Efficacy of Artesunate + Sulfamethoxypyrazine/Pyrimethamine versus Praziquantel in the Treatment of Schistosoma haematobium in Children

BACKGROUND:This study was conducted to determine the efficacy of the antimalarial artemisinin-based combination therapy (ACT) artesunate +sulfamethoxypyrazine/pyrimethamine (As+SMP), administered in doses used for malaria, to treat Schistosoma haematobium in school aged children. METHODOLOGY/PRINCIPAL FINDINGS:The study was conducted in Djalakorodji, a peri-urban area of Bamako, Mali, using a double blind setup in which As+SMP was compared with praziquantel (PZQ). Urine samples were examined for Schistosoma haematobium on days -1, 0, 28 and 29. Detection of haematuria, and haematological and biochemical exams were conducted on day 0 and day 28. Clinical exams were performed on days 0, 1, 2, and 28. A total of 800 children were included in the trial. The cure rate obtained without viability testing was 43.9% in the As+SMP group versus 53% in the PZQ group (Chi(2) = 6.44, p = 0.011). Egg reduction rates were 95.6% with PZQ in comparison with 92.8% with As+SMP, p = 0.096. The proportion of participants who experienced adverse events related to the medication was 0.5% (2/400) in As+SMP treated children compared to 2.3% (9/399) in the PZQ group (p = 0.033). Abdominal pain and vomiting were the most frequent adverse events in both treatment arms. All adverse events were categorized as mild. CONCLUSIONS/SIGNIFICANCE:The study demonstrates that PZQ was more effective than As+SMP for treating Schistosoma haematobium. However, the safety and tolerability profile of As+SMP was similar to that seen with PZQ. Our findings suggest that further investigations seem justifiable to determine the dose/efficacy/safety pattern of As+SMP in the treatment of Schistosoma infections. TRIAL REGISTRATION:ClinicalTrials.gov NCT00510159

Plasmodium falciparum Clearance Is Rapid and Pitting Independent in Immune Malian Children Treated With Artesunate for Malaria

Background. In Plasmodium falciparum-infected patients treated with artemisinins, parasitemia declines through so-called pitting, an innate splenic process that transforms infected red blood cells (iRBCs) into onceinfected RBCs (O-iRBCs). Methods. We measured pitting in 83 French travelers and 42 Malian children treated for malaria with artesunate. Results. In travelers, O-iRBCs peaked at 107.7% initial parasitemia. In Malian children aged 1.5-4 years, OiRBCs peaked at higher concentrations than in children aged 9-13 years (91.60% vs 31.95%; P = .0097). The parasite clearance time in older children was shorter than in younger children (P = .0001), and the decline in parasitemia in children aged 1.5-4 years often started 6 hours after treatment initiation, a lag phase generally absent in infants and older children. A 6-hour lag phase in artificial pitting of artesunate-exposed iRBCs was also observed in vitro. The proportion of iRBCs recognized by autologous immunoglobulin G (IgG) correlated with the parasite clearance time (r = −0.501; P = .0006) and peak O-iRBC concentration (r = −0.420; P = .0033). Conclusions. Antimalarial immunity correlates with fast artemisinin-induced parasite clearance and low pitting rates. In nonimmune populations, artemisinin-induced P. falciparum clearance is related to pitting and starts after a 6-hour lag phase. In immune populations, passively and naturally acquired immune mechanisms operating faster than pitting may exist. This mechanism may mitigate the emergence of artemisinin-resistant P. falciparum in Africa

A comprehensive analysis of drug resistance molecular markers and Plasmodium falciparum genetic diversity in two malaria endemic sites in Mali.

BACKGROUND: Drug resistance is one of the greatest challenges of malaria control programme in Mali. Recent advances in next-generation sequencing (NGS) technologies provide new and effective ways of tracking drug-resistant malaria parasites in Africa. The diversity and the prevalence of Plasmodium falciparum drug-resistance molecular markers were assessed in Dangassa and Nioro-du-Sahel in Mali, two sites with distinct malaria transmission patterns. Dangassa has an intense seasonal malaria transmission, whereas Nioro-du-Sahel has an unstable and short seasonal malaria transmission. METHODS: Up to 270 dried blood spot samples (214 in Dangassa and 56 in Nioro-du-Sahel) were collected from P. falciparum positive patients in 2016. Samples were analysed on the Agena MassARRAY® iPLEX platform. Specific codons were targeted in Pfcrt, Pfmdr1, Pfdhfr, and Pfdhps, Pfarps10, Pfferredoxin, Pfexonuclease and Pfmdr2 genes. The Sanger's 101-SNPs-barcode method was used to assess the genetic diversity of P. falciparum and to determine the parasite species. RESULTS: The Pfcrt_76T chloroquine-resistance genotype was found at a rate of 64.4% in Dangassa and 45.2% in Nioro-du-Sahel (p = 0.025). The Pfdhfr_51I-59R-108N pyrimethamine-resistance genotype was 14.1% and 19.6%, respectively in Dangassa and Nioro-du-Sahel. Mutations in the Pfdhps_S436-A437-K540-A581-613A sulfadoxine-resistance gene was significantly more prevalent in Dangassa as compared to Nioro-du-Sahel (p = 0.035). Up to 17.8% of the isolates from Dangassa vs 7% from Nioro-du-Sahel harboured at least two codon substitutions in this haplotype. The amodiaquine-resistance Pfmdr1_N86Y mutation was identified in only three samples (two in Dangassa and one in Nioro-du-Sahel). The lumefantrine-reduced susceptibility Pfmdr1_Y184F mutation was found in 39.9% and 48.2% of samples in Dangassa and Nioro-du-Sahel, respectively. One piperaquine-resistance Exo_E415G mutation was found in Dangassa, while no artemisinin resistance genetic-background were identified. A high P. falciparum diversity was observed, but no clear genetic aggregation was found at either study sites. Higher multiplicity of infection was observed in Dangassa with both COIL (p = 0.04) and Real McCOIL (p = 0.02) methods relative to Nioro-du-Sahel. CONCLUSIONS: This study reveals high prevalence of chloroquine and pyrimethamine-resistance markers as well as high codon substitution rate in the sulfadoxine-resistance gene. High genetic diversity of P. falciparum was observed. These observations suggest that the use of artemisinins is relevant in both Dangassa and Nioro-du-Sahel

Effects of proactive vs fixed community health care delivery on child health and access to care: a cluster randomised trial secondary endpoint analysis

BACKGROUND: Professional community health workers (CHWs) can help achieve universal health coverage, although evidence gaps remain on how to optimise CHW service delivery. We conducted an unblinded, parallel, cluster randomised trial in rural Mali to determine whether proactive CHW delivery reduced mortality and improved access to health care among children under five years, compared to passive delivery. Here we report the secondary access endpoints. METHODS: Beginning from 26-28 February 2017, 137 village-clusters were offered care by CHWs embedded in communities who were trained, paid, supervised, and integrated into a reinforced public-sector health system that did not charge user fees. Clusters were randomised (stratified on primary health centre catchment and distance) to care during CHWs during door-to-door home visits (intervention) or based at a fixed village site (control). We measured outcomes at baseline, 12-, 24-, and 36-month time points with surveys administered to all resident women aged 15-49 years. We used logistic regression with cluster-level random effects to estimate intention-to-treat and per-protocol effects over time on prompt (24-hour) treatment within the health sector. RESULTS: Follow-up surveys between February 2018 and April 2020 generated 20 105 child-year observations. Across arms, prompt health sector treatment more than doubled compared to baseline. At 12 months, children in intervention clusters had 22% higher odds of receiving prompt health sector treatment than those in control (cluster-specific adjusted odds ratio (aOR) = 1.22; 95% confidence interval (CI) = 1.06, 1.41, P = 0.005), or 4.7 percentage points higher (adjusted risk difference (aRD) = 0.047; 95% CI = 0.014, 0.080). We found no evidence of an effect at 24 or 36 months. CONCLUSIONS: CHW-led health system redesign likely drove the 2-fold increase in rapid child access to care. In this context, proactive home visits further improved early access during the first year but waned afterwards. REGISTRATION: ClinicalTrials.gov NCT02694055

Effect of red blood cell variants on childhood malaria in Mali: a prospective cohort study

Red blood cell (RBC) variants protect African children from severe Plasmodium falciparum malaria. Their individual and interactive impacts on mild disease and parasite density, and their modification by age-dependent immunity, are poorly understood

Peritoneal Sclerosis in a Patient on Long-term Continuous Ambulatory Peritoneal Dialysis (CAPD). : An Autopsy Case.

若年性ネフロン癆による慢性腎不全でCAPD (continuous ambulatory peritoneal dialysis)導入し, 6年6ヵ月後に死亡した20歳男性の1剖検例を報告した。CAPD導入数カ月後, 腹膜炎による除水能低下を起こしたが, 約5ヵ月後に回復した。CAPD導入1年5ヵ月以降重症な腹膜炎罹患により除水能低下状態が遷延したが, 次第に回復した。しかし, 体液貯留傾向のため, 3年2ヵ月後より高張透析液を使用し除水量の増加を得たが, 3年9ヵ月後に不可逆的な除水能低下状態となった。一方, クレアチニンの透析排液/血漿濃度比(D/P)から見た溶質除去能は, その約半年後まで保たれており, 血清クレアチニン値の上昇は軽度であった。剖検にて腹膜の線維性肥厚と高度の内腔狭窄を伴う動静脈硬化を認め, 腹膜硬化症と診断した。本例の腹膜硬化症は, 頻回の腹膜炎と高張透析液の使用が主な原因と考えられた。腹膜機能を長期に維持するためには, 腹膜炎の予防と高張透析液の使用を最小限にすることが重要と考えられた。A 20-year-old man, treated with continuous ambulatory peritoneal dialysis (CAPD) for 6.5 years because of-end-stage renal disease due to juvenile nephronophthysis, died of ultrafiltration failure, and the morphological examination of peritoneum was carried out at autopsy. Nine episodes of peritonitis developed, and ultrafiltration transiently decreased after each episodes. At 2 years after the start of CAPD, severe peritonitis occurred, and then his body weight and blood pressure gradually increased. At 4 years after the beginning of CAPD, when hyperosmotic dialysate was frequently used, ultrafiltration was irreversively deteriorated. On the other hand, creatinine dialysate/plasma ratio remained within normal limits for about several months, and the increase in the level of serum creatinine was very little. The peritoneum obtained at autopsy revealed marked fibrous thickening as well as the conspicuous luminal narrowing of arteries and veins due to intimal thickening. The development of peritoneal sclerosis seemed to be related with the frequency and severity of peritonitis and the use of hyperosmotic dialysate

Malaria protection due to sickle haemoglobin depends on parasite genotype.

Host genetic factors can confer resistance against malaria1, raising the question of whether this has led to evolutionary adaptation of parasite populations. Here we searched for association between candidate host and parasite genetic variants in 3,346 Gambian and Kenyan children with severe malaria caused by Plasmodium falciparum. We identified a strong association between sickle haemoglobin (HbS) in the host and three regions of the parasite genome, which is not explained by population structure or other covariates, and which is replicated in additional samples. The HbS-associated alleles include nonsynonymous variants in the gene for the acyl-CoA synthetase family member2-4 PfACS8 on chromosome 2, in a second region of chromosome 2, and in a region containing structural variation on chromosome 11. The alleles are in strong linkage disequilibrium and have frequencies that covary with the frequency of HbS across populations, in particular being much more common in Africa than other parts of the world. The estimated protective effect of HbS against severe malaria, as determined by comparison of cases with population controls, varies greatly according to the parasite genotype at these three loci. These findings open up a new avenue of enquiry into the biological and epidemiological significance of the HbS-associated polymorphisms in the parasite genome and the evolutionary forces that have led to their high frequency and strong linkage disequilibrium in African P. falciparum populations

Preventive and Curative treatment of malaria during pregnancy in Mali: Evaluation of the Healthcare Professionals based on the Malian National Malaria Control Program (NMCP) Guidelines

Malaria infections in pregnancy should be treated promptly with safe and efficacious antimalarial drugs to prevent harmful effects on the mother and fetus. To succeed, the Malian has developed NMCP guidelines for the management of malaria cases in pregnant women. The study aimed at the analysis of the prescription of antimalarial drugs based on the Mali's NMCP guidelines. We conducted a cross-sectional study during malaria transmission season from June to August 2020. The sampling concerned all prescriptions for pregnant women containing at least one antimalarial drug. The frequency of prescription of antimalarial drugs was 85%. 132 (74.16%) were preventive treatments and 46 (25.84%) curative treatments. 30 (90.91%) of pregnant women in the first trimester received one dose of Sulfadoxine-Pyrimethamine. 6 (12.5%) received three doses in the third trimester. Of the 46 antimalarial drugs prescribed for the treatment of uncomplicated malaria, 30 (65.22%) were Artemether-lumefantrine (tablet), 10 (21.74%) were Quinine (tablet). 29 (63.04%) were compliant with NMCP guidelines and 17 (36.96%) were not. The non-compliances concerned 3 prescriptions of Artemether-lumefantrine in the first trimester, 3 and 5 prescriptions of Quinine (tablet) in the second and third trimester respectively and at the end 2 and 4 non-compliances respectively for the prescription of injectable dosage forms of Quinine and Artesunate. This study showed a great noncompliance with the Mali's NMCP guidelines in the prescription of antimalarial in pregnant women. Chemoprophylaxis should be prohibited in the first trimester.   Keywords: Curative and Preventive Treatment, Malaria in Pregnancy, Malaria Transmission, Mal