Cerebral Malaria Survivors Research Articles

Enriching Clinical Trials Enrolling Children With Cerebral Malaria Using Admission Demographics, Physical Examination and Point-of-care Testing Results.

Multiple clinical trials evaluating therapies for cerebral malaria (CM) have failed to demonstrate improved outcomes. This may derive from inclusion of children at all risk levels, including those at low risk of mortality or neurologic morbidity, limiting power to detect significant differences between intervention arms. One solution is enrichment, enrolling clinical trial participants at higher risk of adverse outcomes. We assessed if demographic, physical examination and point-of-care laboratory testing results in combination could identify children with CM at higher risk of death or neurologic disability. Retrospective case-control study of 1674 children hospitalized with CM in Blantyre, Malawi. We used univariate and multivariate analyses of admission factors to find the most parsimonious model associated with death or neurologic disability. To assess the clinical utility of the models, we evaluated derived probability density curve separation. Blantyre Coma Score (BCS), deep breathing and high blood lactate were independently associated with mortality. The derived receiver operating curve yielded an area under the curve of 0.7118. There was poor separation of derived probability density curves predicting death or survival, indicating limited clinical utility of this model. On multivariate modeling of neurologic sequelae in CM survivors, only BCS was associated with adverse outcomes (area-under-the-curve = 0.6151). Probability density curves again largely overlapped, demonstrating limited utility of BCS alone in outcome prediction. Combinations of admission demographic, clinical and point-of-care laboratory factors are inadequate to predict prognosis in children with CM. Higher technology assessment methods are necessary for clinical trial enrichment.

Synthetic angiotensin II peptide derivatives confer protection against cerebral and severe non-cerebral malaria in murine models

Malaria can have severe long-term effects. Even after treatment with antimalarial drugs eliminates the parasite, survivors of cerebral malaria may suffer from irreversible brain damage, leading to cognitive deficits. Angiotensin II, a natural human peptide hormone that regulates blood pressure, has been shown to be active against Plasmodium spp., the etiologic agent of malaria. Here, we tested two Ang II derivatives that do not elicit vasoconstriction in mice: VIPF, a linear tetrapeptide, which constitutes part of the hydrophobic portion of Ang II; and Ang II-SS, a disulfide-bridged derivative. The antiplasmodial potential of both peptides was evaluated with two mouse models: an experimental cerebral malaria model and a mouse model of non-cerebral malaria. The latter consisted of BALB/c mice infected with Plasmodium berghei ANKA. The peptides had no effect on mean blood pressure and significantly reduced parasitemia in both mouse models. Both peptides reduced the SHIRPA score, an assay used to assess murine health and behavior. However, only the constrained derivative (Ang II-SS), which was also resistant to proteolytic degradation, significantly increased mouse survival. Here, we show that synthetic peptides derived from Ang II are capable of conferring protection against severe manifestations of malaria in mouse models while overcoming the vasoconstrictive side effects of the parent peptide.

Post hospital admission blood lactate measurements are associated with mortality but not neurologic morbidity in children with cerebral malaria.

In children with cerebral malaria (CM) admission blood lactate has previously guided intravenous fluid therapy and been validated as a prognostic biomarker associated with death. The usefulness of post-admission measurements of blood lactate in children with CM is less clear. The strength of association between blood lactate and neurological sequelae in CM survivors, as well as the optimal duration of post-admission measurements of blood lactate to identify children at higher risk of adverse outcomes is unknown. A retrospective cohort study of 1674 Malawian children with CM hospitalized from 2000 to 2018 who had blood lactate measurements every 6h for the first 24h after admission was performed. The strength of association between admission lactate or values measured at any time point in the first 24h post-admission and outcomes (mortality and neurological morbidity in survivors) was estimated. The duration of time after admission that lactate remained a valid prognostic biomarker was assessed. When lactate is analysed as a continuous variable, children with CM who have higher values at admission have a 1.05-fold higher odds (95% CI 0.99-1.11) of death compared to those with lower lactate values. Children with higher blood lactate at 6h have 1.16-fold higher odds (95% CI 1.09-1.23) of death, compared to those with lower values. If lactate levels are dichotomized into hyperlactataemic (lactate > 5.0 mmol/L) or not, the strength of association between admission lactate and mortality increases (OR = 2.49, 95% CI 1.47-4.22). Blood lactate levels obtained after 18h post-admission are not associated with outcomes. Similarly, the change in lactate concentrations through time during the first 24h of hospital admission is not associated with outcomes. Blood lactate during hospitalization is not associated with adverse neurologic outcomes in CM survivors. In children with CM, blood lactate is associated with death but not neurologic morbidity in survivors. To comprehensively estimate prognosis, blood lactate in children with CM should be assessed at admission and for 18h afterwards.

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 >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.

Loss to Hospital Follow-Up in Pediatric Cerebral Malaria Survivors: A Case-Control Study.

Children surviving central nervous system (CNS) infections are at high risk of neurological, behavioral, and cognitive sequalae. Early identification, characterization, and treatment of these sequelae may improve child and family health. In Africa, it is unclear if there are demographic or clinical factors that increase the risk of post-hospital loss to follow-up in children with CNS infections. If these factors exist, targeted educational efforts to increase rates of post-hospital retention could be focused on families at highest risk. We performed a case-control study of Malawian children with cerebral malaria, a locally common CNS infection, previously admitted to a specialized research unit in Blantyre, Malawi. Routine survivor post-hospital follow-up was scheduled for 1 month, 6 months, and 12 months. We compared demographic and clinical characteristics between 84 children who missed one or more of these post-hospital visits with 120 children who attended all visits. There were no statistically significant differences in demographic or clinical characteristics between children whose families returned for all follow-up visits and those who did not. Specifically, when comparing these groups, we found no differences in age (P = 00.646), sex (P = 0.789), duration of hospitalization (P = 0.903), distance from home to hospital (P = 0.355), type or severity of neurological sequelae (P = 0.837), guardian literacy (P = 0.057), or number of discharge medications (P = 0.464). No factors assessed in this study were associated with higher risk of loss to follow-up in Malawian child survivors of CNS infections. During hospitalization, educational efforts to increase post-hospital retention should focus on all families.

Human ApoE2 protects mice against Plasmodium berghei ANKA experimental cerebral malaria.

Cerebral malaria (CM) is the deadliest complication of malaria infection with an estimated 15%-25% mortality. Even with timely and effective treatment with antimalarial drugs such as quinine and artemisinin derivatives, survivors of CM may suffer long-term cognitive and neurological impairment. Here, we show that human apolipoprotein E variant 2 (hApoE2) protects mice from experimental CM (ECM) via suppression of CD8+ T cell activation and infiltration to the brain, enhanced cholesterol metabolism, and increased IFN-γ production, leading to reduced endothelial cell apoptosis, BBB disruption, and ECM symptoms. Our results suggest that hApoE can be an important factor for risk assessment and treatment of CM in humans.

Pathogenetic mechanisms and treatment targets in cerebral malaria.

Malaria, the most prevalent mosquito-borne infectious disease worldwide, has accompanied humanity for millennia and remains an important public health issue despite advances in its prevention and treatment. Most infections are asymptomatic, but a small percentage of individuals with a heavy parasite burden develop severe malaria, a group of clinical syndromes attributable to organ dysfunction. Cerebral malaria is an infrequent but life-threatening complication of severe malaria that presents as an acute cerebrovascular encephalopathy characterized by unarousable coma. Despite effective antiparasite drug treatment, 20% of patients with cerebral malaria die from this disease, and many survivors of cerebral malaria have neurocognitive impairment. Thus, an important unmet clinical need is to rapidly identify people with malaria who are at risk of developing cerebral malaria and to develop preventive, adjunctive and neuroprotective treatments for cerebral malaria. This Review describes important advances in the understanding of cerebral malaria over the past two decades and discusses how these mechanistic insights could be translated into new therapies.

Multimodal diffusion model for increments of electroencephalogram data

AbstractWe propose a new strictly stationary strong mixing diffusion model with marginal multimodal (three-peak) distribution and exponentially decaying autocorrelation function for modeling of increments of electroencephalogram data collected from Ugandan children during coma from cerebral malaria. We treat the increments as discrete-time observations and construct a diffusion process where the stationary distribution is viewed as a mixture of three non-central generalized Gaussian distributions and we state some important properties related to the moments of this mixture. We estimate the distribution parameters using the expectation-maximization algorithm, where the added shape parameter is estimated using the higher order statistics approach based on an analytical relationship between the shape parameter and kurtosis. The derived estimates are then used for prediction of subsequent neurodevelopment and cognition of cerebral malaria survivors using the elastic net regression. We compare different predictive models and determine whether additional information obtained from multimodality of the marginal distributions can be used to improve the prediction.

Temporal Trends of Blood Glucose in Children with Cerebral Malaria.

Hypoglycemia, defined as a blood glucose < 2.2 mmol/L, is associated with death in pediatric cerebral malaria (CM). The optimal duration of glucose monitoring in CM is unknown. We collected data from 1,674 hospitalized Malawian children with CM to evaluate the association between hypoglycemia and death or neurologic disability in survivors. We assessed the optimal duration of routine periodic measurements of blood glucose. Children with hypoglycemia at admission had a 2.87-fold higher odds (95% CI: 1.35-6.09) of death and, if they survived, a 3.21-fold greater odds (95% CI: 1.51-6.86) of sequelae at hospital discharge. If hypoglycemia was detected at 6 hours but not at admission, there was a 7.27-fold higher odds of death (95% CI: 1.85-8.56). The presence of newly developed hypoglycemia after admission was not independently associated with neurological sequelae in CM survivors. Among all new episodes of blood sugar below a treatment threshold of 3.0 mmol/L, 94.7% occurred within 24 hours of admission. In those with blood sugar below 3.0 mmol/L in the first 24 hours, low blood sugar persisted or recurred for up to 42 hours. Hypoglycemia at admission or 6 hours afterward is strongly associated with mortality in CM. Children with CM should have 24 hours of post-admission blood glucose measurements. If a blood glucose less than the treatment threshold of 3.0 mmol/L is not detected, routine assessments may cease. Children who have blood sugar values below the treatment threshold detected within the first 24 hours should continue to have periodic glucose measurements for 48 hours post-admission.

Potential Epha2 Receptor Blockers Involved in Cerebral Malaria from Taraxacum officinale, Tinospora cordifolia, Rosmarinus officinalis and Ocimum basilicum: A Computational Approach.

Cerebral malaria (CM) is a severe manifestation of parasite infection caused by Plasmodium species. In 2018, there were approximately 228 million malaria cases worldwide, resulting in about 405,000 deaths. Survivors of CM may live with lifelong post-CM consequences apart from an increased risk of childhood neurodisability. EphA2 receptors have been linked to several neurological disorders and have a vital role in the CM-associated breakdown of the blood-brain barrier. Molecular docking (MD) studies of phytochemicals from Taraxacum officinale, Tinospora cordifolia, Rosmarinus officinalis, Ocimum basilicum, and the native ligand ephrin-A were conducted to identify the potential blockers of the EphA2 receptor. The software program Autodock Vina 1.1.2 in PyRx-Virtual Screening Tool and BIOVIA Discovery Studio visualizer was used for this MD study. The present work showed that blocking the EphA2 receptor by these phytochemicals prevents endothelial cell apoptosis by averting ephrin-A ligand-expressing CD8+ T cell bioadhesion. These phytochemicals showed excellent docking scores and binding affinity, demonstrating hydrogen bond, electrostatic, Pi-sigma, and pi alkyl hydrophobic binding interactions when compared with native ligands at the EphA2 receptor. The comparative MD study using two PDB IDs showed that isocolumbin, carnosol, luteolin, and taraxasterol have better binding affinities (viz. -9.3, -9.0, -9.5, and -9.2 kcal/mol, respectively). Ocimum basilicum phytochemicals showed a lower docking score but more binding interactions than native ligands at the EphA2 receptor for both PDB IDs. This suggests that these phytochemicals may serve as potential drug candidates in the management of CM. We consider that the present MD study provides leads in drug development by targeting the EphA2 receptor in managing CM. The approach is innovative because a role for EphA2 receptors in CM has never been highlighted.

\u201cI do lack peace, and I\u2019ve run out of answers\u201d: primary caregivers\u2019 perspectives on social and behaviour problems in cerebral malaria survivors in Blantyre, Malawi

BackgroundDespite recent advances in treatment and prevention, the prevalence of cerebral malaria (CM) remains high globally, especially in children under 5 years old. As treatment improves, more children will survive episodes of CM with lasting neurodisabilities, such as social and behavioural issues. Behaviour problems in children who survive CM are poorly characterized, and the impact of caring for a child with post-CM behaviour issues has not been well-explored. Caregivers’ perceptions of and experiences with their child’s post-CM behaviour problems are reported here.MethodsSemi-structured interviews were conducted with 29 primary caregivers of children who survived CM with reported behaviour issues in Blantyre, Malawi. Interviews were conducted in Chicheŵa, audio-recorded, transcribed, and translated into English. Data were coded manually, utilizing inductive and deductive approaches. Identified codes were thematically analysed.ResultsPost-CM behaviours reported include externalizing, aggressive behaviours and learning difficulties. Variable timescales for behaviour change onset were noted, and most caregivers reported some evolution of their child’s behaviour over time. Caregivers experienced a variety of emotions connected to their child’s behaviour and to reactions of family and community members. Caregivers who experienced discrimination were more likely to describe negative emotions tied to their child’s behaviour changes, compared to caregivers who experienced support.ConclusionsCaregiver perceptions of behaviour changes in post-CM survivors are variable, and caregiver experience is strongly impacted by family and community member responses. Future educational, rehabilitation, and support-based programmes should focus on the specific types of behaviour problems identified and the difficulties faced by caregivers and their communities.

Malaria Related Neurocognitive Deficits and Behavioral Alterations.

Typical of tropical and subtropical regions, malaria is caused by protozoa of the genus Plasmodium and is, still today, despite all efforts and advances in controlling the disease, a major issue of public health. Its clinical course can present either as the classic episodes of fever, sweating, chills and headache or as nonspecific symptoms of acute febrile syndromes and may evolve to severe forms. Survivors of cerebral malaria, the most severe and lethal complication of the disease, might develop neurological, cognitive and behavioral sequelae. This overview discusses the neurocognitive deficits and behavioral alterations resulting from human naturally acquired infections and murine experimental models of malaria. We highlighted recent reports of cognitive and behavioral sequelae of non-severe malaria, the most prevalent clinical form of the disease worldwide. These sequelae have gained more attention in recent years and therapies for them are required and demand advances in the understanding of neuropathogenesis. Recent studies using experimental murine models point to immunomodulation as a potential approach to prevent or revert neurocognitive sequelae of malaria.

Association of Plasma Tau With Mortality and Long-term Neurocognitive Impairment in Survivors of Pediatric Cerebral Malaria and Severe Malarial Anemia

Cerebral malaria (CM) and severe malarial anemia (SMA) are associated with persistent neurocognitive impairment (NCI) among children in Africa. Identifying blood biomarkers of acute brain injury that are associated with future NCI could allow early interventions to prevent or reduce NCI in survivors of severe malaria. To investigate whether acutely elevated tau levels are associated with future NCI in children after CM or SMA. This prospective cohort study was conducted at Mulago National Referral Hospital in Kampala, Uganda, from March 2008 to October 2015. Children aged 1.5 to 12 years with CM (n = 182) or SMA (n = 162) as well as community children (CC; n = 123) were enrolled in the study. Data analysis was conducted from January 2020 to May 2021. CM or SMA. Enrollment plasma tau levels were measured using single-molecule array detection technology. Overall cognition (primary) and attention and memory (secondary) z scores were measured at 1 week and 6, 12, and 24 months after discharge using tools validated in Ugandan children younger than 5 years or 5 years and older. A total of 467 children were enrolled. In the CM group, 75 (41%) were girls, and the mean (SD) age was 4.02 (1.92) years. In the SMA group, 59 (36%) were girls, and the mean (SD) age was 3.45 (1.60) years. In the CC group, 65 (53%) were girls, and the mean (SD) age was 3.94 (1.92) years. Elevated plasma tau levels (>95th percentile in CC group; >6.43 pg/mL) were observed in 100 children (55%) with CM and 69 children (43%) with SMA (P < .001). In children with CM who were younger than 5 years, elevated plasma tau levels were associated with increased mortality (odds ratio [OR], 3.06; 95% CI, 1.01-9.26; P = .048). In children with CM who were younger than 5 years at both CM episode and follow-up neurocognitive testing, plasma tau levels (log10 transformed) were associated with worse overall cognition scores over 24-month follow-up (β = -0.80; 95% CI, -1.32 to -0.27; P = .003). In children with CM who were younger than 5 years at CM episode and 5 years or older at follow-up neurocognitive testing, plasma tau was associated with worse scores in attention (β = -1.08; 95% CI, -1.79 to -0.38; P = .003) and working memory (β = -1.39; 95% CI, -2.18 to -0.60; P = .001). In this study, plasma tau, a marker of injury to neuronal axons, was elevated in children with CM or SMA and was associated with mortality and persistent NCI in children with CM younger than 5 years.

NADPH Oxidase: a Possible Therapeutic Target for Cognitive Impairment in Experimental Cerebral Malaria.

Long-term cognitive impairment associated with seizure-induced hippocampal damage is the key feature of cerebral malaria (CM) pathogenesis. One-fourth of child survivors of CM suffer from long-lasting neurological deficits and behavioral anomalies. However, mechanisms on hippocampal dysfunction are unclear. In this study, we elucidated whether gp91phox isoform of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) (a potent marker of oxidative stress) mediates hippocampal neuronal abnormalities and cognitive dysfunction in experimental CM (ECM). Mice symptomatic to CM were rescue treated with artemether monotherapy (ARM) and in combination with apocynin (ARM + APO) adjunctive based on scores of Rapid Murine Come behavior Scale (RMCBS). After a 30-day survivability period, we performed Barnes maze, T-maze, and novel object recognition cognitive tests to evaluate working and reference memory in all the experimental groups except CM. Sensorimotor tests were conducted in all the cohorts to assess motor coordination. We performed Golgi-Cox staining to illustrate cornu ammonis-1 (CA1) pyramidal neuronal morphology and study overall hippocampal neuronal density changes. Further, expression of NOX2, NeuN (neuronal marker) in hippocampal CA1 and dentate gyrus was determined using double immunofluorescence experiments in all the experimental groups. Mice administered with ARM monotherapy and APO adjunctive treatment exhibited similar survivability. The latter showed better locomotor and cognitive functions, reduced ROS levels, and hippocampal NOX2 immunoreactivity in ECM. Our results show a substantial increase in hippocampal NeuN immunoreactivity and dendritic arborization in ARM + APO cohorts compared to ARM-treated brain samples. Overall, our study suggests that overexpression of NOX2 could result in loss of hippocampal neuronal density and dendritic spines of CA1 neurons affecting the spatial working and reference memory during ECM. Notably, ARM + APO adjunctive therapy reversed the altered neuronal morphology and oxidative damage in hippocampal neurons restoring long-term cognitive functions after CM.

The Potential Roles of Glial Cells in the Neuropathogenesis of Cerebral Malaria.

Cerebral malaria (CM) is a severe neurological complication of malaria caused by the Plasmodium falciparum parasite. It is one of the leading causes of death in children under 5 years of age in Sub-Saharan Africa. CM is associated with blood-brain barrier disruption and long-term neurological sequelae in survivors of CM. Despite the vast amount of research on cerebral malaria, the cause of neurological sequelae observed in CM patients is poorly understood. In this article, the potential roles of glial cells, astrocytes, and microglia, in cerebral malaria pathogenesis are reviewed. The possible mechanisms by which glial cells contribute to neurological damage in CM patients are also examined.

Parenteral artemisinins are associated with reduced mortality and neurologic deficits and improved long-term behavioral outcomes in children with severe malaria

BackgroundIn 2011, the World Health Organization recommended injectable artesunate as the first-line therapy for severe malaria (SM) due to its superiority in reducing mortality compared to quinine. There are limited data on long-term clinical and neurobehavioral outcomes after artemisinin use for treatment of SM.MethodsFrom 2008 to 2013, 502 Ugandan children with two common forms of SM, cerebral malaria and severe malarial anemia, were enrolled in a prospective observational study assessing long-term neurobehavioral and cognitive outcomes following SM. Children were evaluated a week after hospital discharge, and 6, 12, and 24 months of follow-up, and returned to hospital for any illness. In this study, we evaluated the impact of artemisinin derivatives on survival, post-discharge hospital readmission or death, and neurocognitive and behavioral outcomes over 2 years of follow-up.Results346 children received quinine and 156 received parenteral artemisinin therapy (artemether or artesunate). After adjustment for disease severity, artemisinin derivatives were associated with a 78% reduction in in-hospital mortality (adjusted odds ratio, 0.22; 95% CI, 0.07–0.67). Among cerebral malaria survivors, children treated with artemisinin derivatives also had reduced neurologic deficits at discharge (quinine, 41.7%; artemisinin derivatives, 23.7%, p=0.007). Over a 2-year follow-up, artemisinin derivatives as compared to quinine were associated with better adjusted scores (negative scores better) in internalizing behavior and executive function in children irrespective of the age at severe malaria episode. After adjusting for multiple comparisons, artemisinin derivatives were associated with better adjusted scores in behavior and executive function in children <6 years of age at severe malaria exposure following adjustment for child age, sex, socioeconomic status, enrichment in the home environment, and the incidence of hospitalizations over follow-up. Children receiving artesunate had the greatest reduction in mortality and benefit in behavioral outcomes and had reduced inflammation at 1-month follow-up compared to children treated with quinine.ConclusionsTreatment of severe malaria with artemisinin derivatives, particularly artesunate, results in reduced in-hospital mortality and neurologic deficits in children of all ages, reduced inflammation following recovery, and better long-term behavioral outcomes. These findings suggest artesunate has long-term beneficial effects in children surviving severe malaria.

Sequential dysregulated plasma levels of angiopoietins (ANG-2 and ratios of ANG-2/ANG-1) are associated with malaria severity and mortality among hospital admitted cases in South Bastar Region of Chhattisgarh, Central India

ABSTRACT Cerebral malaria (CM) is one of the most severe forms of P. falciparum infection, with an associated high case-fatality rate. Angiopoietins (ANG‐1 and ANG‐2) are important biomarkers of endothelial activation and dysfunction. This study was carried out in Maharani Hospital and associated Medical College, Jagdalpur, CG, Central India from 2010 to 2014. Based on the treatment recovery patterns, cases (n = 65) were classified as mild malaria with rapid recovery (MM-RR), n= 14; non-cerebral severe malaria with moderately fast recovery (NCSM‐MFR), n= 9; CM survivors with slow recovery (CMS-SR), n= 36 and deteriorated CM non-survivors (Det‐CMNS), n= 6. Plasma levels (pg/ml) of ANG-1 and ANG-2 were measured by ELISA in all the samples at the time of hospital admission and 48 hours of treatment. Levels were also measured in available samples at the third time point (time of discharge for survivors or 72 hours post-treatment in fatal cases). Data analysis was done by appropriate statistical tests using Stata 11.0 and SPSS 25.0 software. At the time of admission, ANG-2 and ratios of ANG-2/ANG-1 significantly distinguished Det‐CMNS cases from MM-RR and NCSM‐MFR cases with good AUC scores (0.8‐0.9). Further, Det-CMNS cases could also be distinguished from MM-RR, NCSM-MFR, and CMS-SR cases by ANG-2 (AUC scores 0.9) and ratios of ANG‐2/ANG-1 (AUC: 0.8‐0.9) at 48 hours of treatment. Paired analysis of sequential measurement of angiopoietins revealed that compared to admission levels, the ratios of ANG-2/ANG-1 significantly declined 48 hours after treatment in MM-RR (p= 0.041), NCSM-MFR (p= 0.050), and CMS-SR (p= 0.0002) cases but not in cases of Det-CMNS (p= 0.916). In conclusion, plasma levels of ANG-2 and ratios of ANG-2/ANG-1 may serve as good biomarkers to distinguish the malaria severity at the time of hospital admission and recovery patterns upon treatment in Central India

#11: Post-malarial Hemolysis is Rare in Malawian Children with Cerebral Malaria

Abstract Background In severe malaria, artesunate decreases mortality compared to quinine. Artesunate’s introduction into clinical use in malaria-endemic areas revealed a unique adverse effect: severe hemolysis appearing several weeks after treatment completion. Though initial reports of post-artesunate hemolysis (PAH) were gathered from adult returning travelers, studies of African children revealed that PAH was less common in this semi-immune population. There are no published studies establishing the incidence and severity of PAH in several severe malarial syndromes in African children, including cerebral malaria (CM). We determined the incidence and severity of post-treatment hemolysis in Malawian children surviving CM by analyzing hospital and follow-up data from a long-standing study of CM pathogenesis. Methods Children aged 6 months to 14 years admitted to Queen Elizabeth Central Hospital (Blantyre, Malawi) with a clinical diagnosis of CM were enrolled in a retrospective cohort study. Children admitted before 2014 and treated with quinine (n=258) were compared to those admitted in 2014 and after and treated with artesunate (n=235). Hematocrit and parasite density were obtained at admission and every 6 hours until parasite clearance. The last hematocrit obtained during hospitalization was compared with the one-month post-hospitalization hematocrit value. Results The overall rate of a post-hospitalization decrease in hematocrit in children surviving CM was 5.3% (4.7% for quinine, 5.8% for artesunate, p value for difference= 0.582); no patients with a hematocrit decrease were symptomatic; none required transfusion. Of the 26 children with a decrease in hematocrit at one month after hospitalization, 23.1% had evidence of a new malaria infection. When children treated with quinine and artesunate were combined, a higher hematocrit on admission, lower quantitative histidine rich protein 2 level, and splenomegaly were independently associated with a post-treatment decrease in hematocrit. Conclusions In African survivors of CM, post-treatment hemolysis is rare, mild, and unassociated with the antimalarial treatment received.

Post-Malaria Anemia Is Rare in Malawian Children with Cerebral Malaria.

Artesunate therapy for severe malaria syndromes has been associated with post-treatment hemolysis and anemia. We defined post-malaria anemia as any decrease in hematocrit between the index hospitalization for severe malaria and 1 month after. We determined the incidence and severity of post-malaria anemia in Malawian children surviving cerebral malaria (CM) by analyzing hospital and follow-up data from a long-standing study of CM pathogenesis. Children enrolled before 2014 and treated with quinine (N = 258) were compared with those admitted in 2014 and after, and treated with artesunate (N = 235). The last hematocrit value obtained during hospitalization was compared with the 1-month post-hospitalization hematocrit value. The overall rate of a post-hospitalization decrease in hematocrit in children surviving CM was 5.3% (11 of 235 or 4.7% for quinine, 15 of 258 or 5.8% for artesunate; odds ratio, 3.23 [0.88, 18.38]); no patients with a decrease in hematocrit were symptomatic, and none required transfusion after hospitalization. Of the 26 children who had a decrease in hematocrit 1 month after hospitalization, 23.1% had evidence of a new malaria infection. When children treated with quinine and artesunate were combined, a higher hematocrit level on admission, lower quantitative histidine-rich protein level, and splenomegaly were associated independently with post-malaria anemia. In African survivors of CM, post-malaria anemia is rare, mild, and unassociated with the anti-malarial treatment received.

\u201cWe can\u2019t handle things we don\u2019t know about\u201d: perceived neurorehabilitation challenges for Malawian paediatric cerebral malaria survivors

BackgroundWe sought to identify perceptions of neurorehabilitation challenges for paediatric cerebral malaria (CM) survivors post-hospital discharge at Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi.MethodsAn exploratory approach was used to qualitatively investigate the perceived neurorehabilitation challenges for paediatric CM survivors. Data were collected through semi-structured in-depth interviews (IDIs) and focus group discussions (FGDs). Eighteen data-gathering sessions were conducted with 38 total participants, including 3 FGDs with 23 primary caregivers, 11 IDIs with healthcare workers at QECH, and 4 IDIs with community-based rehabilitation workers (CRWs).ResultsFGDs revealed that caregivers lack important knowledge about CM and fear recurrence of CM in their children. Post-CM children and families experience substantial stigma and sociocultural barriers to integrating into their community and accessing neurorehabilitative care. At a community-level, rehabilitation infrastructure, including trained staff, equipment, and programmes, is extremely limited. Rehabilitation services are inequitably accessible, and community-based rehabilitation remains largely unavailable.ConclusionsThere is an urgent need to establish further training of rehabilitation personnel at all levels and to build accessible rehabilitation infrastructure in Malawi for post-CM patients. Additional work is required to expand this study across multiple regions for a holistic understanding of neurorehabilitation needs.