Leprosy

BackgroundLeprosy is an ancient infectious disease with an annual global incidence of around 200,000 over the past decade. Since 2018, the World Health Organization (WHO) recommends single-dose rifampicin as post-exposure prophylaxis (SDR-PEP) for contacts of leprosy patients. The Post ExpOsure Prophylaxis for Leprosy (PEOPLE) trial evaluated PEP with a double dose of rifampicin in Comoros and Madagascar. Preliminary results of this trial show some reduction in leprosy incidence in intervention villages but a stronger regimen may be beneficial. The objective of the current Bedaquiline Enhanced ExpOsure Prophylaxis for LEprosy trial (BE-PEOPLE) is to explore effectiveness of a combination of bedaquiline and rifampicin as PEP.MethodsBE-PEOPLE is a cluster-randomized trial in which 44 clusters in Comoros will be randomized to two study arms. Door-to-door screening will be conducted annually during four years, leprosy patients identified will be offered standard of care treatment. Based on study arm, contacts aged five years and above and living within a 100-meter radius of an index case will either receive bedaquiline (400-800 mg) and rifampicin (150-600 mg) or only rifampicin (150-600 mg). Contacts aged two to four years will receive rifampicin only. Household contacts randomized to the bedaquiline plus rifampicin arm will receive a second dose four weeks later. Incidence rate ratios of leprosy comparing contacts who received either of the PEP regimens will be the primary outcome. We will monitor resistance to rifampicin and/or bedaquiline through molecular surveillance in all incident tuberculosis and leprosy patients nationwide. At the end of the study, we will assess anti-M. leprae PGL-I IgM seropositivity as a proxy for the population burden of M. leprae infection in 8 villages (17,000 individuals) that were surveyed earlier as part of the PEOPLE trial.DiscussionThe COLEP trial on PEP in Bangladesh documented a reduction of 57% in incidence of leprosy among contacts treated with SDR-PEP after two years, which led to the WHO recommendation of SDR-PEP. Preliminary results of the PEOPLE trial show a lesser reduction in incidence. The BE-PEOPLE trial will explore whether reinforcing SDR-PEP with bedaquiline increases effectiveness and more rapidly reduces the incidence of leprosy, compared to SDR-PEP alone.Trial registrationNCT05597280. Protocol version 5.0 on 28 October 2022.

IntroductionLeprosy is a chronic infectious condition and the main cause of neuropathy that occurs brought on by M. leprae. It is known that the biological characteristics of the human host, such as the immunological ones, have a higher influence on the pathology of this disease than the intrinsic mechanisms of the bacterium. The objective of this work was to review the scientific knowledge about the relationship between immunopathology and the severity of leprosy.MethodsA systematic review following the PRISMA 2020 recommendations was conducted in the PUBMED, LILACS, SciELO and Science Direct databases using articles in English, Portuguese or Spanish between January 2011 and May 2022 with the descriptors "Leprosy/Immunology", "Cytokines" and "Mycobacterium leprae". A methodological quality assessment was carried out using the JBI checklists.ResultsA total of 49 articles were included. There is a relationship of greater severity of infection associated with lower release of MHC molecules in response to PGL-1 that inhibit the promotion of resolving T lymphocytes arising from dendritic cells (DCs) stimulation. In addition, the differentiation of macrophage phenotypes dependent on the activation of PRRs can define activation and the distinct type of T helper (Th) cells involved according to severity. Activated CD8+ T cells also have distinct types at the appropriate poles of the disease, and B cells show at the most severe pole of the LL, specific induction of IgA and more Treg-type CD8+ T cells that further contribute to T cell anergy.ConclusionTherefore, the adaptive immune system aggravates nerve damage and defines the type of leprosy, while the innate immune system is considerably more significant in the onset of nerve damage, symptomatic of the initial presentation of illness and in several critical immune responses, including inflammation and elimination of dead M. leprae.

BackgroundDetection of infection with Mycobacterium leprae allows timely prophylactic treatment, thereby reducing transmission as well as the risk of permanent, leprosy-associated nerve damage. However, since there is no worldwide-implemented standard test for M. leprae infection, detection of infection in asymptomatic individuals remains a major challenge for control programs in endemic areas. In previous studies, we developed and field-tested a lateral flow assay (LFA) quantitatively detecting human IgM against M. leprae-specific phenolic glycolipid I (anti-PGL-I), a marker for both active and past infection. This rapid test utilizes luminescent, background-free, up-converting reporter particles (UCP) and immunochromatography (i.e. the UCP-LF test platform) for accurate quantitation of anti-PGL-I IgM without operator bias. The aim of this study was to evaluate the final version of this quantitative UCP-based rapid test (i.e. PGL-I QURapid), using serum and fingerstick blood (FSB).MethodsThe test comprises a lateral flow strip, in a standard plastic or biodegradable cassette. It can be provided with a humanized, recombinant control to monitor test performance and calculate accurate anti-PGL-I IgM levels. The performance of this QUR-test was assessed using serum and FSB from patients with leprosy (n = 214), tuberculosis (n = 20), buruli ulcer (n = 19), leishmaniasis (n = 14), non-tuberculous mycobacterial (n = 35) infections, as well as healthy Dutch individuals (n = 710) and humanized, recombinant anti-PGL-I IgM antibodies. Plot receiver operating characteristic curves were created and sensitivity (Sn), specificity (Sp) and the area under the curve were calculated to evaluate test performance.ResultsTest results classified multibacillary leprosy patients with 95.0% Sn and 100% Sp using serum and 91.5% Sn and 99.8% Sp using FSB. Qualitative test results could be read after 2 min flow time, with accurate quantitation from 10 min onwards. The new anti-PGL-I IgM control supports production of batches with predetermined seropositivity thresholds and monitoring of the PGL-I QUR-test in various settings.ConclusionThe operational version of the PGL-I QURapid with point-of-care applicability, meets the WHO target product profile criteria. Thus, this QUR-test is ready for public health implementations.

Introduction/aimsLeprosy neuropathy (LN) may cause demyelination that worsens during the leprosy reactions (LR). Type-1 LR (T1LR) occurs in patients with cell-mediated immune response against M. leprae, and Type-2 LR (T2LR) occurs in multibacillary cases. The patterns of nerve impairment need to be clarified, as both demyelination and axonal degeneration are commonly observed. This study aimed to describe how to interpret the demyelinating impairment in LN.MethodsRetrospective observational analysis of leprosy patients in a National Reference Center in Brazil between 2014-2023.Results494 participants were included in this study. 3952 nerves were evaluated, with an average of 5.1 (±5.4) nerves affected per patient. 23.5% (116/494) of patients showed a demyelinating pattern defined by standard criteria, and 20.7% (24/116) presented exclusively demyelinating abnormalities without evidence of secondary axonal loss. 81% (94/116) presented conduction block, and 95.7% (111/116) temporal dispersion, with both conditions concomitant in 76.7% (89/116) of patients. 83.6% (97/116) demonstrated prolonged distal motor latency, and 99.1% (115/116) reduction in conduction velocity. 46.1% had T1LR and 17.9% T2LR. The comparison between patients with and without LR showed higher bacillary load, conduction block, and temporal dispersion in LR patients. 93.1% (108/116) of patients fulfilled neurophysiological criteria for chronic inflammatory demyelinating polyneuropathy (CIDP). Among them, 46.3% presented clinical criteria for atypical CIDP.DiscussionLeprosy is a spectral disease in which neural damage can manifest in different phenotypes. Demyelinating impairment is frequent and varies according to the clinical form and presence of LR. Although demyelinating impairment is common in the studied population, it does not reflect active disease. LN can also be misdiagnosed as other peripheral neuropathies, especially CIDP, in non-endemic areas.