA in the nasal mucosa was also a risk factor¹⁴14. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy-a population-based cohort study in Indonesia. Lepr Rev 2006; 77(1): 48-61.. The meta-analysis showed that contacts with bacillus DNA in the bloodstream had a higher risk of developing leprosy (OR = 10.61; 95%CI 4.74 - 23.77; p < 0.0001). However, the studies were conducted at the same reference center, which suggests the possibility of sample overlap and overestimation of the pooled statistics.

Sensitivity analysis in studies with a low risk of bias showed no differences in pooled statistics. Visual inspection via funnel plot of all studies showed asymmetry, suggesting a risk of publication bias (Supplementary Material 5). The presence of a void in the lower-left portion of the funnel suggests that smaller studies that evaluated variables associated with protection may not have been published.

DISCUSSION

The systematic review showed a higher risk of leprosy among contacts who were young and adults, who lived with patients in crowded households, had lower income and low education. The meta-analysis confirmed the greatest risk for illiterate contacts.

The incidence of leprosy among young people indicates early exposure to M. leprae. The disease’s incubation period lasts, on average, five years²⁷27. Goulart IM, Bernardes Souza DO, Marques CR, Pimenta VL, Gonçalves MA, Goulart LR. Risk and protective factors for leprosy development determined by epidemiological surveillance of household contacts. Clin Vaccine Immunol 2008; 15(1): 101-5. https://doi.org/10.1128/CVI.00372-07
https://doi.org/https://doi.org/10.1128/... , which is why the illness in young people denotes continued transmission of the bacillus. Households with a greater density of residents facilitate transmission through close contact¹⁴14. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy-a population-based cohort study in Indonesia. Lepr Rev 2006; 77(1): 48-61.. Systematic reviews and meta-analysis studies reported a greater chance of leprosy among individuals with worse housing conditions, low education, the experience of scarcity or reduction in the variety of foods, unemployment, and lower income. These conditions also contributed to severe physical disabilities, impaired social participation, and worsened quality of life³⁷37. Pescarini JM, Strina A, Nery JS, Skalinski LM, Andrade KVF, Penna MLF, et al. Socioeconomic risk markers of leprosy in high-burden countries: A systematic review and meta-analysis. PLoS Negl Trop Dis 2018; 12(7): e0006622. https://doi.org/10.1371/journal.pntd.0006622
https://doi.org/https://doi.org/10.1371/... ^,3838. Leano HAM, Araújo KMDFA, Bueno IC, Niitsuma ENA, Lana FCF. Socioeconomic factors related to leprosy: an integrative literature review. Rev Bras Enferm 2019; 72(5): 1405-15. http://dx.doi.org/10.1590/0034-7167-2017-0651
https://doi.org/http://dx.doi.org/10.159... . Brazil, India, and Indonesia are the countries with the highest leprosy burden in the world³3. World Health Organization. Global leprosy update, 2017: reducing the disease burden due to leprosy. Wkly Epidemiol Rec 2018; 93(35): 445-56. and have a significant portion of their populations living with extreme difficulty in accessing minimal resources for survival³⁹39. The World Bank [Internet]. Washington, D.C.: The World Bank; 2020 [acessado em 10 out. 2020]. Disponível em: Disponível em: https://databank.worldbank.org/reports.aspx?source=2&series=SI.POV.UMIC&country=
https://databank.worldbank.org/reports.a... . The persistence of poverty, social inequality, and gaps in addressing social determinants are the main challenges in eliminating leprosy. Vulnerable populations commonly face barriers to accessing state goods and services, including access to early diagnosis of leprosy, timely treatment, and management of physical disabilities⁴⁰40. Cruz A. Relatório redigido pela Relatora Especial a respeito da eliminação da discriminação contra pessoas atingidas pela Lepra e seus familiares. Brasília: Defensoria Pública da União; 2020. 18 p..

The systematic review and meta-analysis showed conflicting results of the risk of becoming ill according to the sex of contacts. In the adult population, a lower proportion of leprosy notifications is observed among females, while in children this distribution is usually the same between sexes⁵5. World Health Organization. Global leprosy strategy: accelerating towards a leprosy-free world. Nova Délhi: World Health Organization, Regional Office for South-East Asia; 2016. 34 p.. Differences can be explained by the influence of gender on access to health care, cultural factors, restrictions on women’s social participation, and physiological differences associated with the risk of or protection against leprosy⁵5. World Health Organization. Global leprosy strategy: accelerating towards a leprosy-free world. Nova Délhi: World Health Organization, Regional Office for South-East Asia; 2016. 34 p.^,1313. Feenstra SG, Pahan D, Moet FJ, Oskam L, Richardus JH. Patient-related factors predicting the effectiveness of rifampicin chemoprophylaxis in contacts: 6 year follow up of the COLEP cohort in Bangladesh. Lepr Rev 2012; 83(3): 292-304.^,1717. Fine PEM, Stern JAC, Pönnighaus JM, Bliss L, Saul J, Chihana A, et al. Household and dwelling contact as risk factors for leprosy in Northern Malawi. Am J Epidemiol 1997; 146(1): 91-102. https://doi.org/10.1093/oxfordjournals.aje.a009195
https://doi.org/https://doi.org/10.1093/... .

Consanguinity was repeatedly reported as a risk factor for leprosy in contacts; the meta-analysis, however, did not show a significant association. The number of studies included and their heterogeneity influenced the significance of the analysis. The risk of leprosy seems to depend on the individual’s genetic background⁴¹41. Alter A, Grant A, Abel L, Alcaïs A, Schurr E. Leprosy as a genetic disease. Mamm Genome 2011; 22(1-2): 19-31. https://doi.org/10.1007/s00335-010-9287-1
https://doi.org/https://doi.org/10.1007/... . Genetic susceptibility to leprosy involves genes that encode functional products involved in immunological pathways⁴²42. Alcaïs A, Abel L, Casanova JL. Human genetics of infectious diseases: between proof of principle and paradigm. J Clin Invest 2009; 119(9): 2506-14. https://doi.org/10.1172/JCI38111
https://doi.org/https://doi.org/10.1172/... , such as lymphotoxin-α⁴³43. Mira MT, Alcaïs A, Van Thuc N, Thai VH, Huong NT, Ba NN, et al. Chromosome 6q25 is linked to susceptibility to leprosy in a Vietnamese population. Nat Genet 2003; 33(3): 412-5. https://doi.org/10.1038/ng1096
https://doi.org/https://doi.org/10.1038/... , parkin (PARK2), and parkin coregulated gene (PACRG)⁴⁴44. Schurr E, Alcaïs A, de Léséleuc L, Abel L. Genetic predisposition to leprosy: A major gene reveals novel pathways of immunity to Mycobacterium leprae. Semin Immunol 2006; 18(6): 404-10. https://doi.org/10.1016/j.smim.2006.07.005
https://doi.org/https://doi.org/10.1016/... , interleukin 10 (IL-10)⁴⁵45. Aggarwal S, Ali S, Chopra R, Srivastava A, Kalaiarasan P, Malhotra D, et al. Genetic variations and interactions in anti-inflammatory cytokine pathway genes in the outcome of leprosy: a study conducted on a MassARRAY platform. J Infect Dis 2011; 204(8): 1264-73. https://doi.org/10.1093/infdis/jir516
https://doi.org/https://doi.org/10.1093/... , interferon-gamma (IFN- γ)⁴⁶46. Silva GA, Santos MP, Mota-Passos I, Boechat AL, Malheiro A, Naveca FG, et al. IFN-γ +875 microsatellite polymorphism as a potential protection marker for leprosy patients from Amazonas state, Brazil. Cytokine 2012; 60(2): 493-7. https://doi.org/10.1016/j.cyto.2012.04.043
https://doi.org/https://doi.org/10.1016/... and pattern recognition receptor (PRR) genes⁴⁷47. Marques CS, Brito-de-Souza VN, Guerreiro LT, Martins JH, Amaral EP, Cardoso CC, et al. Toll-like receptor 1 N248S single-nucleotide polymorphism is associated with leprosy risk and regulates immune activation during mycobacterial infection. J Infect Dis 2013; 208(1): 120-9. https://doi.org/10.1093/infdis/jit133
https://doi.org/https://doi.org/10.1093/... ^,4848. Sales-Marques C, Salomão H, Fava VM, Alvarado-Arnez LE, Amaral EP, Cardoso CC, et al. NOD2 and CCDC122-LACC1 genes are associated with leprosy susceptibility in Brazilians. Hum Genet 2014; 133(12): 1525-32. https://doi.org/10.1007/s00439-014-1502-9
https://doi.org/https://doi.org/10.1007/... . The genetic architecture of leprosy is still not well understood. Further studies are needed to clarify the share of the risk attributable to genetics in the susceptibility to leprosy.

Household contact was an important risk factor for leprosy. A survey showed that contact surveillance linked 28% of incident cases to a source of intra-household transmission and 36% to transmission in the neighborhood. The inclusion of social contacts would allow identifying 15% more incident cases⁷7. van Beers SM, Hatta M, Klatser PR. Patient contact is the major determinant in incident leprosy: implications for future control. Int J Lepr Other Mycobact Dis 1999; 67(2): 119-28., reinforcing that the inclusion of social contacts in surveillance allows for greater coverage in the detection of individuals at risk.

There was also a significant risk of leprosy among contacts of high BI cases. Operational difficulties of health services, reflected by the presence of undiagnosed multibacillary patients, the increase in the number of cases in the dwelling environment, and the evolution to physical disabilities, impact the risk of illness in contacts¹⁴14. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy-a population-based cohort study in Indonesia. Lepr Rev 2006; 77(1): 48-61.^,1717. Fine PEM, Stern JAC, Pönnighaus JM, Bliss L, Saul J, Chihana A, et al. Household and dwelling contact as risk factors for leprosy in Northern Malawi. Am J Epidemiol 1997; 146(1): 91-102. https://doi.org/10.1093/oxfordjournals.aje.a009195
https://doi.org/https://doi.org/10.1093/... . To achieve the goals of reducing the burden of leprosy in priority countries, specific strategies may not be enough to reduce the risk of this illness in vulnerable populations. Access to universal health coverage and the strengthening of leprosy control actions are rather necessary.

Bacillus antigens seropositivity, the presence of bacillary DNA in the airways and bloodstream, and a negative response to the Mitsuda test were also risk factors for leprosy in contacts. The positive reaction to the Mitsuda test indicates a predominance of the cellular immune response, resulting in a protective effect of acquired immunity²⁷27. Goulart IM, Bernardes Souza DO, Marques CR, Pimenta VL, Gonçalves MA, Goulart LR. Risk and protective factors for leprosy development determined by epidemiological surveillance of household contacts. Clin Vaccine Immunol 2008; 15(1): 101-5. https://doi.org/10.1128/CVI.00372-07
https://doi.org/https://doi.org/10.1128/... . Bacillary DNA in the airways and/or bloodstream indicates passage of the bacillus through the upper respiratory tract, colonization of macrophages, and passage of the phagocytosed bacillus by immune system cells towards more favorable sites, such as skin and peripheral nerves²⁷27. Goulart IM, Bernardes Souza DO, Marques CR, Pimenta VL, Gonçalves MA, Goulart LR. Risk and protective factors for leprosy development determined by epidemiological surveillance of household contacts. Clin Vaccine Immunol 2008; 15(1): 101-5. https://doi.org/10.1128/CVI.00372-07
https://doi.org/https://doi.org/10.1128/... ^,3232. Reis EM, Araújo S, Lobato J, Neves AF, Costa AV, Gonçalves MA, et al. Mycobacterium leprae DNA in peripheral blood may indicate a bacilli migration route and high-risk for leprosy onset. Clin Microbiol Infect 2014; 20(5): 447-52. https://doi.org/10.1111/1469-0691.12349
https://doi.org/https://doi.org/10.1111/... . The presence of bacillary DNA in biological samples and seropositivity for bacillus antigens suggests subclinical infection in contacts, making them more prone to developing the disease²⁷27. Goulart IM, Bernardes Souza DO, Marques CR, Pimenta VL, Gonçalves MA, Goulart LR. Risk and protective factors for leprosy development determined by epidemiological surveillance of household contacts. Clin Vaccine Immunol 2008; 15(1): 101-5. https://doi.org/10.1128/CVI.00372-07
https://doi.org/https://doi.org/10.1128/... ^,3232. Reis EM, Araújo S, Lobato J, Neves AF, Costa AV, Gonçalves MA, et al. Mycobacterium leprae DNA in peripheral blood may indicate a bacilli migration route and high-risk for leprosy onset. Clin Microbiol Infect 2014; 20(5): 447-52. https://doi.org/10.1111/1469-0691.12349
https://doi.org/https://doi.org/10.1111/... ^,3333. Araújo S, Freitas LO, Goulart LR, Goulart IM. Molecular evidence for the aerial route of infection of Mycobacterium leprae and the role of asymptomatic carriers in the persistence of leprosy. Clin Infect Dis 2016; 63(11): 1412-20. https://doi.org/10.1093/cid/ciw570
https://doi.org/https://doi.org/10.1093/... .

M. leprae antigens seropositivity is a biomarker of infection at the individual level²⁵25. Barreto JG, Bisanzio D, Frade MA, Moraes TM, Gobbo AR, de Souza Guimarães L, et al. Spatial epidemiology and serologic cohorts increase the early detection of leprosy. BMC Infect Dis 2015; 15: 527. .https://doi.org/10.1186/s12879-015-1254-8
https://doi.org/https://doi.org/10.1186/... , indicating a potential source of transmission, the need for greater surveillance and, possibly, the use of chemoprophylaxis¹⁴14. Bakker MI, Hatta M, Kwenang A, Van Mosseveld P, Faber WR, Klatser PR, et al. Risk factors for developing leprosy-a population-based cohort study in Indonesia. Lepr Rev 2006; 77(1): 48-61.. However, as a result of the low sensitivity of the tests, the applicability for early detection of cases is still uncertain and seronegative contacts should not be neglected¹⁸18. Düppre NC, Camacho LA, Sales AM, Illarramendi X, Nery JA, Sampaio EP, et al. Impact of PGL-I seropositivity on the protective effect of BCG vaccination among leprosy contacts: a cohort study. PLoS Negl Trop Dis 2012; 6(6): e1711. https://doi.org/10.1371/journal.pntd.0001711
https://doi.org/https://doi.org/10.1371/... ^,2525. Barreto JG, Bisanzio D, Frade MA, Moraes TM, Gobbo AR, de Souza Guimarães L, et al. Spatial epidemiology and serologic cohorts increase the early detection of leprosy. BMC Infect Dis 2015; 15: 527. .https://doi.org/10.1186/s12879-015-1254-8
https://doi.org/https://doi.org/10.1186/... .

The evaluation of the effect of the BCG vaccine had conflicting results because of the high heterogeneity between studies, possibly due to differences in methodology and related to the setting in which the research was conducted. BCG acts on the immune system by increasing M. leprae-responsive T cells and the production of inflammatory mediators⁴⁹49. Carvalho FM, Rodrigues LS, Duppre NC, Alvim IMP, Ribeiro-Alves M, Pinheiro RO, et al. Interruption of persistent exposure to leprosy combined or not with recent BCG vaccination enhances the response to Mycobacterium leprae specific antigens. PLoS Negl Trop Dis 2017; 11(5): e0005560. https://doi.org/10.1371/journal.pntd.0005560
https://doi.org/https://doi.org/10.1371/... . Leprosy control policies in Brazil recommend that household contacts without signs suggestive of the disease be immunized with an additional dose of BCG⁴4. Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância das Doenças Transmissíveis. Diretrizes para a vigilância, atenção e eliminação da hanseníase como problema de saúde pública: manual técnico-operacional. Brasília: Ministério da Saúde; 2016. 58 p.. Thus, the results of Brazilian studies may be related to the extensive policy of immunization with BCG in childhood and the revaccination of contacts in the country.

Given the multidimensionality and complexity of the interaction between risk factors, the limitations of this study include isolated and punctual analysis, which makes it impossible to assess the relationship between factors jointly, and the comparability between studies from countries that diverge from each other in socioeconomic issues, in the endemicity of leprosy and in the access to health care. The small number of studies included in the analysis of each risk factor, heterogeneity, and the possibility of publication bias are limitations of the meta-analysis.

The risk of becoming ill from contacts permeates social vulnerability, individual susceptibility, and difficulties in accessing health services. Despite the influence of immune responses on disease susceptibility, modifiable risk factors seem to be the main determinants of illness from leprosy among contacts.

A comprehensive analysis of risk factors for leprosy can contribute to improving the surveillance of contacts by health professionals, enabling the application of this knowledge in instruments that allow the stratification of individual risk. Evidence shows that the reduction of leprosy burden involves identifying vulnerable groups and requires intersectoral coordination to ensure access to policies for social inclusion, education, income and the promotion of equity in access to health services, in addition to strengthening the leprosy control activities.

References

Publication Dates

History