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Background: Infection with the filarial nematode Loa loa, endemic in Central and Western Africa, has been associated with increased morbidity and mortality. A number of reports described the presence of spleen nodules, originating from degenerating microfilariae, in humans and animals infected with L. loa. The long-term consequences of this process on individuals chronically exposed to infection in terms of spleen function and possible link with excess mortality are unknown. The aim of this study was to evaluate the prevalence of focal spleen lesions, their evolution over time, and markers of spleen function, in individuals with L. loa infection living in highly endemic areas of Gabon. Methodology/principal findings: This was a cross-sectional study followed by a longitudinal study of the subset of individuals with spleen nodules. Two hundred sixteen participants from Ngounié and Moyen-Ogooué provinces of Gabon, reporting a history of eyeworm migration and/or Calabar swelling, were included. Participants were categorized into infected microfilaraemic with low (N = 74) and high (N = 10) microfilaraemia, and symptomatic amicrofilaraemic (N = 132), based on blood microscopy. Howell-Jolly bodies in erythrocytes, as indirect marker of spleen functional impairment, were within normal ranges. On ultrasound, no evident signs of spleen fibrosis or hypotrophy were observed. Multiple spleen hypoechoic centimetric macronodules were observed in 3/216 participants (1.4%), all with microfilaraemic L. loa infection (3.4% of microfilaraemics); macrondules disappeared at the 6-months follow-up examination in 2/3 individuals. Spleen hypoechoic micronodules, persisting at the 6-months follow-up, were detected in 3/216 participants (1.4%), who were all amicrofilaraemic. Conclusions/significance: Transitory spleen macronodules are present in a small but consistent proportion of individuals with microfilaraemic loiasis, appearing a rather benign phenomenon in terms of impact on spleen morphology and function. Their occurrence should be taken into consideration to avoid misdiagnosis and mistreatment. Prevalence and significance of spleen micronodular ultrasound patterns in the general population would be also worth evaluating. Author summary: Loa loa is a vector borne, filarial worm affecting an estimated 20 million people in Central and West Africa. Long considered a benign infection, more recently it has been associated with substantial morbidity and increased mortality in individuals with high L. loa microfilaraemia, prompted to reconsider the importance this infection and investigate the potential pathophysiological mechanisms. The spleen has a central role in the response to pathogens, including parasites; therefore, its dysfunction may lead to an increase in the risk and severity of infectious diseases, which might contribute to the observed excess mortality in hypermicrofilaremic loiasis. The presence of spleen centimetric nodules, originating from degradation of microfilariae, in humans and animals infected with L. loa, has been described, but the long-term consequences of this process on individuals chronically exposed to infection in terms of spleen function are unknown. In this study performed in individuals with L. loa infection living in highly endemic areas of Gabon, we found a prevalence of 3.4% spleen nodules in microfilaraemic participants, while no such lesions were observed in symptomatic amicrofilaraemic participants. Nodules were transitory and appeared to be a rather benign phenomenon in terms of impact on spleen morphology and function. [ABSTRACT FROM AUTHOR]

Background Current artesunate (ARS) regimens for severe malaria are complex. Once daily intramuscular (i.m.) injection for 3 d would be simpler and more appropriate for remote health facilities than the current WHO-recommended regimen of five intravenous (i.v.) or i.m. injections over 4 d. We compared both a three-dose i.m. and a three-dose i.v. parenteral ARS regimen with the standard five-dose regimen using a non-inferiority design (with non-inferiority margins of 10%). Methods and Findings This randomized controlled trial included children (0.5-10 y) with severe malaria at seven sites in five African countries to assess whether the efficacy of simplified three-dose regimens is non-inferior to a five-dose regimen. We randomly allocated 1,047 children to receive a total dose of 12 mg/kg ARS as either a control regimen of five i.m. injections of 2.4 mg/kg (at 0,12, 24, 48, and 72 h) (n = 348) or three injections of 4 mg/kg (at 0,24, and 48 h) either i.m. (n = 348) or i.v. (n = 351), both of which were the intervention arms. The primary endpoint was the proportion of children with >99% reduction in parasitemia at 24 h from admission values, measured by microscopists who were blinded to the group allocations. Primary analysis was performed on the per-protocol population, which was 96% of the intention-to-treat population. Secondary analyses included an analysis of host and parasite genotypes as risks for prolongation of parasite clearance kinetics, measured every 6 h, and a Kaplan-Meier analysis to compare parasite clearance kinetics between treatment groups. A post hoc analysis was performed for delayed anemia, defined as hemoglobin ≤ 7g/dl 7 d or more after admission. The per-protocol population was 1,002 children (five-dose i.m.: n = 331; three-dose i.m.: n = 338; three-dose i.v.: n = 333); 139 participants were lost to follow-up. In the three-dose i. m. arm, 265/338 (78%) children had a >99% reduction in parasitemia at 24 h compared to 263/331 (79%) receiving the five-dose i.m. regimen, showing non-inferiority of the simplified three-dose regimen to the conventional five-dose regimen (95% CI -7,5; p = 0.02). In the three-dose i.v. arm, 246/333 (74%) children had ≥ 99% reduction in parasitemia at 24 h; hence, non-inferiority of this regimen to the five-dose control regimen was not shown (95% CI -12,1; p = 0.24). Delayed parasite clearance was associated with the [sup.N86Y]Pfmdr1 genotype. In a post hoc analysis, 192/885 (22%) children developed delayed anemia, an adverse event associated with increased leukocyte counts. There was no observed difference in delayed anemia between treatment arms. A potential limitation of the study is its open-label design, although the primary outcome measures were assessed in a blinded manner. Conclusions A simplified three-dose i.m. regimen for severe malaria in African children is non-inferior to the more complex WHO-recommended regimen. Parenteral ARS is associated with a risk of delayed anemia in African children. Trial registration Pan African Clinical Trials Registry PACTR201102000277177, Introduction Studies to optimize artesunate (ARS) treatment regimens in malaria have been surprisingly sparse, given that ARS is now established as the treatment of choice for severe malaria in both [...]

Background: Although Schistosoma haematobium infection has been reported to be associated with alterations in immune function, in particular immune hyporesponsiveness, there have been only few studies that have used the approach of removing infection by drug treatment to establish this and to understand the underlying molecular mechanisms.Methods: Schistosoma haematobium-infected schoolchildren were studied before and after praziquantel treatment and compared with uninfected controls. Cellular responses were characterized by cytokine production and flow cytometry, and in a subset of children RNA sequencing (RNA-Seq) transcriptome profiling was performed.Results: Removal of S haematobium infection resulted in increased schistosome-specific cytokine responses that were negatively associated with CD4+CD25+FOXP3+ T-cells and accompanied by increased frequency of effector memory T-cells. Innate responses to Toll like receptor (TLR) ligation decreased with treatment and showed positive association with CD4+CD25+FOXP3+ T-cells. At the transcriptome level, schistosome infection was associated with enrichment in cell adhesion, whereas parasite removal was associated with a more quiescent profile. Further analysis indicated that alteration in cellular energy metabolism was associated with S haematobium infection and that the early growth response genes 2 and 3 (EGR 2 and EGR3), transcription factors that negatively regulate T-cell activation, may play a role in adaptive immune hyporesponsiveness.Conclusions: Using a longitudinal study design, we found contrasting effects of schistosome infection on innate and adaptive immune responses. Whereas the innate immune system appears more activated, the adaptive immunity is in a hyporesponsive state reflected in alterations in CD4+CD25+FOXP3+ T-cells, cellular metabolism, and transcription factors involved in anergy. [ABSTRACT FROM AUTHOR]