Search

Background: Visceral Leishmaniasis (VL) is a neglected tropical disease (NTD) with the highest regional burden in East Africa. Relapse and Post Kala-azar Dermal Leishmaniasis (PKDL) contribute to the spread of VL in endemic areas, making their surveillance imperative for control and elimination. Little is known about long-term patient outcomes in Kenya through follow-up after VL treatment, despite its requirement for control and elimination by the World Health Organization (WHO) and the Kenya Ministry of Health (KMOH). Methodology/Principal findings: 36 follow-up patients in Tiaty East and West, sub-counties, Kenya, and records from 248 patients at the regional Chemolingot Sub-county Hospital (CSCH) were analyzed separately using Fisher's Exact Tests, two-sample t-tests, and Welch's t-tests in R (Version 4.3.0). The study found a prevalence rate of 88.89% (n = 32) final cure, 5.56% (n = 2) relapse, and 5.56% (n = 2) PKDL in follow-up patients and 92.74% (n = 230) initial cure, 6.86% (n = 17) relapse, and 0.80% (n = 2) PKDL in overall CSCH patients. The mean lengths of time at which follow-up patients relapsed and developed PKDL were 4.5 and 17 months, respectively. Young age (p = 0.04, 95% CI 0.63–24.31), shorter length of time from initial treatment to follow-up (p = 0.002, 95% CI 1.03-∞), lower Hb level at primary treatment (p = 0.0002, 95% CI 1.23–3.24), and living in Tiaty East sub-county (p = 0.04, 95% CI 0.00–1.43) were significantly associated (p<0.05) with VL relapse in follow-up study patients. Female sex (p = 0.04, 95% CI 0.84-∞) and living in Tiaty East sub-county (p = 0.03, 95% CI 0.00–1.43) were significantly associated with PKDL in follow-up study patients. Conclusions/Significance: More research should be done on PKDL in Kenya with active follow-up to understand its true burden. These results on prevalence and risk factors for PKDL and relapse in Kenya should inform knowledge of patient outcomes and interventions in the region. [ABSTRACT FROM AUTHOR]

Background: Neutrophils are involved in the initial host responses to pathogens. Neutrophils can activate T cell responses either independently or through indirect involvement of Dendritic cells (DCs). Recently we have demonstrated direct neutrophil-T cell interactions that initiate adaptive immune responses following immunization with live attenuated Leishmania donovani centrin deleted parasite vaccine (LdCen-/-). However, neutrophil-DC interactions in T cell priming in vaccine immunity in general are not known. In this study we evaluated the interaction between neutrophils and DCs during LdCen-/- infection and compared with wild type parasite (LdWT) both in vitro and in vivo. Methodology/findings: LdCen-/- parasite induced increased expression of CCL3 in neutrophils caused higher recruitment of DCs capable of inducing a strong proinflammatory response and elevated co-stimulatory molecule expression compared to LdWT infection. To further illustrate neutrophil-DCs interactions in vivo, we infected LYS-eGFP mice with red fluorescent LdWT/LdCen-/- parasites and sort selected DCs that engulfed the neutrophil containing parasites or DCs that acquired the parasites directly in the ear draining lymph nodes (dLN) 5d post infection. The DCs predominantly acquired the parasites by phagocytosing infected neutrophils. Specifically, DCs containing LdCen-/- parasitized neutrophils exhibited a proinflammatory phenotype, increased expression of costimulatory molecules and initiated higher CD4+T cell priming ex-vivo. Notably, potent DC activation occurred when LdCen-/- parasites were acquired indirectly via engulfment of parasitized neutrophils compared to direct engulfment of LdCen-/- parasites by DCs. Neutrophil depletion in LdCen-/- infected mice significantly abrogated expression of CCL3 resulting in decreased DC recruitment in ear dLN. This event led to poor CD4+Th1 cell priming ex vivo that correlated with attenuated Tbet expression in ear dLN derived CD4+ T cells in vivo. Conclusions: Collectively, LdCen-/- containing neutrophils phagocytized by DC markedly influence the phenotype and antigen presenting capacity of DCs early on and thus play an immune-regulatory role in shaping vaccine induced host protective response. Author summary: Visceral Leishmaniasis (VL), caused by the protozoan parasites of the genus Leishmania is a neglected tropical disease. Leishmania donovani is the principal causative agent of VL in East Africa and the Indian subcontinent whereas in Europe, North Africa, and Latin America VL is mainly caused by Leishmania infantum. No licensed vaccine exists against VL. We have reported previously that live attenuated centrin gene-deleted L. donovani (LdCen-/-) parasite vaccine induced strong innate immunity which leads to a protective Th1 response in animal models. We recently demonstrated that neutrophils play an indispensable role following immunization with LdCen-/- parasites in inducing protective Th1 immune response. However, neutrophils also secrete chemokines that attract other innate cells such as dendritic cells and regulate their activities. In the current study we analyzed the interplay between neutrophils and DCs, and its effects on T cell activation during LdCen-/- infection and compared with wild type parasite (LdWT) infection. We observed that higher recruitment of DCs occurred in LdCen-/- infected mice ear draining lymph nodes compared to LdWT. This recruitment is facilitated by increased secretion of the chemokine CCL3 by neutrophils. A markedly decreased DC recruitment was observed in LdCen-/- infected mice following CCL3 neutralization indicating the key role of neutrophils in DC recruitment. Further, we demonstrated that DCs that ingest LdCen-/- infected neutrophils are better activated than those that acquire the parasites independent of neutrophils. Notably neutrophil depletion in LdCen-/- infected mice also attenuated activation of DCs in the ear dLN that resulted in poor CD4+T cell priming. Our results reveal that interaction between neutrophils and DCs play an important role in shaping proinflammatory immune response induced by a live attenuated Leishmania vaccine. [ABSTRACT FROM AUTHOR]

Background: Visceral leishmaniasis (VL) is one of the most neglected tropical infectious diseases. It is fatal if left untreated. The objective of this study was to assess the efficacy and safety of 17-day injections of combined regimen of sodium stibogluconate and paromomycin (SSG/PM) in HIV-negative VL patients. Methods: A retrospective analysis of medical records of VL patients treated in the University of Gondar Hospital during period 2012–2019 was carried out. Results: A total of 2836 patients were treated for VL from 2012 to 2019. Of these 1233 were treated with SSG-PM, and 1000 of them were included in the study. Initial cure was achieved in 922 (92.2%) patients. The frequency of treatment failure, treatment interruptions, default and deaths respectively were 30 (3%), 20 (2%), 13 (1.3%) and 15 (1.5%). Among 280 patients who completed 6-month follow up, the final cure was 93.9% (263/280), 4 (1.4%) relapsed and 13 (4.6%) developed post-kala-azar dermal leishmaniasis (PKDL). The most common adverse events (AEs) were raised liver transaminases (35.1%; 351 patients), injection site pain (29.1%, 291 patients) and raised serum alpha-amylase (29.1%, 291 patients). Factors associated with poor treatment outcomes were sepsis, pneumonia, and adverse events. Conclusion: A combination of SSG at 20mg/kg with upper daily maximum dose of 850mg and PM was effective for achieving initial cure at end of treatment and safe for treatment of HIV negative VL patients in northwestern Ethiopia. Our data are consistent with previous reports and confirms effectiveness of SSG/PM treatment regimen in the Eastern African countries. Efficacy at 6-months (93.9%) was estimated on data derived from patients who completed follow up and needs to be interrogated by future studies. Author summary: Visceral leishmaniasis is one of the most neglected tropical diseases caused by the parasite of the genus leishmania. We assessed the efficacy and safety of a 17-day combined regimen of sodium stibogluconate 20mg/kg /day with daily upper maximum dose limit of 850mg and paromomycin 15mg/kg/day injections in HIV negative visceral leishmaniasis patients. We also identified factors associated with poor treatment outcomes in HIV negative VL patients treated with SSG/PM. Seventy two percent of the study participants developed at least one AE during the initial treatment course but most AEs were reversible. The overall initial efficacy was 92.2% which is comparable with previous study results in East Africa. Among patients who completed six-month follow-up, the efficacy was 93.9%, which appears to be biased due to the small proportion of patients (29%) evaluated at 6-month follow-up. The results affirm that the combination of sodium stibogluconate (20mg/kg b.wt) and paromomycin (15mg/kg b.wt) given for 17 days is still effective in Eastern Africa VL endemic countries. This data applies to VL patients who are HIV negative and not presenting with severe signs/symptoms. [ABSTRACT FROM AUTHOR]