Leprosy is a chronic human disease caused by the yet-uncultured pathogen Mycobacterium leprae. Although readily curable with multidrug therapy (MDT), over 200,000 new cases are still reported annually. Here, we obtain M. leprae genome sequences from DNA extracted directly from patients’ skin biopsies using a customized protocol. Comparative and phylogenetic analysis of 154 genomes from 25 countries provides insight into evolution and antimicrobial resistance, uncovering lineages and phylogeographic trends, with the most ancestral strains linked to the Far East. In addition to known MDT-resistance mutations, we detect other mutations associated with antibiotic resistance, and retrace a potential stepwise emergence of extensive drug resistance in the pre-MDT era. Some of the previously undescribed mutations occur in genes that are apparently subject to positive selection, and two of these (ribD, fadD9) are restricted to drug-resistant strains. Finally, nonsense mutations in the nth excision repair gene are associated with greater sequence diversity and drug resistance.
BackgroundMore than 200,000 new cases of leprosy were reported by 105 countries in 2011. The disease is a public health problem in Brazil, particularly within high-burden pockets in the Amazon region where leprosy is hyperendemic among children.MethodologyWe applied geographic information systems and spatial analysis to determine the spatio-temporal pattern of leprosy cases in a hyperendemic municipality of the Brazilian Amazon region (Castanhal). Moreover, we performed active surveillance to collect clinical, epidemiological and serological data of the household contacts of people affected by leprosy and school children in the general population. The occurrence of subclinical infection and overt disease among the evaluated individuals was correlated with the spatio-temporal pattern of leprosy.Principal FindingsThe pattern of leprosy cases showed significant spatio-temporal heterogeneity (p<0.01). Considering 499 mapped cases, we found spatial clusters of high and low detection rates and spatial autocorrelation of individual cases at fine spatio-temporal scales. The relative risk of contracting leprosy in one specific cluster with a high detection rate is almost four times the risk in the areas of low detection rate (RR = 3.86; 95% CI = 2.26–6.59; p<0.0001). Eight new cases were detected among 302 evaluated household contacts: two living in areas of clusters of high detection rate and six in hyperendemic census tracts. Of 188 examined students, 134 (71.3%) lived in hyperendemic areas, 120 (63.8%) were dwelling less than 100 meters of at least one reported leprosy case, 125 (66.5%) showed immunological evidence (positive anti-PGL-I IgM titer) of subclinical infection, and 9 (4.8%) were diagnosed with leprosy (8 within 200 meters of a case living in the same area).Conclusions/SignificanceSpatial analysis provided a better understanding of the high rate of early childhood leprosy transmission in this region. These findings can be applied to guide leprosy control programs to target intervention to high risk areas.
BackgroundLeprosy remains an important public health problem in some specific high-burden pockets areas, including the Brazilian Amazon region, where it is hyperendemic among children.MethodsWe selected two elementary public schools located in areas most at risk (cluster of leprosy or hyperendemic census tract) to clinically evaluate their students. We also followed anti-PGL-I seropositive and seronegative individuals and households for 2 years to compare the incidence of leprosy in both groups.ResultsLeprosy was detected in 11 (8.2 %) of 134 school children in high risk areas. The difference in the prevalence was statistically significant (p < .05) compared to our previous findings in randomly selected schools (63/1592; 3.9 %). The 2-year follow-up results showed that 22.3 and 9.4 % of seropositive and seronegative individuals, respectively, developed leprosy (p = .027). The odds of developing overt disease in seropositive people were 2.7 times that of negative people (p < .01), indicating that a follow-up of 10 seropositives has a >90 % probability to detect at least one new case in 2 years. The odds of clinical leprosy were also higher in “positive houses” compared to “negative houses” (p < .05), indicating that a follow-up of ten people living in households with at least one seropositive dweller have a 85 % probability to detect at least one new case in 2 years.ConclusionsTargeted screening involving school-based surveillance planned using results obtained by spatial analysis and targeted household and individual continuous surveillance based on serologic data should be applied to increase the early detection of new leprosy cases.
Mycobacterium leprae (M. leprae) is a human pathogen and the causative agent for leprosy, a chronic disease characterized by lesions of the skin and peripheral nerve damage. Zoonotic transmission of M. leprae to humans by nine-banded armadillos (Dasypus novemcinctus) has been shown to occur in the southern United States, mainly in Texas, Louisiana, and Florida. Nine-banded armadillos are also common in South America, and residents living in some areas in Brazil hunt and kill armadillos as a dietary source of protein. This study examines the extent of M. leprae infection in wild armadillos and whether these New World mammals may be a natural reservoir for leprosy transmission in Brazil, similar to the situation in the southern states of the U.S. The presence of the M. leprae-specific repetitive sequence RLEP was detected by PCR amplification in purified DNA extracted from armadillo spleen and liver tissue samples. A positive RLEP signal was confirmed in 62% of the armadillos (10/16), indicating high rates of infection with M. leprae. Immunohistochemistry of sections of infected armadillo spleens revealed mycobacterial DNA and cell wall constituents in situ detected by SYBR Gold and auramine/rhodamine staining techniques, respectively. The M. leprae-specific antigen, phenolic glycolipid I (PGL-I) was detected in spleen sections using a rabbit polyclonal antibody specific for PGL-I. Anti-PGL-I titers were assessed by ELISA in sera from 146 inhabitants of Belterra, a hyperendemic city located in western Pará state in Brazil. A positive anti-PGL-I titer is a known biomarker for M. leprae infection in both humans and armadillos. Individuals who consumed armadillo meat most frequently (more than once per month) showed a significantly higher anti-PGL-I titer than those who did not eat or ate less frequently than once per month. Armadillos infected with M. leprae represent a potential environmental reservoir. Consequently, people who hunt, kill, or process or eat armadillo meat are at a higher risk for infection with M. leprae from these animals.
with leprosy varies from 1•2% to 39•8% (or why grade 2 disability ranges from 0•0% to 28•0%) 4 in different, but all equally poor, countries? The answers will only be possible when we understand that absence of diagnosis of leprosy is not the same as the absence of leprosy. The elimination target has become the mantra everywhere, but it is now meaningless. Although the zero-transmission strategy 1 is highly desirable, comprehension and acknowledgment of the real worldwide leprosy situation is imperative fi rst.
OBJECTIVESShow that hidden endemic leprosy exists in a municipality of inner São Paulo state (Brazil) with active surveillance actions based on clinical and immunological evaluations.METHODSThe study sample was composed by people randomly selected by a dermatologist during medical care in the public emergency department and by active surveillance carried out during two days at a mobile clinic. All subjects received a dermato-neurological examination and blood sampling to determine anti-PGL-I antibody titers by enzyme-linked immunosorbent assay (ELISA).RESULTSFrom July to December 2015, 24 new cases of leprosy were diagnosed; all were classified as multibacillary (MB) leprosy, one with severe Lucio's phenomenon. Seventeen (75%) were found with grade-1 or 2 disability at the moment of diagnosis. Anti-PGL-I titer was positive in 31/133 (23.3%) individuals, only 6/24 (25%) were positive in newly diagnosed leprosy cases.CONCLUSIONSDuring the last ten years before this study, the average new case detection rate (NCDR) in this town was 2.62/100,000 population. After our work, the NCDR was raised to 42.8/100,000. These results indicate a very high number of hidden leprosy cases in this supposedly low endemic area of Brazil.
(WHO) 2016-2020 Global Leprosy Strategy aims to reinvigorate efforts to control leprosy and avert leprosy disability to less than 1 per million population. OBJECTIVE To systematically identify clinical factors associated with physical disability in patients with leprosy. DATA SOURCE Searches were conducted in Scopus, PubMed, and Web of Science databases to identify studies published from January 23, 1988, to May 23, 2018, using the keywords leprosy and physical disability and related terms. STUDY SELECTION Studies that evaluated patients using the WHO leprosy disability grading system and reported the number of patients with and without disability by clinical characteristics were included. DATA EXTRACTION AND SYNTHESIS The odds ratio (OR) was used as a measure of association between the clinical features and physical disability. Summary estimates were calculated using random-effects models. MAIN OUTCOMES AND MEASURES The primary outcome was physical disability according to the WHO disability classification. The association between clinical features and physical disability was evaluated. RESULTS The search identified 2447 reports. After screening titles and abstracts, 177 full-text articles were assessed for eligibility, and 32 studies were included in the systematic review; 24 of the 32 studies included sex information (39 571 patients), of whom 24 218 (61.2%) were male. Male patients with leprosy were more likely to have physical disability than female patients with leprosy (pooled OR, 1.66; 95% CI, 1.43-1.93; I 2 , 81.3%; P < .001). Persons with multibacillary leprosy were 4-fold more likely to have physical disability than those with paucibacillary leprosy (pooled OR, 4.32; 95% CI, 3.37-5.53; I 2 , 88.9%, P < .001). Patients having leprosy reactions were more likely to have disability (pooled OR, 2.43; 95% CI, 1.35-4.36; I 2 , 92.1%; P < .001). Patients with lepromatous leprosy experienced 5-to 12-fold higher odds of disability. CONCLUSIONS AND RELEVANCE This systematic review and meta-analysis confirms the association between the presence of physical disabilities and male sex, multibacillary leprosy, leprosy reactions, and lepromatous presentation. These findings can guide the development of targeted interventions for early identification of individuals at greater risk of developing physical disabilities and education campaigns to promote early consultation to institute treatment for leprosy reactions and prevent physical disability.
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