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Background: African children with severe malaria are at increased risk of non-typhoidal salmonellae co-infection. Broad-spectrum antibiotics are recommended by guidelines but the optimal class and dose have not been established. We investigated the optimal dose of oral dispersible azithromycin and whether simple clinical criteria and point-of-care biomarkers could target antibiotics to those at greatest risk of bacterial co-infection., Methods: We conducted a phase I/II trial in Ugandan children with severe malaria comparing a 5-day course of azithromycin: 10, 15 and 20 mg/kg of azithromycin (prescribed by weight bands) spanning the dose-range effective for other salmonellae infection. We generated relevant pharmacokinetic (PK) data by sparse sampling during dosing intervals and investigated associations between azithromycin exposure and potential mechanisms (PK-pharmacodynamics) using change in C-reactive protein (CRP), a putative marker of sepsis, at 72 h (continuous) and microbiological cure (7-day) (binary), alone and as a composite with 7-day and 90-day survival. To assess whether clinical or biomarkers could identify those at risk of sepsis, a non-severe malaria control was concurrently enrolled., Results: Between January 2020 and January 2022, 105 cases were randomised azithromycin doses: 35 to 10 mg/kg, 35 to 15 mg/kg and 35 to 20 mg/kg. Fifty non-severe malaria controls were concurrently enrolled. CRP reduced in all arms by 72 h with a mean reduction of 65.8 mg/L (95% CI 57.1, 74.5) in the 10 mg/kg arm, 64.8 mg/L (95% CI 56.5, 73.1; p = 0.87) in the 20 mg/kg arm and a smaller reduction 51.2 mg/L (95% CI 42.9, 59.5; p = 0.02) in the 15 mg/kg arm. Microbiological cure alone outcome was not analysed as only one pathogen was found among cases. Three events contributed to the composite outcome of 7-day survival and microbiological cure, with no events in the 15 mg/kg arm. The odds ratio comparing 20 vs 10 mg/kg was 0.50 (95% CI 0.04, 5.79); p = 0.58. Due to the low number of pathogens identified, it was not possible to identify better methods for targeting antibiotics including both the cases and controls., Conclusions: We found no evidence for an association between systemic azithromycin exposure and reduction in CRP. Further work is needed to better identify children at highest risk from bacterial co-infection., Trial Registration: ISRCTN49726849 (registered on 27th October 2017)., (© 2024. The Author(s).)

This study aimed to synthesise evidence comparing the levels of cytokines in severe falciparum malaria with those in uncomplicated malaria from available systematic reviews and meta- analyses. Relevant individual meta-analyses were searched in PubMed, Ovid, and Google Scholar, following the selection criteria specified for this umbrella review. The AMSTAR-2 tool was applied to grade the quality of the meta-analyses identified. The random-effects model was applied to recalculate the effect sizes of each included meta-analysis. Heterogeneity between meta-analyses was investigated with I 2 value. 95% predicting interval (PI) for the summary random-effects model was also made. In each meta-analysis identified, information on largest study's effect, the excess significance test, small study effects, and publication bias were addressed. This umbrella review included nine meta-analyses (n = 12,674) for nine unique cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, and TNF-α). Only one individual meta-analysis showed significantly higher levels of cytokine IL-1β (p: 0.009) amongst those with severe falciparum malaria compared to those with uncomplicated malaria. The 95% PIs did not show significance in any individual meta-analyses. Nine individual meta-analyses showed substantial heterogeneity, with I 2 tests ranging from 81% to 99%. Two independent meta-analyses (the IL-4 and IL-12) showed evidence of 'excess significant bias'. The meta-analysis of IL-1β only showed "Class III evidence", indicating that this cytokine was "suggestive" in contributing to those with severity of malaria in comparison to those with uncomplicated malaria. The remaining eight cytokines showed "Class IV evidence," indicating "weak" evidence on the impact of malaria severity. In conclusion, the findings suggest that compared to uncomplicated malaria, pro-inflammatory cytokine IL-1β contributes to the development of severe falciparum malaria. Due to the limited level of evidence, further well-designed larger studies with multiple cytokines are needed to investigate cytokine levels as reliable biomarkers in malaria severity., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Pulmonary oedema is a feared and difficult to predict complication of severe malaria that can emerge after start of antimalarial treatment. Proinflammatory mediators are thought to play a central role in its pathogenesis., Methods: An exploratory study was conducted to evaluate the predictive capacity of biomarkers for development of clinical pulmonary oedema in patients with severe falciparum malaria at two hospitals in Bangladesh. Plasma concentrations of interleukin-6 (IL-6), IL-8, tumour necrosis factor (TNF), soluble Receptor of Advanced Glycation End-products (sRAGE), surfactant protein-D (SP-D), club cell secretory protein (CC16), and Krebs von den Lungen-6 (KL-6) on admission were compared with healthy controls. Correlations between these biomarker and plasma lactate and Plasmodium falciparum histidine-rich protein 2 (PfHRP2) levels were evaluated. Receiver Operating Characteristic (ROC) curves were constructed to assess the predictive capacity for clinical pulmonary oedema of the biomarkers of interest., Results: Of 106 screened patients with falciparum malaria, 56 were classified as having severe malaria with a mortality rate of 29%. Nine (16%) patients developed clinical pulmonary oedema after admission. Plasma levels of the biomarkers of interest were higher in patients compared to healthy controls. IL-6, IL-8, TNF, sRAGE, and CC16 levels correlated well with plasma PfHRP2 levels (r s = 0.39; P = 0.004, r s = 0.43; P = 0.001, r s = 0.54; P < 0.001, r s = 0.44; P < 0.001, r s = 0.43; P = 0.001, respectively). Furthermore, IL-6 and IL-8 levels correlated well with plasma lactate levels (r s = 0.37; P = 0.005, r s = 0.47; P < 0.001, respectively). None of the biomarkers of interest had predictive capacity for development of clinical pulmonary oedema., Conclusions: IL-6, IL-8, TNF, sRAGE, SP-D, CC16 and KL-6 cannot be used in predicting clinical pulmonary oedema in severe malaria patients., (© 2024. The Author(s).)

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe complications that can occur in infections caused by any Plasmodium species. Due to the high lethality rate and the lack of specific treatment for ALI/ARDS, studies aimed at understanding and searching for treatment strategies for such complications have been fundamental. Here, we investigated the protective role of dietary supplementation with DHA-rich fish oil against lung damage induced by Plasmodium berghei ANKA in a murine model. Our results demonstrated that alveolar vascular damage, lung edema, and histopathological alterations were significantly reduced in mice that received dietary supplementation compared to those that did not receive the supplementation. Furthermore, a significant reduction in the number of CD8+ T lymphocytes, in addition to reduced infiltration of inflammatory cells in the bronchoalveolar lavage fluid was also observed. High levels of IL-10, but not of TNF-α and IFN-γ, were also observed in infected mice that received the supplementation, along with a reduction in local oxidative stress. Together, the data suggest that dietary supplementation with DHA-rich fish oil in malarial endemic areas may help reduce lung damage resulting from the infection, thus preventing worsening of the condition.

Background: In February 2022, the Ministry of Health received reports of more than 100 child deaths from a 'strange disease' in Namutumba District over a period of 6 months from politicians through the media. Preliminary investigations by the district rapid response team confirmed the strange disease to be severe malaria. The scope of severe malaria deaths was investigated, associated factors identified, and recommendations made for control measures to inform early malaria treatment strategies in Namutumba District., Methods: A retrospective study was conducted in March 2022 in the most affected subcounty (Ivukula Subcounty) involving cases and controls. A case was defined as a death with a positive malaria test, fever and any of the following: convulsions, difficulty breathing, yellowing of eyes or palms, tea-coloured urine, anaemia (evidenced by pale eyes or palms, or clinically-identified in medical records), loss of consciousness, or reduced urine output (very little or no urine in a day) in a child ≤ 12 years from September 2021 to February 2022 in Ivukula Subcounty, Namutumba District. Controls were survivors with the same signs and symptoms, recruited in a 2:1 ratio with cases. Cases and controls were actively searched using a door-to-door approach with the help of community health workers. Caretakers were interviewed to obtain data on signs and symptoms, socio-demographic information, health-seeking behaviours and health system risk factors. Drugs and bloodstock status information was obtained from health workers using an interview guide. Factors associated with death were identified using multivariate logistic regression and thematic analysis for qualitative data., Results: Among 46 cases, 29 (63%) were < 5 years, and 23 (50%) were female. Death among children with severe malaria was significantly associated with treatment non-completion (aOR = 9.7, 95%CI 1.8-53) and inability to receive blood transfusion for anaemic patients (aOR = 7.1, (95%CI 1.4-36). Healthcare workers reported that inability to reach referral sites due to transport costs, stockouts of anti-malarials and blood products at health facilities, and absence of integrated community case management of childhood illnesses (iCCM) contributed to deaths among children with severe malaria., Conclusion: Lack of access to anti-malarial treatment and to blood transfusions among anaemic patients due to stockouts were associated with severe malaria deaths among children ≤ 12 years in Ivukula Subcounty. Recommendations made were: accurate quantification of anti-malarials for health facilities, offering transport support to severe patients referred to higher-level facilities, and increasing access to blood products. Activation of iCCM could facilitate public health efforts against severe malaria in the district., (© 2024. The Author(s).)

Background: Genome-wide association studies have identified several nonfunctional tag single-nucleotide polymorphisms (SNPs) associated with severe malaria. We hypothesized that causal SNPs could play a significant role in severe malaria by altering promoter or enhancer activity. Here, we sought to identify such regulatory SNPs., Methods: SNPs in linkage disequilibrium with tagSNPs associated with severe malaria were identified and were further annotated using FUMA. Then, SNPs were prioritized using the integrative weighted scoring method to identify regulatory ones. Gene reporter assays were performed to assess the regulatory effect of a region containing candidates. The association between SNPs and severe malaria was assessed using logistic regression models in a Senegalese cohort., Results: Among 418 SNPs, the best candidates were rs116525449 and rs79644959, which were in full disequilibrium between them, and located within the ARL14 promoter. Our gene reporter assay results revealed that the region containing the SNPs exhibited cell-specific promoter or enhancer activity, while the SNPs influenced promoter activity. We detected an association between severe malaria and those 2 SNPs using the overdominance model and we replicated the association of severe malaria with the tagSNP rs116423146., Conclusions: We suggest that these SNPs regulate ARL14 expression in immune cells and the presentation of antigens to T lymphocytes, thus influencing severe malaria development., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Post-discharge malaria chemoprevention (PDMC) is an intervention aimed at reducing morbidity and mortality in patients hospitalized with severe anaemia, with its effectiveness established in several clinical trials. The aim of this study was to better understand factors that would influence the scale up of this intervention, and to identify preferences for two delivery mechanisms, facility-based or community-based., Methods: Forty-six qualitative individual interviews were conducted in five sub-Saharan countries amongst malaria key opinion leaders and national decision makers. Findings were analysed following a thematic inductive approach., Results: Half of participants were familiar with PDMC, with a satisfactory understanding of the intervention. Although PDMC was perceived as beneficial by most respondents, there was some unclarity on the target population. Both delivery approaches were perceived as valuable and potentially complementary. From an adoption perspective, relevant evidence generation, favorable policy environment, and committed funding were identified as key elements for the scale up of PDMC., Conclusions: The findings suggest that although PDMC was perceived as a relevant tool to prevent malaria, further clarification was needed in terms of the relevant patient population, delivery mechanisms, and more evidence should be generated from implementation research to ensure policy adoption and funding., (© 2024. The Author(s).)

Background: Malaria is the leading cause of hospitalizations and death in Uganda, particularly in children under the age of five. Studies have shown that adherence to the World Health Organization (WHO) guidelines for the management of severe malaria reduces mortality in hospitalized children. This study aimed to determine the impact of targeted interventions on adherence to the WHO severe malaria treatment guidelines in children at a Ugandan hospital as part of a quality improvement initiative., Methods: Interventions included workflow changes, such as obtaining patient blood samples for diagnostic testing by the admitting healthcare provider as well as utilizing patient caregivers to assist nursing staff in timing medications. An additional intervention was the use of an admission checklist sticker. The post-intervention sample was compared to the baseline assessment. The primary outcome was the proportion of patients receiving care consistent with all aspects of the WHO guidelines. Secondary outcomes included the proportion of patients receiving malaria diagnostic testing, those receiving at least 3 doses of artesunate, the timely administration of artesunate, and adherence to other guideline components. Statistical analyses were conducted using GraphPad PRISM 9.0. Comparisons between groups were analysed using Chi-square or Fisher's exact test for categorical variables and Mann-Whitney test for continuous variables., Results: The post-intervention group included 230 patients with a median age of 5 years [4-8], and 58% of patients were male. Adherence to all aspects of the WHO guidelines was achieved in 10% of patients in the post-intervention group compared to 3% of patients in the baseline (P = 0.007). Appropriate malaria diagnostic testing was performed in 85% of patients post-intervention compared to 66% of patients in the baseline (P < 0.0001). Patients in the post-intervention group were more likely to receive the minimum 3 doses of artesunate (86%) than in the baseline (74%) (P = 0.008). Patients in the post-intervention group were more likely to receive artesunate doses on time than in the baseline (dose 2 P = 0.02, dose 3 P = 0.003)., Conclusions: Targeted, low-cost interventions led to improvement in adherence to severe malaria treatment guidelines. The most notable changes were in malaria diagnostic testing and antimalarial administration., (© 2024. The Author(s).)

Background: Even on the best antimalarial treatments (injectable artesunate) African children with severe malaria have poor outcomes with most deaths occurring early in the course of hospital admission (<24hours). Lactic acidosis, largely due to impairment of the microcirculatory flow due to parasite sequestration, is a main risk factor for poor outcome. There are no adjuvant treatments for severe malaria that target this complication. Sevuparin, a heparin-like drug, binds to Plasmodium falciparum erythrocyte membrane protein blocking merozoite invasion, preventing cytoadherence and transiently de-sequestering infected erythrocytes. Leading to improved microcirculatory flow by reversing/preventing parasite sequestration. If given early during admission this could result in improvements in outcomes. Sevuparin has been shown to be safe and well tolerated in adults with only some mild transient effects on activated partial thromboplastin time (APTT) were reported, without clinical consequences., Methods: A Phase I trial designed to provide data on safety, dosing, feasibility of sevuparin as an adjuvant therapy in Kenya and Zambian children with severe malaria complicated by lactic acidosis (> 2mmol/l). Three intravenous doses will be given at admission (0 hours), 8 and 16 hours. APPT will be measured 1 hour after each dose (to assess maximum toxicity). Studying 20 children will allow sufficient data on safety to be generated across a range of doses to identify the maximum tolerated dose (MTD) using the Continual Reassessment Method, which adapts or informs subsequent doses for each child based on the data from previously enrolled children. The MTD will be identified based on the dose-toxicity model updated by each previous patient's APTT results using standard methods., Conclusions: The results of the Phase I trial will identify the final dose to be tested in a Phase II trial in terms of both efficacy and safety outcomes., Registration: PACTR number: 202007890194806 (date 20/07/2020) ISRCTN32271864 (date 28/07/2021)., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Maitland K et al.)

Malaria is a worldwide health concern, but a great majority of cases occur in tropical countries like India. With almost 95% of Indian population living in malaria endemic regions, India contributes to most of the global malaria cases and deaths, outside of African countries. Despite significant advances towards malaria control and eradication, mortality associated with severe malaria remains particularly high. Changing epidemiology, vulnerable patient population, overlapping symptomatology, and limited availability of parenteral preparations of artemisinin derivatives pose significant challenges in management of severe malaria. Further, the dearth of large-scale randomized trials from the developing countries makes it difficult to establish evidence-based guidelines pertaining to their situation. Thus, this position paper aims to provide guidance to critical care physicians across the country on managing patients with severe malaria in intensive care units (ICUs)., How to Cite This Article: Hegde A, Chhallani AK, Gupta B, Kadapatti K, Karnad D, Maheshwarappa HM, et al . ISCCM Position Statement on the Management of Severe Malaria in Intensive Care Unit. Indian J Crit Care Med 2024;28(S2):S59-S66., Competing Interests: Source of support: Nil Conflict of interest: None, (Copyright © 2024; The Author(s).)

Background: This study aimed to investigate existing evidence regarding the associations of obesity and diabetes with Plasmodium infection and severe malaria in adults., Methods: We comprehensively searched relevant studies using EMBASE, MEDLINE, Global Health, and CINAHL. The primary exposures were obesity and diabetes. The primary outcomes were Plasmodium infection and severe malaria. We performed meta-analyses to pool unadjusted and adjusted odds ratios (ORs) using a random-effects model., Results: We found 9 studies that met our inclusion criteria; all these studies were eligible for meta-analyses. None of the 9 studies investigated the potential link between obesity and Plasmodium infection. The meta-analysis results showed that there was no statistically significant relationship between obesity and severe malaria (two studies), diabetes and Plasmodium infection (five studies), or diabetes and severe malaria (three studies)., Conclusion: Our study findings showed that obesity was not associated with severe malaria, and diabetes was not associated with neither Plasmodium infection nor severe malaria. Additional epidemiological studies should be conducted to elucidate the relationships between obesity, diabetes, and Plasmodium infection., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Plasmodium falciparum is the dominant malaria species in the sub-Saharan Africa and the main cause of severe disease and death. Notwithstanding, severe malaria and death due to non-falciparum infections have been reported, but at much lower rates than P. falciparum infections. Following increasing use of molecular detection techniques in epidemiological studies, a higher prevalence of non-falciparum species has been reported in the region than previously thought. This article reviews the literature on the prevalence of non-falciparum malaria species in Uganda and the clinical figures of their severe diseases. It aims to elucidate the extent to which mono non-falciparum malaria infections in a highly malaria-endemic country contribute to malaria mortality and outline its policy implications on malaria case management., Methods: The available English-language published peer-reviewed literature up to March 2024 was sought via PubMed and Google Scholar. The keywords used were severe malaria, AND P. falciparum, P. malariae, P. vivax, P. ovale spp., mixed infections AND Uganda. The review encompassed 53 articles. Articles using molecular diagnosis methods were accounted for analysis., Results: The literature reported a substantial prevalence of non-falciparum infections in Uganda. Plasmodium malariae and Plasmodium ovale spp. were the second and third most prevalent reported malaria species respectively after P. falciparum as dominant species. Non-falciparum malaria infections often occur as mixed infections rather than mono-infections. Besides, molecular diagnostics revealed that 21% of initially reported mono-infections of P. falciparum were, in fact, mixed infections. No article was found on the prevalence of severe malaria or case fatality rate due to mixed or non-falciparum infections., Conclusion: A critical knowledge gap exists regarding the impact of mixed and non-falciparum species on severe malaria and death in Uganda. Robust evidence on prevalence, recurrent parasitaemia, and severe clinical manifestations of mixed and non-falciparum malaria infections is crucial for evidence-based and effective policymaking regarding malaria case management., (© 2024. The Author(s).)

Strain-transcending antibodies against virulence-associated subsets of P. falciparum -infected erythrocyte surface antigens could protect children from severe malaria. However, the evidence supporting the existence of such antibodies is incomplete and inconsistent. One subset of surface antigens associated with severe malaria, rosette-mediating Plasmodium falciparum Erythrocyte Membrane Protein one (PfEMP1) variants, cause infected erythrocytes to bind to uninfected erythrocytes to form clusters of cells (rosettes) that contribute to microvascular obstruction and pathology. Here, we tested plasma from 80 individuals living in malaria-endemic regions for IgG recognition of the surface of four P. falciparum rosetting strains using flow cytometry. Broadly reactive plasma samples were then used in antibody elution experiments in which intact IgG was eluted from the surface of infected erythrocytes and transferred to heterologous rosetting strains to look for strain-transcending antibodies. We found that seroprevalence (percentage of positive plasma samples) against allopatric rosetting strains was high in adults (63%-93%) but lower in children (13%-48%). Strain-transcending antibodies were present in nine out of eleven eluted antibody experiments, with six of these recognizing multiple heterologous rosetting parasite strains. One eluate had rosette-disrupting activity against heterologous strains, suggesting PfEMP1 as the likely target of the strain-transcending antibodies. Naturally acquired strain-transcending antibodies to rosetting P. falciparum strains in humans have not been directly demonstrated previously. Their existence suggests that such antibodies could play a role in clinical protection and raises the possibility that conserved epitopes recognized by strain-transcending antibodies could be targeted therapeutically by monoclonal antibodies or vaccines., Competing Interests: The authors declare no conflict of interest.

Introduction Malaria is the most common parasitic disease affecting humans. Haematological alterations in malaria are expected, and these changes play a significant role in fatal complications. The present study aims to assess the clinical and haematological profile in patients with acute falciparum malaria and the significance of various haematological and coagulation alterations with the clinical severity of malaria. Methods The prospective cross-sectional study included 68 acute falciparum malaria cases. Thick and thin blood film microscopy and a rapid diagnostic kit were used to diagnose malaria. The cases were subjected to various haematological and biochemical investigations. Bone marrow aspiration samples were also collected. Using appropriate statistical methods, the findings were compared between severe and uncomplicated malaria cases. A p-value below 0.05 was considered significant. Results The participants' ages ranged from 14 to 78. Most participants (n = 51, 75%) were male and belonged to the lower income group (33, 48.5%). Significant variations in mean parasite count between severe and uncomplicated malaria cases (p-value < 0.01) were observed. The severe and uncomplicated groups showed significant differences in haemoglobin (gm/dL), haematocrit, red blood cell count, reticulocyte, serum iron, and ESR levels (p-value < 0.05). The severe malaria group had considerably reduced mean platelet counts (p-value < 0.01). Only five instances (7.3%) had an appropriate erythropoietic response after day 28. Erythroid hyperplasia with dyserythropoietic alterations was most common in patients with severe anaemia and low-grade parasitaemia. Conclusion Acute falciparum malaria is often associated with haematological alterations. Anaemia and thrombocytopenia were the most expected alterations associated with disease prognosis and mortality., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Gauhati Medical College and Hospital issued approval EC/MC/GMC/150. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Roy et al.)

Background: The current definition of severe malaria in non-endemic areas follows WHO criteria, which mainly target children in malaria-endemic areas, potentially misclassifying cases in non-endemic regions. We assessed the performance of a modified severe malaria classification criteria within our patient cohort., Methods: A cohort study of patients managed for malaria in a non-endemic setting (2005-2023) was analyzed. We classified patients into severe malaria (SM) using WHO 2013 criteria except for hyperparasitemia, where 2 % threshold was applied. Patients with SM were distinguished as very severe malaria (VSM) when presenting at least one of the following conditions: parasitemia >10 %, pulmonary edema, impaired consciousness, seizures, renal failure, metabolic acidosis or hyperlactatemia, shock or hypoglycemia. In patients with SM and no criteria for VSM, less severe malaria (LSM) was defined by: 2-10 % parasitemia, hyperbilirubinemia, prostration, anemia or minor bleeding. The primary composite outcome was death or the need for a life-saving intervention, as analyzed in the three comparative groups. Secondary outcome was the prevalence of co-infections., Results: Among 506 patients with malaria, 176 (34.8 %) presented with SM. A total of 37 (7.3 %) patients developed a life-threatening condition, namely death (n = 4) and/or the need for life-saving interventions (n = 34). All fatalities and 33 out of the 34 life-saving interventions occurred in the VSM group. Patients in LSM group did not develop any life-threatening conditions. As to co-infections, 28 (5.5 %) patients had a community-acquired co-infection, with no differences between groups (p = 0.763)., Conclusions: Severity criteria definitions would benefit from a review when assessing patients with malaria in non-endemic areas. Within the spectrum of SM, patients reclassified as LSM have a low risk of developing a life-threatening condition and present low co-infection incidence and could benefit from management out of intensive care units and a restrictive use of empirical antibiotics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Imported malaria continues to be reported in Sri Lanka after it was eliminated in 2012, and a few progress to life-threatening severe malaria., Methods: Data on imported malaria cases reported in Sri Lanka from 2013 to 2023 were extracted from the national malaria database maintained by the Anti Malaria Campaign (AMC) of Sri Lanka. Case data of severe malaria as defined by the World Health Organization were analysed with regard to patients' general characteristics and their health-seeking behaviour, and the latter compared with that of uncomplicated malaria patients. Details of the last three cases of severe malaria in 2023 are presented., Results: 532 imported malaria cases were diagnosed over 11 years (2013-2023); 46 (8.6%) were severe malaria, of which 45 were Plasmodium falciparum and one Plasmodium vivax. Most severe malaria infections were acquired in Africa. All but one were males, and a majority (87%) were 26-60 years of age. They were mainly Sri Lankan nationals (82.6%). Just over half (56.5%) were treated at government hospitals. The average time between arrival of the person in Sri Lanka and onset of illness was 4 days. 29 cases of severe malaria were compared with 165 uncomplicated malaria cases reported from 2015 to 2023. On average both severe and uncomplicated malaria patients consulted a physician equally early (mean = 1 day) with 93.3% of severe malaria doing so within 3 days. However, the time from the point of consulting a physician to diagnosis of malaria was significantly longer (median 4 days) in severe malaria patients compared to uncomplicated patients (median 1 day) (p = 0.012) as was the time from onset of illness to diagnosis (p = 0.042). All severe patients recovered without sequelae except for one who died., Conclusions: The risk of severe malaria among imported cases increases significantly beyond 5 days from the onset of symptoms. Although patients consult a physician early, malaria diagnosis tends to be delayed by physicians because it is now a rare disease. Good access to expert clinical care has maintained case fatality rates of severe malaria at par with those reported elsewhere., (© 2024. The Author(s).)

Nigeria accounts for 39% of global malaria deaths in children under 5 years of age and the effective management of severe malaria is a health priority. The Annual Nigeria Severe Malaria Stakeholders Workshop, held on the 5-6th of July 2023 in Abuja, Nigeria brought together representatives from 36 States, the Federal Capital Territory, and other key stakeholders to address the management of severe malaria across all levels of the health service. Aims were to provide updates and review progress on severe malaria activities, the burden of disease, commodity logistics management, and pre-referral national policy implementation as well as to disseminate research findings. Two roundtable discussions were conducted to identify the challenges, barriers, and facilitators to the effective management of severe malaria in Nigeria. A key challenge was the limited awareness of updated guidelines and strategic documents among frontline health workers, leading to the misuse of non-recommended medications, like α-β-arteether. Further to this, the need to ensure appropriate treatments during pregnancy and the adoption of the WHO directive on the use of rectal artesunate were highlighted. To address these issues, innovative dissemination channels for guideline awareness were recommended and collaboration with professional organizations to enrich training materials emphasized. Other areas for improvement considered the processes involved in severe malaria management, with insufficient coordination among government agencies, inadequate referral linkages, and inadequate human resources identified as barriers. Recommendations focused on practical measures to minimize wastage of injectable artesunate, enhance data management through scaling up electronic medical records, and strengthen referral systems. The extension of severe malaria surveillance to patients older than 5 years was also proposed. To deliver these changes, actionable plans for sustained recruitment and training are needed, as well as committed advocacy at all levels to ensure timely fund disbursement and institutional support. A key overarching theme from the workshop was that a multifaceted approach was needed to address severe malaria in Nigeria, emphasizing collaborative efforts, evidence-based practices, and strategic resource allocation. With the largest malaria burden globally, the potential impact of addressing the challenges of severe malaria management in Nigeria cannot be understated and must be urgently addressed., (© 2024. The Author(s).)

Background: Severe malaria is a life-threatening infection, particularly affecting children under the age of 5 years in Africa. Current treatment with parenteral artemisinin derivatives is highly efficacious. However, artemisinin partial resistance is widespread in Southeast Asia, resulting in delayed parasite clearance after therapy, and has emerged independently in South America, Oceania, and Africa. Hence, new treatments for severe malaria are needed, and it is prudent to define their characteristics now. This manuscript focuses on the target product profile (TPP) for new treatments for severe malaria. It also highlights preparedness when considering ways of protecting the utility of artemisinin-based therapies., Target Product Profile: Severe malaria treatments must be highly potent, with rapid onset of antiparasitic activity to clear the infection as quickly as possible to prevent complications. They should also have a low potential for drug resistance selection, given the high parasite burden in patients with severe malaria. Combination therapies are needed to deter resistance selection and dissemination. Partner drugs which are approved for uncomplicated malaria treatment would provide the most rapid development pathway for combinations, though new candidate molecules should be considered. Artemisinin combination approaches to severe malaria would extend the lifespan of current therapy, but ideally, completely novel, non-artemisinin-based combination therapies for severe malaria should be developed. These should be advanced to at least phase 2 clinical trials, enabling rapid progression to patient use should current treatment fail clinically. New drug combinations for severe malaria should be available as injectable formulations for rapid and effective treatment, or as rectal formulations for pre-referral intervention in resource-limited settings., Conclusion: Defining the TPP is a key step to align responses across the community to proactively address the potential for clinical failure of artesunate in severe malaria. In the shorter term, artemisinin-based combination therapies should be developed using approved or novel drugs. In the longer term, novel combination treatments should be pursued. Thus, this TPP aims to direct efforts to preserve the efficacy of existing treatments while improving care and outcomes for individuals affected by this life-threatening disease., (© 2024. The Author(s).)

Following a 2-week trip to Kazakhstan, a 42-year-old woman presented at the emergency department in Germany with fever, headache, nausea, and neurological symptoms. An infection with Plasmodium falciparum was rapidly diagnosed. The patient was immediately treated with intravenous artesunate and transferred to an intensive care unit. The initial parasite density was as high as 30% infected erythrocytes with 845,880 parasites/µL. Since Kazakhstan was declared malaria-free in 2012, molecular testing for Plasmodium has been initiated to identify a possible origin. Genotyping of the msp-1 gene and microsatellite markers showed that the parasites are of African origin, with two different alleles indicating a polyclonal infection. After a hospitalization of 10 days, the patient was discharged in good health. Overall, our results emphasize that malaria must be on the list of differential diagnoses for patients with fever of unknown origin, even if they come from countries where malaria does not commonly occur., Competing Interests: Declarations of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Purpose: This study explored severe malaria-related disability in children from the perspectives of their caregivers., Materials and Methods: The interpretive description qualitative approach was employed. The participants were selected using the purposive sampling technique considering the child's history of severe malaria, age (0-10 years), and location (urban/rural). Data were collected through face-to-face interviews with sixteen caregivers. Reflexive thematic data analysis was utilized. Through prolonged engagement, reflective journaling, an audit trail, and co-authors' review, trustworthiness was enhanced., Results: The study generated five themes from the interviews: mitigators of disability, contributors of disability, impact on body function, impact on activities and participation, and uncertainties about future well-being. The findings revealed previously unstudied social components of disability and environmental factors. Furthermore, the research uncovered health-related quality of life aspects that are out of the scope of the current comprehensive disability framework., Conclusions: The study contributes to a deeper understanding of severe malaria-related disability in children from the biopsychosocial perspective. The findings could help policymakers, researchers, and clinicians who want to design rehabilitation interventions for the affected children or examine the components of disability on a large scale using quantitative methods.IMPLICATIONS FOR REHABILITATIONVarious contextual factors interacted with severe malaria and influenced functioning either as facilitators or barriers, implying disability related to malaria can be prevented or created.The long-term impacts of severe malaria are not limited to functioning and disability but also affect the health-related quality of life of children who survive severe malaria.Rehabilitation professionals should consider applying comprehensive functioning and disability frameworks such as the ICF when designing (or applying) screening tools, planning interventions, and evaluating the outcomes of intervention for children with severe malaria-related disability.Rehabilitation interventions for children with severe malaria-related disability should consider patient- or caregiver-reported outcomes (components of disability).

Background: Plasmodium falciparum malaria is still a leading cause of child mortality in sub-Saharan Africa. The clinical manifestations of malaria range from asymptomatic infection to severe disease. The variation in clinical presentation is partly attributed to host genetic factors with estimated narrow-sense heritability of 23%. Here, we investigate the associations between candidate gene polymorphisms and the likelihood of severe malaria (SM) in a cohort of Malian children., Methods: Based on our previous genome-wide association studies (GWAS) analysis, candidate genes were selected for in-depth analysis using several criteria including gene-level GWAS scores, functional overlap with malaria pathogenesis, and evidence of association with protection or susceptibility to other infectious or inflammatory diseases. Single Nucleotide Polymorphisms (SNPs) residing within these genes were selected mainly based on p -values from previous severe malaria susceptibility GWAS studies and minor allele frequency (MAF) in West African populations., Results: Of 182 candidate genes reported in our previous study, 11 genes and 22 SNPs residing in these genes were selected. The selected SNPs were genotyped using KASP technology in 477 DNA samples (87 SM and 390 controls). Logistic regression analysis revealed that a common intron variant, rs13340578 in CUB and Sushi Multi Domain (CSMD1) gene, is associated with increased odds of SM in recessive mode of inheritance (MAF = 0.42, OR = 1.8, 95% CI = [1.78, 1.84], p = 0.029). The SNP is in linkage disequilibrium (LD) with multiple variants with regulatory features., Conclusion: Taken together, the current study showed that an intron variant rs13340578, residing in CSMD1 gene, is associated with increased susceptibility to malaria. This finding suggests that modified regulation of complement may contribute to malaria disease severity. Further studies are needed to identify the causal variants and the underlying molecular mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Damena, Barry, Morrison, Gaoussou, Mahamar, Attaher, Issiaka, Dicko, Dicko, Duffy and Fried.)

Background: African children with cerebral malaria and seizures caused Plasmodium falciparum are at greater risk of poor outcomes including death and neurological sequelae. The agonal events are severe hypoventilation and respiratory arrest often triggered by seizures. We hypothesised that prophylactic anti-seizure medication (ASM) could avert 'spikes' of intracranial pressure during or following seizures and that adequate ventilation could be supported by biphasic Cuirass Ventilation (BCV) which requires no intubation., Methods: A Phase I trial conducted in Kilifi, Kenya designed to provide data on safety, feasibility and preliminary data on seizure control using prophylactic ASM (levetiracetam) and BCV as non-invasive ventilatory support in children with cerebral malaria. Children aged 3 months to 12-years hospitalised with P falciparum malaria (positive rapid diagnostic test or a malaria slide), a Blantyre Coma Score ≤2 and a history of acute seizures in this illness are eligible for the trial. In a phased evaluation we will study i) BCV alone for respiratory support (n=10); ii) prophylactic LVT: 40mg/kg loading dose then 30mg/kg every 12 hours given via nasogastric tube for 72 hours (or until fully conscious) plus BCV support (n=10) and; iii) prophylactic LVT: 60mg/kg loading dose then 45mg/kg every 12 hours given via nasogastric tube for 72 hours (or until fully conscious) plus BCV support (n=10). Primary outcome measure: cumulative time with a clinically detected seizures or number of observed seizures over 36 hours. Secondary outcomes will be assessed by feasibility or ability to implement BCV, and recovery from coma within 36 hours. Safety endpoints include: aspiration during admission; death at 28 days and 180 days; and de-novo neurological impairments at 180 days., Conclusions: This is a Phase I trial largely designed to test the feasibility, tolerability and safety of using non-invasive ventilatory support and LVT prophylaxis in cerebral malaria., Registration: ISRCTN76942974 (5.02.2019); PACTR202112749708968 (20.12.2021)., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Maitland K et al.)

Background: Malaria is an important cause of mortality in African children. Identification of biomarkers to identify children at risk of mortality has the potential to improve outcomes., Methods: We evaluated 11 biomarkers of host response in 592 children with severe malaria. The primary outcome was biomarker performance for predicting mortality. Biomarkers were evaluated using receiver operating characteristic (ROC) curve analysis comparing the area under the ROC curve (AUROC)., Results: Mortality was 7.3% among children in the study with 72% of deaths occurring within 24 hours of admission. Among the candidate biomarkers, soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) had the highest AUROC (0.78 [95% confidence interval, .70-.86]), outperforming several other biomarkers including C-reactive protein and procalcitonin. sTREM-1 was the top-performing biomarker across prespecified subgroups (malaria definition, site, sex, nutritional status, age). Using established cutoffs, we evaluated mortality across sTREM-1 risk zones. Among children with acute kidney injury, 39.9% of children with a critical-risk sTREM-1 result had an indication for dialysis. When evaluated relative to a disease severity score, sTREM-1 improved mortality prediction (difference in AUROC, P = .016)., Conclusions: sTREM-1 is a promising biomarker to guide rational allocation of clinical resources and should be integrated into clinical decision support algorithms, particularly when acute kidney injury is suspected., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Imported malaria is often misdiagnosed due to the aspecific symptoms and lack of familiarity among clinicians. This study aims to evaluate a decade-long trend of imported malaria cases in a Belgian teaching hospital by analyzing demographics, clinical characteristics, and outcomes., Methods: Medical records of 223 patients with confirmed malaria diagnoses between 2010 and 2019 were analyzed., Results: Most patients were male (63.2%), aged 18-65 years (77.1%), and visiting friends or relatives (40.8%). Central Africa was the most common travel destination (54.3%), and 63.7% did not take prophylaxis. Symptoms were flu-like, with fever (91.9%) being most prevalent. P. falciparum was identified in 88.3% of cases. A high proportion of severe cases (41.7%) and a low mortality rate (0.9%) were recorded. A severe form of the disease is associated with a more extended hospital stay than uncomplicated form (median of 5 vs. 4 days, p < 0.001). Thirty-five-point five percent [33/93] of patients with severe malaria have had a previous malaria infection compared to 50.8% [66/130] of uncomplicated patients (p= 0.013) wich was statistically significant., Conclusion: Malaria disproportionately affects VFRs traveling to Central Africa, and flu-like symptoms should raise suspicion. Prophylaxis is essential to prevent the disease, and early diagnosis is critical for effective management. A severe form of the disease is associated with a more extended hospital stay than uncomplicated form and people with a previous history of malaria have a less severe disease., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Malaria infection is a multifactorial disease partly modulated by host immuno-genetic factors. Recent evidence has demonstrated the importance of Interleukin-17 family proinflammatory cytokines and their genetic variants in host immunity. However, limited knowledge exists about their role in parasitic infections such as malaria. We aimed to investigate IL-17A serum levels in patients with severe and uncomplicated malaria and gene polymorphism's influence on the IL-17A serum levels. In this research, 125 severe (SM) and uncomplicated (UM) malaria patients and 48 free malaria controls were enrolled. IL-17A serum levels were measured with ELISA. PCR and DNA sequencing were used to assess host genetic polymorphisms in IL-17A. We performed a multivariate regression to estimate the impact of human IL-17A variants on IL-17A serum levels and malaria outcomes. Elevated serum IL-17A levels accompanied by increased parasitemia were found in SM patients compared to UM and controls (P < 0.0001). Also, the IL-17A levels were lower in SM patients who were deceased than in those who survived. In addition, the minor allele frequencies (MAF) of two IL-17A polymorphisms (rs3819024 and rs3748067) were more prevalent in SM patients than UM patients, indicating an essential role in SM. Interestingly, the heterozygous rs8193038 AG genotype was significantly associated with higher levels of IL-17A than the homozygous wild type (AA). According to our results, it can be concluded that the IL-17A gene rs8193038 polymorphism significantly affects IL-17A gene expression. Our results fill a gap in the implication of IL-17A gene polymorphisms on the cytokine level in a malaria cohort. IL-17A gene polymorphisms also may influence cytokine production in response to Plasmodium infections and may contribute to the hyperinflammatory responses during severe malaria outcomes., (© 2024. The Author(s).)

Background: The aim of this study is to design ad hoc malaria learning (ML) approaches to predict clinical outcome in all patients with imported malaria and, therefore, to identify the best clinical setting., Methods: This is a single-centre cross-sectional study, patients with confirmed malaria, consecutively hospitalized to the Lazzaro Spallanzani National Institute for Infectious Diseases, Rome, Italy from January 2007 to December 2020, were recruited. Different ML approaches were used to perform the analysis of this dataset: support vector machines, random forests, feature selection approaches and clustering analysis., Results: A total of 259 patients with malaria were enrolled, 89.5% patients were male with a median age of 39 y/o. In 78.3% cases, Plasmodium falciparum was found. The patients were classified as severe malaria in 111 cases. From ML analyses, four parameters, AST, platelet count, total bilirubin and parasitaemia, are associated to a negative outcome. Interestingly, two of them, aminotransferase and platelet are not included in the current list of World Health Organization (WHO) criteria for defining severe malaria., Conclusion: In conclusion, the application of ML algorithms as a decision support tool could enable the clinicians to predict the clinical outcome of patients with malaria and consequently to optimize and personalize clinical allocation and treatment., (© 2024. The Author(s).)

Cerebral malaria (CM) is one of the most severe complications of malaria infection characterized by coma and neurological effects. Despite standardized treatment of malaria infection with artemisinin-based combination therapies (ACT), the mortality rate is still high, and it primarily affects pediatric patients. ACT reduces parasitemia but fails to adequately target the pathogenic mechanisms underlying CM, including blood-brain-barrier (BBB) disruption, endothelial activation/dysfunction, and hyperinflammation. The need for adjunctive therapies to specifically treat this form of severe malaria is critical as hundreds of thousands of people continue to die each year from this disease. Here we present a summary of some potential promising therapeutic targets and treatments for CM, as well as some that have been tested and deemed ineffective or, in some cases, even deleterious. Further exploration into these therapeutic agents is warranted to assess the effectiveness of these potential treatments for CM patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bensalel and Gallego-Delgado.)

Severe malaria is a life-threatening condition that is associated with a high mortality. Severe Plasmodium falciparum infections are mediated primarily by high parasitemia and binding of infected red blood cells (iRBCs) to the blood vessel endothelial layer, a process known as sequestration. Here, we show that including the 5-amino-2-methoxybenzenesulfonate (AMBS) chemical modification in soluble biopolymers (polyglutamic acid and heparin) and poly(acrylic acid)-exposing nanoparticles serves as a universal tool to introduce a potent parasite invasion inhibitory function in these materials. Importantly, the modification did not add or eliminated (for heparin) undesired anticoagulation activity. The materials protected RBCs from invasion by various parasite strains, employing both major entry pathways. Two further P. falciparum strains, which either expose ligands for chondroitin sulfate A (CSA) or intercellular adhesion molecule 1 (ICAM-1) on iRBCs, were tested in antisequestration assays due to their relevance in placental and cerebral malaria, respectively. Antisequestration activity was found to be more efficacious with nanoparticles vs gold-standard soluble biopolymers (CSA and heparin) against both strains, when tested on receptor-coated dishes. The nanoparticles also efficiently inhibited and reversed the sequestration of iRBCs on endothelial cells. First, the materials described herein have the potential to reduce the parasite burden by acting at the key multiplication stage of reinvasion. Second, the antisequestration ability could help remove iRBCs from the blood vessel endothelium, which could otherwise cause vessel obstruction, which in turn can lead to multiple organ failure in severe malaria infections. This approach represents a further step toward creation of adjunctive therapies for this devastating condition to reduce morbidity and mortality.

Purpose: Disability is a consequence of severe malaria for a significant proportion of African children. This scoping review aims to describe the impact of severe malaria on African children according to current literature using an international biopsychical classification and framework of disability and functioning., Materials and Methods: MEDLINE, EMBASE, Global Health, and CINHAL databases were searched for original research conducted on African children aged 0-18 using terms related to severe malaria and components of disability. Independent and dependent variables were extracted and classified using the World Health Organization's International Classification of Functioning, Disability, and Health-Children and Youth version (ICF-CY) using standardized coding methods., Results: Seventy-two percent of the measured variables in the 34 included studies were coded as "body functions," (i.e., impairments), such as mental, neuromusculoskeletal, movement, and sensory functions, and 23.3% of variables were coded as "activities and participation" (i.e., activity limitations/participation restrictions), such as difficulties with general tasks and demands, communication, mobility, interpersonal interactions, and relationships. "Environment" variables such as family support, health access, education, or societal attitudes were not found in the included studies., Conclusions: Existing peer-reviewed quantitative research of severe malaria-related disability is focused on neurological sequelae, with less research about activity limitations and participation restrictions.

Infections with Plasmodium falciparum and Plasmodium vivax cause over 600,000 deaths each year, concentrated in Africa and in young children, but much of the world's population remain at risk of infection. In this article, we review the latest developments in the immunogenicity and pathogenesis of malaria, with a particular focus on P. falciparum , the leading malaria killer. Pathogenic factors include parasite-derived toxins and variant surface antigens on infected erythrocytes that mediate sequestration in the deep vasculature. Host response to parasite toxins and to variant antigens is an important determinant of disease severity. Understanding how parasites sequester, and how antibody to variant antigens could prevent sequestration, may lead to new approaches to treat and prevent disease. Difficulties in malaria diagnosis, drug resistance, and specific challenges of treating P. vivax pose challenges to malaria elimination, but vaccines and other preventive strategies may offer improved disease control.

Persistent neurodisability is a known complication in paediatric survivors of cerebral malaria and severe malarial anaemia. Tau, ubiquitin C-terminal hydrolase-L1, neurofilament-light chain, and glial fibrillary acidic protein have proven utility as biomarkers that predict adverse neurologic outcomes in adult and paediatric disorders. In paediatric severe malaria, elevated tau is associated with mortality and neurocognitive complications. We aimed to investigate whether a multi-analyte panel including ubiquitin C-terminal hydrolase-L1, neurofilament-light chain, and glial fibrillary acidic protein can serve as biomarkers of brain injury associated with mortality and neurodisability in cerebral malaria and severe malarial anaemia. In a prospective cohort study of Ugandan children, 18 months to 12 years of age with cerebral malaria ( n = 182), severe malarial anaemia ( n = 158), and asymptomatic community children ( n = 118), we measured admission blood levels of ubiquitin C-terminal hydrolase-L1, neurofilament-light chain, and glial fibrillary acidic protein. We investigated differences in biomarker levels, associations with mortality, blood-brain barrier integrity, neurodeficits and cognitive Z -scores in survivors up to 24-month follow-up. Admission ubiquitin C-terminal hydrolase-L1 levels were elevated >95th percentile of community children in 71 and 51%, and neurofilament-light chain levels were elevated >95th percentile of community children in 40 and 37% of children with cerebral malaria and severe malarial anaemia, respectively. Glial fibrillary acidic protein was not elevated in disease groups compared with controls. In cerebral malaria, elevated neurofilament-light chain was observed in 16 children who died in hospital compared with 166 survivors ( P = 0.01); elevations in ubiquitin C-terminal hydrolase-L1 levels were associated with degree of blood-brain barrier disruption ( P = 0.01); and the % predictive value for neurodeficits over follow-up (discharge, 6-, 12-, and 24 months) increased for ubiquitin C-terminal hydrolase-L1 (60, 67, 72, and 83), but not neurofilament-light chain (65, 68, 60, and 67). In cerebral malaria, elevated ubiquitin C-terminal hydrolase-L1 was associated with worse memory scores in children <5 years at malaria episode who crossed to over 5 years old during follow-up cognitive testing [ β -1.13 (95% confidence interval -2.05, -0.21), P = 0.02], and elevated neurofilament-light chain was associated with worse attention in children ≥5 years at malaria episode and cognitive testing [ β -1.08 (95% confidence interval -2.05, -1.05), P = 0.03]. In severe malarial anaemia, elevated ubiquitin C-terminal hydrolase-L1 was associated with worse attention in children <5 years at malaria episode and cognitive testing [ β -0.42 (95% confidence interval -0.76, -0.07), P = 0.02]. Ubiquitin C-terminal hydrolase-L1 and neurofilament-light chain levels are elevated in paediatric cerebral malaria and severe malarial anaemia. In cerebral malaria, elevated neurofilament-light chain is associated with mortality whereas elevated ubiquitin C-terminal hydrolase-L1 is associated with blood-brain barrier dysfunction and neurodeficits over follow-up. In cerebral malaria, both markers are associated with worse cognition, while in severe malarial anaemia, only ubiquitin C-terminal hydrolase-L1 is associated with worse cognition., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: There has been a concerted effort to reduce malaria burden and bring malaria related mortality to zero. The objectives of this survey were to assess the level of adherence to the current revised malaria control guidelines in the public health facilities in Cross River State of Nigeria and to identify the challenges as well as suggest ways for improvement in treatment outcomes., Methods: This was a mixed observational and qualitative survey conducted in 32 public health facilities from 21st to 25th June 2022. Treatment records on malaria were assessed for adherence to the National guidelines. In-depth interviews were conducted with 36 key informants and 4 purposefully selected stakeholders to identify the successes and challenges. Quantitative data were summarized and presented in simple proportions and percentages while qualitative information was recorded, the transcripts thematically coded, analyzed and presented using NVivo 11 software., Results: The survey revealed that vector control program was poorly implemented across the state. For case management, presumptive treatment was frequently practiced especially at secondary health facilities for uncomplicated malaria. More than 60% of uncomplicated malaria were being treated with parenteral artemether instead of oral artemisinin combination therapy (ACTs) as recommended. Severe malaria were not treated with Intravenous (IV) Artesunate as first line drug in about 40% of the secondary health facilities. Key successes were noted in malaria management in pregnancy. Major challenges identified include: stock out of commodities, shortage of clinical man power, and low trust in parasitological diagnosis., Conclusion: The survey showed that adherence to the key recommendations in various categories of malaria control among health care providers in the public health facilities was below expectation. Malaria preventive treatment in pregnancy with SP fared better perhaps because of its inclusion in ANC packages., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author declares that this is an original research work that is not currently being considered for submission by any other Journals., (© The Author(s) 2023.)

Background: Plasmodium falciparum pigment-containing leucocytes (PCLs) are associated with adverse clinical manifestations of severe malaria in African children. However, limited data exist on the association of PCLs in settings outside of Africa., Methods: Thin films on peripheral blood slides obtained from children ages 6 months-10 y with severe malaria were examined for PCLs. The intraleucocytic pigment data were correlated with clinical phenotypic data such as severe anaemia, metabolic acidosis and coma to determine the association of PCLs with clinical phenotypes of severe malaria and outcome., Results: Of the 169 children with severe P. falciparum malaria confirmed by microscopy, 76% (129/169) had PCLs. Compared with children without PCLs, the presence (adjusted odds ratio [AOR] 3.2 [95% confidence interval {CI} 1.5 to 6.9], p≤0.01) and quantity (AOR 1.0 [95% CI 1.0 to 1.1], p=0.04) of pigment-containing monocytes (PCMs) was significantly associated with severe anaemia, while the quantity of both PCMs (AOR 1.0 [95% CI 1.0 to 1.1], p≤0.01) and pigment-containing neutrophils (AOR 1.0 [95% CI 1.0 to 1.1], p=0.01) was significantly associated with metabolic acidosis. Plasma P. falciparum histidine-rich protein-2 level negatively correlated with the platelet count (r=-0.5, p≤0.01) in patients with PCLs and no PCLs., Conclusions: In Papua New Guinean children with severe P. falciparum malaria, the presence and quantity of PCLs are predictors of disease severity, severe anaemia and metabolic acidosis., (© The Author(s) 2023. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Malaria is responsible for approximately three-quarters of a million deaths in humans globally each year. Most of the morbidity and mortality reported are from Sub-Saharan Africa and Asia, where the disease is endemic. In non-endemic areas, malaria is the most common cause of imported infection and is associated with significant mortality despite recent advancements and investments in elimination programs. Severe malaria often requires intensive care unit admission and can be complicated by cerebral malaria, respiratory distress, acute kidney injury, bleeding complications, and co-infection. Intensive care management includes prompt diagnosis and early initiation of effective antimalarial therapy, recognition of complications, and appropriate supportive care. However, the lack of diagnostic capacities due to limited advances in equipment, personnel, and infrastructure presents a challenge to the effective diagnosis and management of malaria. This article reviews the clinical classification, diagnosis, and management of malaria as relevant to critical care clinicians, highlighting the role of diagnostic capacity, treatment options, and supportive care., (© 2023 The Author(s).)

Importance: Malaria is a devastating disease caused by Plasmodium parasites. The evolution of parasite drug resistance continues to hamper progress toward malaria elimination, and despite extensive efforts to control malaria, it remains a leading cause of death in Mozambique and other countries in the region. The development of successful vaccines and identification of molecular markers to track drug efficacy are essential for managing the disease burden. We present an analysis of the parasite genome in Mozambique, a country with one of the highest malaria burdens globally and limited available genomic data, revealing current selection pressure. We contribute additional evidence to limited prior studies supporting the effectiveness of SWGA in producing reliable genomic data from complex clinical samples. Our results provide the identity of genomic loci that may be associated with current antimalarial drug use, including artemisinin and lumefantrine, and reveal selection pressure predicted to compromise the efficacy of current vaccine candidates., Competing Interests: The authors declare no conflict of interest.

Antibody responses to variant surface antigens (VSAs) produced by the malaria parasite Plasmodium falciparum may contribute to age-related natural immunity to severe malaria. One VSA family, P. falciparum erythrocyte membrane protein-1 (PfEMP1), includes a subset of proteins that binds endothelial protein C receptor (EPCR) in human hosts and potentially disrupts the regulation of inflammatory responses, which may lead to the development of severe malaria. We probed peptide microarrays containing segments spanning five PfEMP1 EPCR-binding domain variants with sera from 10 Malian adults and 10 children to determine the differences between adult and pediatric immune responses. We defined serorecognized peptides and amino acid residues as those that elicited a significantly higher antibody response than malaria-naïve controls. We aimed to identify regions consistently serorecognized among adults but not among children across PfEMP1 variants, potentially indicating regions that drive the development of immunity to severe malaria. Adult sera consistently demonstrated broader and more intense serologic responses to constitutive PfEMP1 peptides than pediatric sera, including peptides in EPCR-binding domains. Both adults and children serorecognized a significantly higher proportion of EPCR-binding peptides than peptides that do not directly participate in receptor binding, indicating a preferential development of serologic responses at functional residues. Over the course of a single malaria transmission season, pediatric serological responses increased between the start and the peak of the season, but waned as the transmission season ended. IMPORTANCE Severe malaria and death related to malaria disproportionately affect sub-Saharan children under 5 years of age, commonly manifesting as cerebral malaria and/or severe malarial anemia. In contrast, adults in malaria-endemic regions tend to experience asymptomatic or mild disease. Our findings indicate that natural immunity to malaria targets specific regions within the EPCR-binding domain, particularly peptides containing EPCR-binding residues. Epitopes containing these residues may be promising targets for vaccines or therapeutics directed against severe malaria. Our approach provides insight into the development of natural immunity to a binding target linked to severe malaria by characterizing an "adult-like" response as recognizing a proportion of epitopes within the PfEMP1 protein, particularly regions that mediate EPCR binding. This "adult-like" response likely requires multiple years of malaria exposure, as increases in pediatric serologic response over a single malaria transmission season do not appear significant., Competing Interests: The authors declare no conflict of interest.

Background: Antibodies to variant surface antigens (VSAs) such as Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) may vary with malaria severity. The influence of ABO blood group on antibody development is not understood., Methods: Immunoglobulin G antibodies to VSAs in Papua New Guinean children with severe (n = 41) or uncomplicated (n = 30) malaria were measured by flow cytometry using homologous P falciparum isolates. Isolates were incubated with ABO-matched homologous and heterologous acute and convalescent plasma. RNA was used to assess var gene transcription., Results: Antibodies to homologous, but not heterologous, isolates were boosted in convalescence. The relationship between antibody and severity varied by blood group. Antibodies to VSAs were similar in severe and uncomplicated malaria at presentation, higher in severe than uncomplicated malaria in convalescence, and higher in children with blood group O than other children. Six var gene transcripts best distinguished severe from uncomplicated malaria, including UpsA and 2 CIDRα1 domains., Conclusions: ABO blood group may influence antibody acquisition to VSAs and susceptibility to severe malaria. Children in Papua New Guinea showed little evidence of acquisition of cross-reactive antibodies following malaria. Var gene transcripts in Papua New Guinean children with severe malaria were similar to those reported from Africa., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Malaria remains a major public health issue in the Democratic Republic of the Congo (DRC), accounting for 44% deaths among outpatient visits in children < 5 years of age, and 22% of facility deaths. Understanding determinants of caregivers' treatment-seeking patterns and decision-making is crucial in reducing the malaria burden., Methods: In the frame of the Community Access to Rectal Artesunate for Malaria (CARAMAL) project, cross-sectional household surveys that randomly sampled villages and households were carried-out in three rural DRC health zones prior to the rollout of pre-referral Rectal Artesunate (RAS) and then 9 and 19 months after RAS rollout (post-RAS). Data were captured electronically through face-to-face interviews with the main caregivers of children < 5 years. Capillary blood samples of the children were tested for malaria and anaemia. The main study outcome was whether caregiver "sought treatment outside home" when the child had fever. Multilevel mixed effects logistic regression models using village as random effect and health zone as a fixed effect was performed to assess treatment-seeking predictors., Results: 2439 household interviews were completed (pre-RAS 888 and post-RAS 1551), including 316 and 653 treatment-seeking interviews. Overall, 3499 children < 5 years were tested for malaria and anaemia (pre-RAS 1,315 and post-RAS 2184). Caregiver's recognition of severe malaria signs was poor, while knowledge of symptoms of uncomplicated malaria seemed high. Despite this, danger signs significantly increased the odds of seeking treatment (aOR = 2.12, 95%CI 1.03-4.38), the same was found for the "least poor" quintile (aOR = 3.01, 95%CI 1.03-8.82), as well as residents of Kingandu (aOR = 2.78, 95%CI 1.01-7.65). "Doing something at home" against fever negatively affected treatment-seeking in both study phases. RAS acceptance was high, at almost 100%. Malaria prevalence was higher post-RAS (45.2%) compared to pre-RAS (34.4%), p = 0.003, but anaemia, although high (≥ 75%), was similar in both study phases (p = 0.92)., Conclusion: In remote communities with high malaria prevalence in the DRC, malaria remains a major problem. Improving the recognition of danger signs of severe disease and introducing pre-referral RAS may improve treatment-seeking and contribute to reducing malaria-related mortality among children-if quality of care can be guaranteed., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Malaria is a significant cause of morbidity and mortality in adults and children. Plasmodium falciparum is the primary cause of severe malaria, but recently Plasmodium vivax is also recognized to cause severe malaria-associated morbidity and mortality. The study focuses on determining the mortality related to severity parameters in individuals under 12 years and their critical presentation in P.vivax malaria-infected children., Methods: A prospective cross-sectional hospital-based study was conducted at Safdarjung Hospital, New Delhi, and ICMR-NIMR, New Delhi. All clinically suspected cases were admitted for screening. Exclusion criteria (rapid malaria antigen test, microscopy and medication history) were applied to all the admitted patients (n = 221) to obtain P.vivax patients only. Patients aged ≤ 12 years were included in the study. DNA was extracted from dried blood spots and amplified by nested PCR, followed by visualization on gel electrophoresis., Result: A total of 221 clinically suspected cases of malaria were screened for P.vivax. After implementing various exclusion criteria, 45/221 cases were enrolled for the study, among which 44.4% (20/45) of children had the symptoms of severe malaria in terms of cerebral malaria, thrombocytopenia, anemia, pancytopenia, acute respiratory distress syndrome and hemophagocytic lymphohistiocytosis., Conclusion: Plasmodium vivax mono-infection can cause severe manifestation and must be treated as P.falciparum without any delay because it may lead to increased morbidity and mortality. A changing trend in clinical symptoms has shown in P.vivax which was an earlier phenomenon of P.falciparum., (© The Author(s) [2023]. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background & Objectives: Severe malaria is a medical emergency and can lead to severe complications and death if not treated promptly and appropriately. Along with Plasmodium falciparum, P. knowlesi is increasingly recognised as a significant cause of fatal and severe malaria., Methods: We performed a retrospective review on 54 cases of severe malaria in a district hospital in Kapit, Sarawak, from January 2018 to May 2019. The patients' demographics, clinical features, complications based on organ involvement, and treatment outcomes were examined., Results: There were 54 cases of severe malaria, with the majority being male (70%) and between the ages of 40 and 49 (26%). All patients with severe malaria were febrile or had a history of pyrexia except for one patient. P. knowlesi (81.5%) was the most common species causing severe malaria in our study, followed by P. falciparum (13%), and P. vivax (5.5%). There were no cases of severe malaria caused by P. ovale or P. malariae. Hyperparasitaemia was present in 76% of patients and the median parasitemia value at hospital admission was 33,944 parasites/μL (interquartile range: 19,920-113,285 parasites/μL). Circulatory shock was observed in 17 patients (31.5%). There were eight patients with acute renal failure and six patients with respiratory distress. One patient died as a result of severe malaria with multiorgan involvement (1.9% fatality rate)., Interpretation & Conclusion: P. knowlesi is the most common cause of severe malaria in Kapit, Sarawak, Malaysia. Recognizing symptoms of severe malaria and prompt administration of antimalarial are critical for good clinical outcomes.

This article presents a severe cerebral malaria patient in shock with a close contact of COVID-19 that was successfully cured in a negative pressure ward during the global pandemic of COVID-19. The patient experienced a sudden onset of high fever and coma in a designated isolation hotel after returning from Africa, and was transferred to a designated hospital. Following antimalarial therapy, blood pressure elevation, increase of blood volume, bedside hemodialysis, mechanical ventilation, plasma and platelet transfusions, the case gradual recovered.

Background: Globally, a very high percentage of acute kidney injury (AKI) occurs in low- and middle-income countries (LMICs) where late recognition contributes to increased mortality. There are challenges with using existing biomarkers of AKI in LMICs. Emerging evidence suggests renin may serve as a biomarker of kidney injury that can overcome limitations in creatinine-based diagnostics., Methods: Two study populations in Uganda were assessed. Cohort #1 was a two-site, prospective cohort study enrolling 600 children with severe malaria (SM). Cohort #2 was a prospective cohort study enrolling 185 children with sickle cell disease (SCD) hospitalized with a vaso-occlusive crisis. Plasma or serum renin concentrations were measured in both cohorts of children at the time of hospital admission using Luminex® (Luminex Corporation, Austin, Texas, United States) or enzyme-linked immunosorbent assay (ELISA), respectively. We assessed the ability of renin to discriminate between children with or without AKI and between children who survived and children who died using receiver operating characteristic curves., Results: In both cohorts, renin concentrations were strongly associated with AKI and mortality. Renin was able to discriminate between children with or without AKI with an area under the curve (AUC) of 0.70 (95%CI, 0.65-0.74) in children with SM and 0.72 (95%CI, 0.6co3-0.81) in children with SCD. Renin was able to discriminate between children who survived and children who died with an AUC of 0.73 (95%CI, 0.63-0.83) in children with SM and 0.94 (95%CI, 0.89-0.99) in children with SCD. In Cohort #2, we compared renin against urine neutrophil gelatinase-associated lipocalin (NGAL) as the leading biomarker of AKI, and it had comparable performance in discriminating AKI and predicting mortality., Conclusions: In two independent populations of children at risk of AKI with key differences in the etiology of kidney injury, renin was strongly associated with AKI and mortality and had moderate to good diagnostic performance to predict mortality., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Adan Jr. et al.)

Background: The northwestern border of Thailand is an area of low seasonal malaria transmission. Until recent successful malaria elimination activities, malaria was a major cause of disease and death. Historically the incidences of symptomatic Plasmodium falciparum and Plasmodium vivax malaria were approximately similar., Methods: All malaria cases managed in the Shoklo Malaria Research Unit along the Thailand-Myanmar border between 2000 and 2016 were reviewed., Results: There were 80 841 consultations for symptomatic P. vivax and 94 467 for symptomatic P. falciparum malaria. Overall, 4844 (5.1%) patients with P. falciparum malaria were admitted to field hospitals, of whom 66 died, compared with 278 (0.34%) with P. vivax malaria, of whom 4 died (3 had diagnoses of sepsis, so the contribution of malaria to their fatal outcomes is uncertain). Applying the 2015 World Health Organization severe malaria criteria, 68 of 80 841 P. vivax admissions (0.08%) and 1482 of 94 467 P. falciparum admissions (1.6%) were classified as severe. Overall, patients with P. falciparum malaria were 15 (95% confidence interval, 13.2-16.8) times more likely than those with P. vivax malaria to require hospital admission, 19 (14.6-23.8) times more likely to develop severe malaria, and ≥14 (5.1-38.7) times more likely to die., Conclusions: In this area, both P. falciparum and P. vivax infections were important causes of hospitalization, but life-threatening P. vivax illness was rare., Competing Interests: Potential conflicts of interest. M. Stolbrink reports a Clinical PhD fellowship from Wellcome Trust, unrelated to this manuscript or the topic. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: Malaria is still one of the main reasons for hospitalization in children living in sub-Saharan Africa. Rapid risk stratification at admission is essential for optimal medical care and improved prognosis. Whereas coma, deep breathing, and, to a lesser degree, severe anemia are established predictors of malaria-related death, the value of assessing prostration for risk stratification is less certain., Methods: Here we used a retrospective multi-center analysis comprising over 33,000 hospitalized children from four large studies, including two observational studies from the Severe Malaria in African Children network, a randomized controlled treatment study, and the phase-3-clinical RTS,S-malaria vaccine trial, to evaluate known risk factors of mortality and with a specific emphasis on the role of prostration., Results: Despite comparable age profiles of the participants, we found significant inter- and intra-study variation in the incidence of fatal malaria as well as in the derived risk ratios associated with the four risk factors: coma, deep breathing, anemia, and prostration. Despite pronounced variations, prostration was significantly associated with an increased risk of mortality (P <0.001) and its consideration resulted in improved predictive performance, both in a multivariate model and a univariate model based on the Lambaréné Organ Dysfunction Score., Conclusion: Prostration is an important clinical criterion to determine severe pediatric malaria with possible fatal outcomes., Competing Interests: Declarations of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Severe malaria in pregnancy causes maternal mortality, morbidity, and adverse foetal outcomes. The factors contributing to adverse maternal and foetal outcomes are not well defined. We aimed to identify the factors predicting higher maternal mortality and to describe the foetal mortality and morbidity associated with severe falciparum malaria in pregnancy., Methods: A retrospective cohort study was conducted of severe falciparum malaria in pregnancy, as defined by the World Health Organization severe malaria criteria. The patients were managed prospectively by the Shoklo Malaria Research Unit (SMRU) on the Thailand-Myanmar border or were included in hospital-based clinical trials in six Southeast Asian countries. Fixed-effects multivariable penalised logistic regression was used for analysing maternal mortality., Results: We included 213 (123 SMRU and 90 hospital-based) episodes of severe falciparum malaria in pregnancy managed between 1980 and 2020. The mean maternal age was 25.7 (SD 6.8) years, and the mean gestational age was 25.6 (SD 8.9) weeks. The overall maternal mortality was 12.2% (26/213). Coma (adjusted odds ratio [aOR], 7.18, 95% CI 2.01-25.57, p = 0.0002), hypotension (aOR 11.21, 95%CI 1.27-98.92, p = 0.03) and respiratory failure (aOR 4.98, 95%CI 1.13-22.01, p = 0.03) were associated with maternal mortality. Pregnant women with one or more of these three criteria had a mortality of 29.1% (25/86) (95%CI 19.5 to 38.7%) whereas there were no deaths in 88 pregnant women with hyperparasitaemia (> 10% parasitised erythrocytes) only or severe anaemia (haematocrit < 20%) only. In the SMRU prospective cohort, in which the pregnant women were followed up until delivery, the risks of foetal loss (23.3% by Kaplan-Meier estimator, 25/117) and small-for-gestational-age (38.3%, 23/60) after severe malaria were high. Maternal death, foetal loss and preterm birth occurred commonly within a week of diagnosis of severe malaria., Conclusions: Vital organ dysfunction in pregnant women with severe malaria was associated with a very high maternal and foetal mortality whereas severe anaemia or hyperparasitaemia alone were not associated with poor prognosis, which may explain the variation of reported mortality from severe malaria in pregnancy. Access to antenatal care must be promoted to reduce barriers to early diagnosis and treatment of both malaria and anaemia., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Severe malaria (SM) is a fatal multi-system disease which accounted for an estimated 619,000 deaths in 2021. Less than 30% of children presenting with SM are diagnosed and treated promptly, resulting in increased mortality and neurologic impairments in survivors. Studies have identified cytokine profiles that differentiate the various clinical manifestations of malaria (severe and uncomplicated). However, the diagnostic capability of these cytokines in differentiating between the disease states in terms of cut-off values has not yet been determined., Methods: The plasma levels of 22 pro-inflammatory cytokines (Eotaxin/CCL 11, interferon-gamma (IFN-γ), interleukin (IL)- 2, IL-6, IL-1β, IL-12p40/p70, IL-17A, RANTES, MCP-1, IL-15, IL-5, IL-1RA, IL-2R, IFN-α, IP-10, TNF, MIG, MIP-1α, MIP-1β, IL-7, IL-8 and Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF), and 3 anti-inflammatory cytokines-(IL-4, IL-13 and IL-10) in patients with SM, uncomplicated malaria (UM) and other febrile conditions, were measured and compared using the Human Cytokine Magnetic 25-Plex Panel. The receiver operating characteristic (ROC) curve analysis was used to determine the diagnostic value of these cytokines., Results: The level of the pro-inflammatory cytokine, IL-17A, was significantly higher in the SM group as compared to the UM group. Levels of the anti-inflammatory cytokines however did not differ significantly among the SM and UM groups. Only IL-1β and IL-17A showed good diagnostic potential after ROC curve analysis., Conclusion: The data show that levels of pro-inflammatory cytokines correlate with malaria disease severity. IL-1β and IL-17A showed good diagnostic potentials and can be considered for use in clinical practice to target treatment., (© 2023. The Author(s).)

Background: Severe imported P. falciparum malaria is a source of morbi-mortality in non-endemic regions. WHO criteria don't accurately classify patients at risk of complications. There is a need to evaluate new tools such as biomarkers to better identify patients with severe imported malaria., Methods: A case-control study was conducted in Barcelona, from January 2011-January 2021. Adult patients with microbiologically confirmed P. falciparum malaria were classified according to WHO criteria. Patients with imported non-malarial fevers were included as controls. In each group, angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), soluble triggering receptor expressed on myeloid cells (sTREM-1), C-reactive protein (CRP) and platelets were measured and their concentrations were compared between groups. New groups were made with a modified WHO severity classification and biomarkers' performance was evaluated using multiple imputation models., Results: 131 participants were included: 52 severe malaria, 30 uncomplicated malaria and 49 non-malarial fever cases. All biomarkers except sTREM-1 showed significant differences between groups. Using the modified WHO severity classification, Ang-2 and CRP presented the best AUROC; 0.79 (95%CI 0.64-0.94) and 0.80(95%CI 0.67-0.93). A model combining CRP and Ang-2 showed the best AUROC, of 0.84(95%CI 0.68-0.99), with the highest sensitivity and specificity: 84.6%(95%CI 58.9-98.1) and 77.4% (95%CI 65.9-87.7), respectively., Conclusions: The combination of Ang-2 and CRP may be a reliable tool for the early identification of severe imported malaria. The use of a rapid prognostic test including the mentioned biomarkers could optimize imported malaria management, with the potential to decrease the rate of complications and hospitalizations in patients with imported malaria., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)