Malaria Anaemia Research Articles

A Qualitative Method To Assess a History of Cerebral Malaria in Malian Children.

The investigation of factors associated with susceptibility to severe malaria is best achieved using case-control studies. The presence of a history of severe malaria in controls could affect the quality of their phenotype and study findings and hence should be rigorously determined. Here, we assessed the performance of a qualitative questionnaire to identify a history of cerebral malaria in controls in a case-control study of severe malaria in Mali. We evaluated the archived medical records of 220 children diagnosed with severe diseases at health care centers in rural and urban settings in Mali from 2018 to 2019. Parents of enrolled children were then identified and interviewed using a structured questionnaire by an investigator blinded to the diagnosis. The diagnosis derived from the interview was then compared with the diagnosis from the medical records as the reference diagnosis. The sensitivity and specificity of the questionnaire to detect cerebral malaria in history were, respectively, 84% and 76%. The questionnaire was concordant with the medical record diagnosis in 60% (95% CI: 50-71%) of cases. For other clinical phenotypes of malaria (severe malaria anemia, uncomplicated malaria, and severe malaria anemia concurrent with cerebral malaria), sensitivity and specificity ranged from 42% to 85% and 88% to 96%, respectively. Positive and negative predictive values were, respectively, 75% and 85%. The questionnaire demonstrated suitable sensitivity and specificity to identify cerebral malaria in a participant's history. In sub-Saharan Africa, a region with suboptimal medical record archives, such a tool could be used in case-control studies of severe malaria to select controls.

Assessment of Malaria, Anemia and Nutrition status of school-going children in the rural area of Charsadda, Pakistan

Malaria, anemia, and malnutrition are global health challenges with significant morbidity and mortality, and higher rates among children particularly in Africa. This study evaluated the prevalence and risk factors of malaria infection, anemia, and malnutrition among school-going children of Charsadda (a city of Khyber, Pakistan). A total of 400 children of aged 5-10 years were included in the study in 2023. Malaria infection was confirmed by rapid diagnostic tests. Hematocrit level was obtained using a centrifuge microhematocrit and converted to hemoglobin using standard conversion. Nutritional status was determined by the anthropometric measurements, and demographic characteristics were obtained by questionnaire. Anemia and malnutrition were defined according to the World Health Organization standards. Logistic regression analysis was used to determine association between the predictor variables and primary outcomes. In current research work 400 children were selected for the assessment of malaria and nutritional status, malaria infection was found more frequent among the students 120(12%). In addition, high prevalence of anemia 105(10.5%), malnutrition 90(9%), and stunting 70(7%) was observed, while wasting 2(0.2%) and underweight 20(2%0 had very low frequency. Malaria infection, anemia, and malnutrition were observed in12%, 10.5% and 9% of the children population, respectively. To the best of our knowledge, this is the first study showing the current health problems among the school-going children of district Charsadda the prevalence of malaria, anemia and malnutrition and their co-existence in children 5-10 years.

ABO and Rhesus blood group variability and their associations with clinical malaria presentations

BackgroundPlasmodium falciparum infection is associated with the human ABO blood group. However, there is a paucity of data on the role that ABO and Rhesus blood groups play in malaria clinical presentations. Therefore, the objective of this study was to assess the association of human ABO blood groups and the Rhesus blood (Rh) types with the severity of malaria.MethodsThis cross-sectional study was carried out at the Suhum Government Hospital in the Eastern region of Ghana. Conveniently, study participants with malaria, diagnosed by microscopy, were selected into the study. Subsequently, their ABO and Rh blood groups were determined (Accucare ABO/Rh monoclonal antibodies, Chennai, India). Malaria severity was assessed using the criteria for assessing severe malarial anaemia published by the World Health Organization. According to the criteria, severe malarial anaemia was classified as having haemoglobin (Hb) < 5 g/dL for children < 12 years and in patients ≥ 12 years, Hb level < 7 g/dL, with parasitaemia > 10,000/µL in both cases. Severe malarial anaemia was also classified as having plasma bilirubin > 50 µmol/L with parasitaemia ≥ 100,000/µL, for all ages. Chi square statistical analysis was used to test the association between the blood groups and the clinical or laboratory findings, while multivariate analysis was performed to identify which blood groups were more vulnerable to develop severe malarial anaemia.ResultsOf the total number of the study participants (n = 328), most of the patients had blood group O Rh positive (35.7%) while few of them had blood group AB Rh negative (2.1%). The types of Rhesus did not associate with malaria. However, compared to blood group O, the odds of developing severe malarial anaemia, in children < 12 years and in patients ≥ 12 years, were 16 times and 17.8 times higher among patients with blood group A, respectively. Furthermore, the odds of having bilirubin level > 50 µmol/L with parasitaemia ≥ 100,000 /µL was 10 times higher among patients with blood groups A and 2.6 times higher in patients with blood group B, compared to blood group O. Finally, in patients with blood group A majority (71.6%) of them developed high temperature (> 37.5 °C) while 43.3% of them vomited and had diarrhoea. However, pallor (group B = 46.2% vs group A = 37.3%), fever (group B = 84.6% vs group A = 79.1%) and nausea (group B = 46.2% vs group A = 25.4%) were more frequent in patients with blood group B than A.ConclusionsThis study found that people with blood groups A and B were severely affected by malaria, with group A being the most vulnerable. It is recommended that blood group assessment be performed for all patients with malaria. Patients found to have blood group A or B must be promptly and efficiently managed to avoid the development of severe malaria anaemia.

Pursuing the elusive footsteps of malaria in peripheral blood smears utilizing artificial intelligence.

For over a century, the need to identify malaria in the peripheral blood has been the driving force behind the development of fundamental clinical microscopy techniques. In the study by Moysis etal., artificial intelligence-based model was utilized to identify and provide quantitative morphological characteristics of red blood cells typical to severe malaria anaemia, irrespective to the actual presence of visible parasites. Commentary on: Moysis etal. Leveraging deep learning for detecting red blood cell morphological changes in blood films from children with severe malaria anaemia. Br J Haematol 2024;205:699-710.

Leveraging deep learning for detecting red blood cell morphological changes in blood films from children with severe malaria anaemia.

In sub-Saharan Africa, acute-onset severe malaria anaemia (SMA) is a critical challenge, particularly affecting children under five. The acute drop in haematocrit in SMA is thought to be driven by an increased phagocytotic pathological process in the spleen, leading to the presence of distinct red blood cells (RBCs) with altered morphological characteristics. We hypothesized that these RBCs could be detected systematically and at scale in peripheral blood films (PBFs) by harnessing the capabilities of deep learning models. Assessment of PBFs by a microscopist does not scale for this task and is subject to variability. Here we introduce a deep learning model, leveraging a weakly supervised Multiple Instance Learning framework, to Identify SMA (MILISMA) through the presence of morphologically changed RBCs. MILISMA achieved a classification accuracy of 83% (receiver operating characteristic area under the curve [AUC] of 87%; precision-recall AUC of 76%). More importantly, MILISMA's capabilities extend to identifying statistically significant morphological distinctions (p < 0.01) in RBCs descriptors. Our findings are enriched by visual analyses, which underscore the unique morphological features of SMA-affected RBCs when compared to non-SMA cells. This model aided detection and characterization of RBC alterations could enhance the understanding of SMA's pathology and refine SMA diagnostic and prognostic evaluation processes at scale.

Association between asymptomatic Plasmodium falciparum malaria infection, anaemia and mean corpuscular volume of school children in the Volta Region of Ghana.

Although, several studies have reported abnormal Mean Corpuscular Volume (MCV) values and anaemia associated with malaria infections with a focus on Plasmodium falciparum among patients with complicated and uncomplicated malaria, none has looked at the association with asymptomatic malaria. This study aimed to assess this association. We conducted a cross-sectional study using 3 mL of blood samples from 549 children aged 5-17 years attending 5 schools selected in the Volta Region. Semi-structured questionnaires were administered to the children to obtain demographic data. Blood samples were collected to estimate the children's full blood count (FBC) and malaria status. Data obtained wereanalysed using STATA 15 software. P-values of less than 0.05 were considered statistically significant. Most of the children inthis study (49.9%) had normal MCV (81.3-91.3 fL) with an overall malaria prevalence of 55.6%(95% CI: 51.3-59.8) and anaemia prevalence of 48.6% (95% CI 44.4-52.9). Most anaemic children had normal MCV (81.3-91.3 fL) (49.8, 95% CI 43.7-56.0). The predicted probability of malaria was highly likely among children with normal MCV (81.3-91.3 fL) but with high variability and uncertainty among those with low MCV (<81.3 fL) and high MCV (>91.3 fL). This study shows a reduced predicted probability of malaria among children with low and high MCV, playing a protective function against malaria. Further studies are required to elucidate the interaction.

Chronic malaria exposure is associated with inhibitory markers on T cells that correlate with atypical memory and marginal zone-like B cells.

Chronic immune activation from persistent malaria infections can induce immunophenotypic changes associated with T-cell exhaustion. However, associations between T and B cells during chronic exposure remain undefined. We analyzed peripheral blood mononuclear cells from malaria-exposed pregnant women from Papua New Guinea and Spanish malaria-naïve individuals using flow cytometry to profile T-cell exhaustion markers phenotypically. T-cell lineage (CD3, CD4, and CD8), inhibitory (PD1, TIM3, LAG3, CTLA4, and 2B4), and senescence (CD28-) markers were assessed. Dimensionality reduction methods revealed increased PD1, TIM3, and LAG3 expression in malaria-exposed individuals. Manual gating confirmed significantly higher frequencies of PD1+CD4+ and CD4+, CD8+, and double-negative (DN) T cells expressing TIM3 in malaria-exposed individuals. Increased frequencies of T cells co-expressing multiple markers were also found in malaria-exposed individuals. T-cell data were analyzed with B-cell populations from a previous study where we reported an alteration of B-cell subsets, including increased frequencies of atypical memory B cells (aMBC) and reduction in marginal zone (MZ-like) B cells during malaria exposure. Frequencies of aMBC subsets and MZ-like B cells expressing CD95+ had significant positive correlations with CD28+PD1+TIM3+CD4+ and DN T cells and CD28+TIM3+2B4+CD8+ T cells. Frequencies of aMBC, known to associate with malaria anemia, were inversely correlated with hemoglobin levels in malaria-exposed women. Similarly, inverse correlations with hemoglobin levels were found for TIM3+CD8+ and CD28+PD1+TIM3+CD4+ T cells. Our findings provide further insights into the effects of chronic malaria exposure on circulating B- and T-cell populations, which could impact immunity and responses to vaccination.

Malaria Infection in Patients with Sickle Cell Disease in Nigeria: Association with Markers of Hyposplenism.

Malaria is considered an important cause of morbidity and mortality among people living with sickle cell disease (SCD). This has partly been attributed to the loss of splenic function that occurs early in the disease process. We conducted a cross-sectional study and determined the frequency of malaria infection among SCD patients and explored the association with spleen's presence on ultrasonography and spleen function assessed using the frequency of Howell-Jolly bodies (HJBs). A total of 395 participants consisting of 119 acutely-ill SCD patients, 168 steady-state SCD controls, and 108 healthy non-SCD controls were studied. The prevalence of Plasmodium falciparum parasitemia was 51.3% in acutely-ill SCD patients, 31.7% in steady-state SCD controls, and 11.0% in the healthy non-SCD controls; however, the mean parasite density was significantly higher in the non-SCD controls compared to both SCD groups (p = 0.0001). Among the acutely-ill SCD patients, the prevalence of clinical malaria and severe malaria anemia were highest in children <5 years of age. The prevalence of parasitemia (p = 0.540) and parasite density (p = 0.975) showed no association with spleen presence or absence on ultrasonography. Similarly, the frequency of HJB red cells was not associated with the presence of parasitemia (p = 0.183). Our study highlights the frequency and role of malaria infection in acutely-ill SCD patients, especially in those younger than five years. Although we have found no evidence of an increased risk of malaria parasitemia or parasite density with markers of hyposplenism, the role played by an underlying immunity to malaria among SCD patients in malaria-endemic region is not clear and needs further studies.

Malaria as a Catalyst: Spotlight on Childhood Anemia Management

Malaria, a devastating vector-borne disease caused by Plasmodium parasites, continues to be a major global health concern, particularly affecting children in endemic regions. This review explores the intricate relationship between malaria and childhood anemia, shedding light on the multifaceted impact of malaria as a catalyst for anemia in pediatric populations. The article delves into the epidemiological aspects of both malaria and childhood anemia, emphasizing the critical need for integrated management strategies to address this coexisting health burden. Additionally, the review highlights the latest advancements in antimalarial interventions and their potential implications for managing childhood anemia.

The Impact of Blood Transfusion on Pediatric Severe Malaria Cases with HIV Co Infection A Review

Pediatric severe malaria cases complicated by HIV co-infection present a formidable healthcare challenge, necessitating a nuanced and comprehensive approach to treatment. This review critically examines the efficacy of blood transfusion as a therapeutic intervention in managing severe malaria among pediatric patients co-infected with HIV. We delve into the current state of knowledge, discussing the immunological complexities, potential interactions with antiretroviral therapy, and the inherent challenges associated with this dual burden of disease. Despite the complexities, blood transfusion remains a vital element in addressing severe anemia in pediatric malaria. This review synthesizes existing literature, identifies gaps in knowledge, and proposes avenues for future research to enhance our understanding and optimize treatment strategies for this vulnerable population.

Association of Sickle Cell Disease, Malaria and HIV in Multi Drug Resistant Invasive Non-typhoidal Salmonella Isolated from Outpatient and Hospitalised Children Below 16 Years in Informal Settlements in Nairobi County, Kenya.

Invasive non-typhoidal Salmonella (iNTS) disease continues to be a major public health problem, especially in sub-Saharan Africa (SSA), where incidence rates are 227 cases [range 152-341] per 100,000 populations. Populations at risk of iNTS include adults with human immunodeficiency virus (HIV) infection, malnourished children, and those with recent malaria or sickle-cell anaemia (SCA). In Kenya, iNTS disease is particularly a major challenge in poor informal settlements, with infants and young children less than 5 years of age being the most affected. Our study aimed to investigate the association between sickle cell disease, malaria, and HIV in multi-drug-resistant invasive non-typhoidal Salmonella from outpatient and hospitalised children ≤16 years in informal settlements in Nairobi County, Kenya. This study recruited 16,679 children aged ≤16 years who presented with salmonellosis symptoms for a period of 6 years (2013-2018). The patients were age-matched with controls (asymptomatic individuals). The study was conducted at 3 outpatient sites and 1 inpatient site; the outpatient sites were all located within the Mukuru informal settlement. The inpatient site was Mbagathi district hospital, which serves patients residing in Kibera informal settlement. Blood and stool samples from children with fever ≥38°C and/or diarrhea and stool samples alone from controls were collected for processing for the presence of iNTS using basic microbiology procedures including culture, serology, and Kirby Bauer disc diffusion for sensitivity testing. Dry blood spots were also taken and processed for sickle cell protein markers using high-performance liquid chromatography (HPLC). HIV and malaria tests were also conducted using rapid tests, respectively. From the total of 22,246 blood and stool samples tested, 741 (3.3%) tested positive for Salmonella species. A total of 338 (45.6%) iNTS were isolated across all 4 sites; these consisted of 158 (21.3%) Salmonella Enteritidis and 180 (24.3%) Salmonella Typhimurium. The most common resistance phenotype was against ampicillin, chloramphenicol, and sulfamethoxazole trimethoprim. A total of 118 (34.9%) isolates were multidrug-resistant (MDR). Out of 2,684 dry blood samples subjected to HPLC for investigation of sickle cell disease traits, 1820 (67.8%) had normal haemoglobin (Hb AA/Hb AF); 162/2684 (6%) tested positive for sickle cell traits (Hb AS/Hb AFS). Some patients positive for iNTS were also found to have other co-morbidities; 4 (0.1%) tested positive for sickle cell disease (Hb FS), malaria, and HIV 8 (2.4%) and 5 (1.5%), respectively. The high prevalence of MDR iNTS isolates and emerging resistance to third-generation cephalosporins is of great concern, as they are the recommended drugs for the management of iNTS in our settings. Sickle cell disease, malaria, and HIV were all not major factors associated with iNTS disease among children in Mukuru and Kibera informal settlements.

Plasmodium Falciparum Rifins: Role in malaria pathogenesis

Malaria kills an estimated 600,000 people each year, especially children under five years who reside in sub-Saharan Africa. Malaria fatalities are associated with severe forms such as cerebral malaria, acute respiratory failure, severe anaemia, renal failure, hypoglycaemia, and pulmonary oedema. Although the underlying pathogenic mechanisms in immune responses and parasite immune evasion, cytoadherence of parasitized red blood cells, and rosetting are enumerated, the mechanisms are not fully understood. P. falciparum parasite-derived surface protein, repetitive interspersed family (RIFIN) genes are involved in rosetting, blocking microcirculation, and playing a role in malaria pathogenesis; it is unclear which RIFIN family genes are involved in the various pathogenic mechanisms in malaria. RIFINs are the extensive malaria family genes expressed throughout the malaria parasite stages, indicating their diverse roles. Malaria pathogenesis occurs in erythrocyte-stage infection, and the expression of RIFINs at this phase could play a diverse role in the various pathogenic mechanisms. They are involved in major phenomena such as cytoadherence, merozoite evasion, and immune evasion. RIFINs aid in the immune evasion of P. falciparum through various molecular interactions by binding to the inhibitory receptors LAIR1, LILRB1, and LILRB2. RIFINs in severe forms of malaria (such as cerebral malaria and severe anaemia) require a considerable understanding to target and control malaria severity and mortality. RIFINs are implicated in severe malaria and are discussed together with other variant surface antigens such as STEVORS or PfEMP1 in the specific pathophysiology of malaria. This review details the role of RIFINs in the various malaria pathophysiological mechanisms underlying severe malaria and mortality

Association between asymptomatic Plasmodium falciparum malaria infection, anemia and mean corpuscular volume of school children in the Volta Region of Ghana

Abstract Introduction/Objective Although several studies have reported abnormal MCV values and anemia associated with malaria infections with a focus on P. falciparum among patients with complicated and uncomplicated malaria. This study assessed the association between asymptomatic P. falciparum malaria infection, anemia, and the MCV values of school children in Ghana. Methods/Case Report We conducted a cross-sectional study using 3 ml of blood samples from 549 children aged 5- 17 years attending 5 schools selected in the Volta Region. Semi-structured questionnaires were administered to the children to obtain demographic data. Blood samples were collected into a K2EDTA tube and then used to estimate the children’s automated full blood count (FBC) and malaria status using microscopy. MCV was classified into low, normal, and high. Data obtained were analyzed using STATA 15 software. P-values less than 0.05 were considered statistically significant. Results (if a Case Study enter NA) Most of the children in this study (49.9%) had normal MCV (81.3-91.3 fL) with an overall malaria prevalence of 55.6 % (95% CI: 51.3-59.8) and anemia prevalence of 48.6% (95% CI 44.4-52.9). The majority of the anemic children had normal MCV (81.3-91.3 fL) (49.8, 95% CI 43.7-56.0). The predicted probability of malaria was highly likely among children whose MCV fell within the first and third quartiles. Conclusion This study shows a reduced predicted probability of malaria among children with low and high MCV, playing a protective function against malaria. Further studies are required to elucidate the association and interaction between MCV, anemia, and asymptomatic Plasmodium falciparum infection.

Retention of uninfected red blood cells causing congestive splenomegaly is the major mechanism of anemia in malaria.

Splenomegaly frequently occurs in patients with Plasmodium falciparum (Pf) or P. vivax (Pv) malarial anemia, but mechanisms underlying this co-occurrence are unclear. In malaria-endemic Papua, Indonesia, we prospectively analyzed red blood cell (RBC) concentrations in the spleen and spleen-mimetic retention in 37 subjects splenectomized for trauma or hyperreactive splenomegaly, most of whom were infected with Plasmodium. Splenomegaly (median 357 g [range: 80-1918 g]) was correlated positively with the proportion of red-pulp on histological sections (median 88.1% [range: 74%-99.4%]; r = .59, p = .0003) and correlated negatively with the proportion of white-pulp (median 8.3% [range: 0.4%-22.9%]; r = -.50, p = .002). The number of RBC per microscopic field (>95% uninfected) was correlated positively with spleen weight in both Pf-infected (r = .73; p = .017) and Pv-infected spleens (r = .94; p = .006). The median estimated proportion of total-body RBCs retained in Pf-infected spleens was 8.2% (range: 1.0%-33.6%), significantly higher than in Pv-infected (2.6% [range: 0.6%-23.8%]; p = .015) and PCR-negative subjects (2.5% [range: 1.0%-3.3%]; p = .006). Retained RBCs accounted for over half of circulating RBC loss seen in Pf infections. The proportion of total-body RBC retained in Pf- and Pv-infected spleens correlated negatively with hemoglobin concentrations (r = -.56, p = .0003), hematocrit (r = -.58, p = .0002), and circulating RBC counts (r = -.56, p = .0003). Splenic CD71-positive reticulocyte concentrations correlated with spleen weight in Pf (r = 1.0; p = .003). Retention rates of peripheral and splenic RBCs were correlated negatively with circulating RBC counts (r = -.69, p = .07 and r = -.83, p = .008, respectively). In conclusion, retention of mostly uninfected RBC in the spleen, leading to marked congestion of the red-pulp, was associated with splenomegaly and is the major mechanism of anemia in subjects infected with Plasmodium, particularly Pf.

Cish knockout mice exhibit similar outcomes to malaria infection despite altered hematopoietic responses.

The Cytokine-inducible Src homology 2 domain-containing (CISH) protein is a negative feedback regulator induced by cytokines that play key roles in immunity and erythropoiesis. Single nucleotide polymorphisms (SNPs) in the human CISH gene have been associated with increased susceptibility to severe malaria disease. To directly assess how CISH might influence outcomes in the BALB/c model of malaria anemia, CISH knockout (Cish-/-) mice on this background were infected with Plasmodium berghei and their hematopoietic responses, cytokine production and ability to succumb to severe malaria disease evaluated. Despite basal erythrocytic disruption, upon P. berghei infection, the Cish -/- mice were better able to maintain peripheral blood cell counts, hemoglobin levels and a steady-state pattern of erythroid differentiation compared to wild-type (Cish+/+) mice. Ablation of CISH, however, did not influence the outcome of acute malaria infections in either the BALB/c model or the alternative C57BL/6 model of experimental cerebral malaria, with the kinetics of infection, parasite load, weight loss and cytokine responses being similar between Cish+/+ and Cish-/- mice, and both genotypes succumbed to experimental cerebral malaria within a comparable timeframe.

Blood biomarkers of neuronal injury in paediatric cerebral malaria and severe malarial anaemia

Abstract 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 &amp;gt;95th percentile of community children in 71 and 51%, and neurofilament-light chain levels were elevated &amp;gt;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 &amp;lt;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 &amp;lt;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.

Natural immunity to malaria preferentially targets the endothelial protein C receptor-binding regions of PfEMP1s.

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.

Xanthine oxidase levels and immune dysregulation are independently associated with anemia in Plasmodium falciparum malaria

Severe anemia is an important contributor to mortality in children with severe malaria. Anemia in malaria is a multi-factorial complication, since dyserythropoiesis, hemolysis and phagocytic clearance of uninfected red blood cells (RBCs) can contribute to this syndrome. High levels of oxidative stress and immune dysregulation have been proposed to contribute to severe malarial anemia, facilitating the clearance of uninfected RBCs. In a cohort of 552 Ugandan children with severe malaria, we measured the levels of xanthine oxidase (XO), an oxidative enzyme that is elevated in the plasma of malaria patients. The levels of XO in children with severe anemia were significantly higher compared to children with severe malaria not suffering from severe anemia. Levels of XO were inversely associated with RBC hemoglobin (ρ = − 0.25, p < 0.0001), indicating a relation between this enzyme and severe anemia. When compared with the levels of immune complexes and of autoimmune antibodies to phosphatidylserine, factors previously associated with severe anemia in malaria patients, we observed that XO is not associated with them, suggesting that XO is associated with severe anemia through an independent mechanism. XO was associated with prostration, acidosis, jaundice, respiratory distress, and kidney injury, which may reflect a broader relation of this enzyme with severe malaria pathology. Since inhibitors of XO are inexpensive and well-tolerated drugs already approved for use in humans, the validation of XO as a contributor to severe malarial anemia and other malaria complications may open new possibilities for much needed adjunctive therapy in malaria.

Effects of uncomplicated malaria parasitaemia on selected haematological parameters and phagocytes of children living in Port Harcourt, Southern Nigeria

This cross-sectional and case control study evaluated the effects of malaria parasites on selected haematological parameters of children living in Port Harcourt, Nigeria. A total of 352 participants were randomly recruited and their blood samples collected. Malaria diagnosis and estimation of haematological parameters were determined using standard parasitological and haematological methods respectively. Sociodemographics of participants showed that 109 (31%) of female children and 106 (30%) of male children were infected with malaria parasites. Overall prevalence of Plasmodium falciparum found was 215(61%). The study found a statistically significant difference in the mean values of packed cell volume (PCV), haemoglobin concentration (Hb), and white blood cell count (WBC) of Plasmodium parasitized children compared with their matched controls: PCV(34.83±2.76% versus 36.06±1.41%; P=0.001); Hb(11.58±0.92g/dL versus 11.98±0.46g/dL; P=0.001); WBC (8.96±4.56(x109/L) versus 7.33±1.39(x109/L); P=0.001).While the mean values of lymphocyte counts were relatively reduced in malaria infected children than their control participants (41.66±13.57(x109/L) versus 42.95±8.36(x109/L); P=0.27). A weak relationship was found to exist between density of parasitaemia and ages of children infected with malaria parasites (R2=0.0093; P=0.1584). Though more children had low parasitaemia (1-999 parasites/μL), followed with high parasitaemia (&gt;10,000 parasites/μL), while few had moderate parasitaemia (1000-9999 parasites/μL). There was no case of complication with respect to WHO standard which described complicated or severe anaemia in malaria as haemoglobin (Hb) of &lt; 5g/dl or packed cell volume (PCV) of &lt; 15% with parasitemia of &gt; 250,000 parasites/μL. Malaria parasites affect outcomes of some haematological parameters. We recommend that all febrile children in our study area should be tested for malaria parasites in conjunction with estimation of their full blood count for effective malaria diagnosis and treatment particularly in sub patent cases.

Hematological Abnormalities Among Malaria Infected Adult Patients in Association with ABO Blood Groups at Jinella Health Center, Harar, Eastern Ethiopia.

Hematological abnormalities are a common complication of malaria infection. However, there is a paucity of evidence regarding it among malaria-infected adult patients in association with the ABO blood group in Ethiopia, particularly in the Harari Region. Therefore, this study aimed to assess the hematological abnormalities among malaria-infected adult patients in association with ABO blood groups at Jinella Health Center, Harar, Eastern Ethiopia. An institutional-based cross-sectional study was conducted from July 10, 2022, to January 10, 2023. Four milliliters of venous blood were collected from each study participant. Drops of blood were used for blood film preparation. ABO blood group was determined by agglutination test using monoclonal anti-sera (Agape Diagnostics Ltd., India). A complete blood count was done using the DxH 800 (Beckman Coulter, Inc, Miami, FL) hematology analyzer. The data were analyzed using SPSS version 26. Bivariable and multivariable logistic regression models were fitted. The level of significance was declared at a p-value of <0.05. The study revealed that 47.2% (95% CI: 41.0 53.6) of the participants were anemic. Being female (AOR = 3.18, 95% CI = 1.67, 6.04), having the A blood group (AOR = 2.75, CI = 1.20, 6.31), and being infected with P. falciparum (AOR = 2.64, CI = 1.26, 5.53) were all significantly associated with malaria anemia. The overall prevalence of thrombocytopenia was also 67.7% (95% CI: 61.7-73.4%). It was significantly associated with P. falciparum infection (AOR = 8.03, CI = 3.53, 18.25) and high parasitemia levels (AOR = 4.40, CI = 1.57, 12.32). Patients with malaria who belonged to the "A" blood group in the study area had anemia as a serious health problem. Hence, frequently checking for anemia in patients with malaria who have blood group "A" can help with early detection and better management of anemia.