Clinical characteristics of acute kidney injury associated with tropical acute febrile illness

Tropical acute febrile illness (TAFI) is one of the most frequent causes of acute kidney injury (AKI). The prevalence of AKI varies worldwide because there are limited reports available and different definitions are used. This retrospective study aimed to determine the prevalence, clinical characteristics, and outcomes of AKI associated with TAFI among patients. Patients with TAFI were classified into non-AKI and AKI cases based on the Kidney Disease Improving Global Outcomes (KDIGO) criteria. Of 1019 patients with TAFI, 69 cases were classified as having AKI, a prevalence of 6.8%. Signs, symptoms, and laboratory results were significantly abnormal in the AKI group, including high-grade fever, dyspnea, leukocytosis, severe transaminitis, hypoalbuminemia, metabolic acidosis, and proteinuria. 20.3% of AKI cases required dialysis and 18.8% received inotropic drugs. Seven patients died, all of which were in the AKI group. Risk factors for TAFI-associated AKI were being male (adjusted odds ratio (AOR) 3.1; 95% CI 1.3-7.4), respiratory failure (AOR 4.6 95% CI 1.5-14.1), hyperbilirubinemia (AOR 2.4; 95% CI 1.1-4.9), and obesity (AOR 2.9; 95% CI 1.4-6). We recommend clinicians investigate kidney function in patients with TAFI who have these risk factors to detect AKI in its early stages and offer appropriate management

Impact of ivermectin components on Anopheles dirus and Anopheles minimus mosquito survival

Background: Ivermectin mass drug administration to humans or livestock is a potential vector control tool for malaria elimination. Racemic ivermectin is composed of two components, namely a major component (> 80%; ivermectin B1a), which has an ethyl group at C-26, and a minor component (< 20%; ivermectin B1b), which has a methyl group at C-26. There is no difference between the efficacy of ivermectin B1a and ivermectin B1b efficacy in nematodes, but only ivermectin B1b has been reported to be lethal to snails. The ratios of ivermectin B1a and B1b ratios in ivermectin formulations and tablets can vary between manufacturers and batches. The mosquito-lethal effects of ivermectin B1a and ivermectin B1b have never been assessed. As novel ivermectin formulations are being developed for malaria control, it is important that the mosquito-lethal effects of individual ivermectin B1a and ivermectin B1b compounds be evaluated. Methods: Racemic ivermectin, ivermectin B1a or ivermectin B1b, respectively, was mixed with human blood at various concentrations, blood-fed to Anopheles dirus sensu stricto and Anopheles minimus sensu stricto mosquitoes, and mortality was observed for 10 days. The ivermectin B1a and B1b ratios from commercially available racemic ivermectin and marketed tablets were assessed by liquid chromatography-mass spectrometry. Results: The results revealed that neither the lethal concentrations that kills 50% (LC50) nor 90% (LC90) of mosquitoes differed between racemic ivermectin, ivermectin B1a or ivermectin B1b for An. dirus or An. minimus, confirming that the individual ivermectin components have equal mosquito-lethal effects. The relative ratios of ivermectin B1a and B1b derived from sourced racemic ivermectin powder were 98.84% and 1.16%, respectively, and the relative ratios for ivermectin B1a and B1b derived from human oral ivermectin tablets were 98.55% and 1.45%, respectively. Conclusions: The ratio of ivermectin B1a and B1b does not influence the Anopheles mosquito-lethal outcome, an ideal study result as the separation of ivermectin B1a and B1b components at scale is cost prohibitive. Thus, variations in the ratio of ivermectin B1a and B1b between batches and manufacturers, as well as potentially novel formulations for malaria control, should not influence ivermectin mosquito-lethal efficacy

Culturally responsive research ethics: how the socio-ethical norms of Arr-nar/Kreng-jai inform research participation at the Thai-Myanmar border

Despite advances, international research ethics guidelines still tend to consist of high-level ethical principles reflecting residual influence from North American and European traditions of ethics. Local ethics committees and community advisory boards can offer more culturally-sensitive approaches to training but most institutions lack substantive practical ethics guidance to engage rich moral understandings in day-to-day research practice in diverse cultural contexts. To address this gap, we conducted an international series of qualitative research ethics case studies, linked prospectively to active research programs in diverse settings. Here, we share findings from two case studies with a research team working on malaria and hepatitis B prevention with pregnant women in clinics serving migrants along the Thai-Myanmar border. In this sociocultural ethical analysis, we consider how core ethical requirements of voluntary participation, provision of fair benefits, and understandings of research risks and burdens are shaped, enriched, and in some instances challenged, by deep-seated and widespread Burmese, Karen and Thai cultural norms known as Arr-nar (in Burmese and Karen) or Kreng-jai (in Thai), encompassing multiple meanings including consideration for others and graciousness. We offer a model illustrating how one might map ethically significant sociocultural influences across the research practice pathway and close with lessons for developing a more culturally responsive research ethics practice in other international settings

Rickettsial infections are neglected causes of acute febrile illness in Teluk Intan, Peninsular Malaysia

Rickettsial infections are among the leading etiologies of acute febrile illness in Southeast Asia. However, recent data from Malaysia are limited. This prospective study was conducted in Teluk Intan, Peninsular Malaysia, during January to December 2016. We recruited 309 hospitalized adult patients with acute febrile illness. Clinical and biochemistry data were obtained, and patients were stratified into mild and severe infections based on the sepsis-related organ failure (qSOFA) scoring system. Diagnostic assays including blood cultures, real-time PCR, and serology (IFA and MAT) were performed. In this study, pathogens were identified in 214 (69%) patients, of which 199 (93%) patients had a single etiology, and 15 (5%) patients had >1 etiologies. The top three causes of febrile illness requiring hospitalization in this Malaysian study were leptospirosis (68 (32%)), dengue (58 (27%)), and rickettsioses (42 (19%)). Fifty-five (18%) patients presented with severe disease with a qSOFA score of >/=2. Mortality was documented in 38 (12%) patients, with the highest seen in leptospirosis (16 (42%)) followed by rickettsiosis (4 (11%)). While the significance of leptospirosis and dengue are recognized, the impact of rickettsial infections in Peninsular Malaysia remains under appreciated. Management guidelines for in-patient care with acute febrile illness in Peninsular Malaysia are needed

Rickettsial infections are neglected causes of acute febrile illness in Teluk Intan, Peninsular Malaysia

Rickettsial infections are among the leading etiologies of acute febrile illness in Southeast Asia. However, recent data from Malaysia are limited. This prospective study was conducted in Teluk Intan, Peninsular Malaysia, during January to December 2016. We recruited 309 hospitalized adult patients with acute febrile illness. Clinical and biochemistry data were obtained, and patients were stratified into mild and severe infections based on the sepsis-related organ failure (qSOFA) scoring system. Diagnostic assays including blood cultures, real-time PCR, and serology (IFA and MAT) were performed. In this study, pathogens were identified in 214 (69%) patients, of which 199 (93%) patients had a single etiology, and 15 (5%) patients had >1 etiologies. The top three causes of febrile illness requiring hospitalization in this Malaysian study were leptospirosis (68 (32%)), dengue (58 (27%)), and rickettsioses (42 (19%)). Fifty-five (18%) patients presented with severe disease with a qSOFA score of ≥2. Mortality was documented in 38 (12%) patients, with the highest seen in leptospirosis (16 (42%)) followed by rickettsiosis (4 (11%)). While the significance of leptospirosis and dengue are recognized, the impact of rickettsial infections in Peninsular Malaysia remains under appreciated. Management guidelines for in-patient care with acute febrile illness in Peninsular Malaysia are needed

Primaquine in glucose-6-phosphate dehydrogenase deficiency: an adaptive pharmacometric assessment of ascending dose regimens in healthy volunteers

Background: Primaquine is an 8-aminoquinoline antimalarial. It is the only widely available treatment to prevent relapses of Plasmodium vivax malaria. The 8-aminoquinolines cause dose-dependent haemolysis in glucose-6-phosphate dehydrogenase deficiency (G6PDd). G6PDd is common in malaria endemic areas but testing is often not available. As a consequence primaquine is underused. Methods: We conducted an adaptive pharmacometric study to characterise the relationship between primaquine dose and haemolysis in G6PDd. The aim was to explore shorter and safer primaquine radical cure regimens compared to the currently recommended 8-weekly regimen (0.75 mg/kg once weekly), potentially obviating the need for G6PD testing. Hemizygous G6PDd healthy adult Thai and Burmese male volunteers were admitted to the Hospital for Tropical Diseases in Bangkok. In Part 1, volunteers were given ascending dose primaquine regimens whereby daily doses were increased from 7.5 mg up to 45 mg over 15–20 days. In Part 2 conducted at least 6 months later, a single primaquine 45 mg dose was given. Results: 24 volunteers were enrolled in Part 1, and 16 in Part 2 (13 participated in both studies). In three volunteers, the ascending dose regimen was stopped because of haemolysis (n=1) and asymptomatic increases in transaminases (n=2; one was hepatitis E positive). Otherwise the ascending regimens were well tolerated with no drug-related serious adverse events. In Part 1, the median haemoglobin concentration decline was 3.7 g/dL (range: 2.1–5.9; relative decline of 26% [range: 15–40%]). Primaquine doses up to 0.87 mg/kg/day were tolerated subsequently without clinically significant further falls in haemoglobin. In Part 2, the median haemoglobin concentration decline was 1.7 g/dL (range 0.9–4.1; relative fall of 12% [range: 7–30% decrease]). The ascending dose primaquine regimens gave seven times more drug but resulted in only double the haemoglobin decline. Conclusions: In patients with Southeast Asian G6PDd variants, full radical cure treatment can be given in under 3 weeks compared with the current 8-week regimen. Funding: Medical Research Council of the United Kingdom (MR/R015252/1) and Wellcome (093956/Z/10/C, 223253/Z/21/Z)

Activity of Ivermectin and Its Metabolites against Asexual Blood Stage Plasmodium falciparum and Its Interactions with Antimalarial Drugs

Ivermectin is an endectocide used widely to treat a variety of internal and external parasites. Field trials of ivermectin mass drug administration for malaria transmission control have demonstrated a reduction of Anopheles mosquito survival and human malaria incidence. Ivermectin will mostly be deployed together with artemisinin-based combination therapies (ACT), the first-line treatment of falciparum malaria. It has not been well established if ivermectin has activity against asexual stage Plasmodium falciparum or if it interacts with the parasiticidal activity of other antimalarial drugs. This study evaluated antimalarial activity of ivermectin and its metabolites in artemisinin-sensitive and artemisinin-resistant P. falciparum isolates and assessed in vitro drug-drug interaction with artemisinins and its partner drugs. The concentration of ivermectin causing half of the maximum inhibitory activity (IC50) on parasite survival was 0.81 μM with no significant difference between artemisinin-sensitive and artemisinin-resistant isolates (P = 0.574). The ivermectin metabolites were 2-fold to 4-fold less active than the ivermectin parent compound (P &lt; 0.001). Potential pharmacodynamic drug-drug interactions of ivermectin with artemisinins, ACT-partner drugs, and atovaquone were studied in vitro using mixture assays providing isobolograms and derived fractional inhibitory concentrations. There were no synergistic or antagonistic pharmacodynamic interactions when combining ivermectin and antimalarial drugs. In conclusion, ivermectin does not have clinically relevant activity against the asexual blood stages of P. falciparum. It also does not affect the in vitro antimalarial activity of artemisinins or ACT-partner drugs against asexual blood stages of P. falciparum.</p

Ivermectin metabolites reduce Anopheles survival

Ivermectin mass drug administration to humans or livestock is a potential vector control tool for malaria elimination. The mosquito-lethal effect of ivermectin in clinical trials exceeds that predicted from in vitro laboratory experiments, suggesting that ivermectin metabolites have mosquito-lethal effect. The three primary ivermectin metabolites in humans (i.e., M1 (3″-O-demethyl ivermectin), M3 (4-hydroxymethyl ivermectin), and M6 (3″-O-demethyl, 4-hydroxymethyl ivermectin) were obtained by chemical synthesis or bacterial modification/metabolism. Ivermectin and its metabolites were mixed in human blood at various concentrations, blood-fed to Anopheles dirus and Anopheles minimus mosquitoes, and mortality was observed daily for fourteen days. Ivermectin and metabolite concentrations were quantified by liquid chromatography linked with tandem mass spectrometry to confirm the concentrations in the blood matrix. Results revealed that neither the LC50 nor LC90 values differed between ivermectin and its major metabolites for An. dirus or An. minimus., Additionally, there was no substantial differences in the time to median mosquito mortality when comparing ivermectin and its metabolites, demonstrating an equal rate of mosquito killing between the compounds evaluated. These results demonstrate that ivermectin metabolites have a mosquito-lethal effect equal to the parent compound, contributing to Anopheles mortality after treatment of humans

A randomised trial of malaria vaccine R21/Matrix-M™ with and without antimalarial drugs in Thai adults

In preparation for mass vaccinations with R21/Matrix-M™ combined with mass administrations of dihydroartemisinin, piperaquine, and a single low dose primaquine we assessed the tolerability, safety, and potential interactions of this combination affecting immunogenicity or pharmacokinetics. 120 healthy Thai volunteers were randomised to receive either antimalarials combined with vaccinations (n = 50), vaccinations alone (n = 50), or antimalarials only (n = 20). Three rounds of vaccines and antimalarials were administered one month apart. The vaccine was well tolerated alone and in combination with the antimalarials. None of the participants failed completion of the 3-dose vaccine course. There was no significant difference in the vaccine immunogenicity or in the pharmacokinetics of piperaquine given individually or in combination. This study supports proceeding to a large trial of mass vaccinations with R21/Matrix-M™ combined with mass antimalarial administration in Bangladesh

Good participatory practice for coronavirus disease 2019 (COVID-19) research: the case of a COVID-19 prevention study

Background: The COPCOV study (chloroquine/ hydroxychloroquine prevention of coronavirus disease), which started recruitment in April 2020, is a multi-country double-blind, randomised, placebo-controlled trial which is being conducted in healthcare facilities involved in COVID-19 case management. Participants are staff employed in facilities managing people with proven or suspected COVID-19. As part of the study, we conducted a series of engagement sessions. The aims were to assess the feasibility of the study, to identify context-specific ethical issues, to understand possible concerns, to fine tune research procedures and to refine the COPCOV information materials. Methods: The COPCOV study was approved by relevant institutional review boards. The sessions described in this paper were part of the study. We conducted a series of engagement sessions, each involving a short presentation of the study, a section where attendees were asked to express their willingness to participate in such a study, which information they would need to change their view and an open Q&A section. Answers were transcribed and coded into themes by two independent investigators. Themes were derived from the data. They complemented other site-specific engagement, communication, and public relation activities such as press releases and websites. Results and conclusions: From 16 th March 2020 to 20 th January 2021, 13 engagement sessions were conducted in Thailand, Laos, Vietnam, Nepal and the UK involving 222 attendees in total. Issues raised revolved around the social value and study rationale; safety of trial medications and risk-benefit balance; study design and commitments. These sessions helped us identify concerns people had, which helped us refine information materials as well as complement site feasibility assessments. Our experience strongly supports the use of participatory practices prior to conducting clinical trials