scholarly journals Bisphosphoglycerate Mutase Deficiency Protects against Cerebral Malaria and Severe Malaria-Induced Anemia

Cell Reports ◽  
2020 ◽  
Vol 32 (12) ◽  
pp. 108170
Author(s):  
Guoyue Xu ◽  
Rebekah van Bruggen ◽  
Christian O. Gualtieri ◽  
Neda Moradin ◽  
Adrien Fois ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Severe Malaria ◽  
Bisphosphoglycerate Mutase

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

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Andrea L. Conroy ◽  
Robert O. Opoka ◽  
Paul Bangirana ◽  
Ruth Namazzi ◽  
Allen E. Okullo ◽  
...  
Keyword(s):  
Executive Function ◽  
Hospital Mortality ◽  
Cerebral Malaria ◽  
Severe Malaria ◽  
Behavioral Outcomes ◽  
Artemisinin Derivatives ◽  
Neurologic Deficits ◽  
Adjusted Scores

Abstract Background In 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. Methods From 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. Results 346 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. Conclusions Treatment 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.

scholarly journals Circulatory hepcidin is associated with the anti-inflammatory response but not with iron or anemic status in childhood malaria

Blood ◽  
2013 ◽  
Vol 121 (15) ◽  
pp. 3016-3022 ◽  
Author(s):  
Florence Burté ◽  
Biobele J. Brown ◽  
Adebola E. Orimadegun ◽  
Wasiu A. Ajetunmobi ◽  
Nathaniel K. Afolabi ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cerebral Malaria ◽  
Severe Malaria ◽  
Severe Malarial Anemia ◽  
Key Points ◽  
Mild Malaria ◽  
Anti Inflammatory ◽  
Childhood Malaria ◽  
Malarial Anemia

Key Points Hepcidin rises more dramatically in mild malaria than in severe malaria. Hepcidin levels are linked to inflammation, not anemia, in severe malarial anemia and cerebral malaria.

scholarly journals Endothelial Nitric Oxide Synthase Gene Polymorphisms and Plasmodium falciparum Infection in Indian Adults

2009 ◽  
Vol 77 (7) ◽  
pp. 2943-2947 ◽  
Author(s):  
Gunanidhi Dhangadamajhi ◽  
Biranchi N. Mohapatra ◽  
Shantanu K. Kar ◽  
Manoranjan Ranjit
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Cerebral Malaria ◽  
Severe Malaria ◽  
Endothelial Nitric Oxide Synthase ◽  
No Production ◽  
Unique Haplotype ◽  
Mild Malaria ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

ABSTRACT To explore the hypothesis that susceptibility to cerebral malaria is influenced by genetic variation in endothelial nitric oxide synthase (eNOS), we genotyped three commonly defined polymorphic loci of eNOS, Glu298→Asp, intron 4 variable number of tandem repeat region, and T-786→C, in 244 patients (mean age, 36.2 years) with mild malaria and 194 patients (mean age, 35.6 years) with severe malaria belonging to same ethnic group in Orissa, an eastern Indian state. We found that there was an association of the Glu298→Asp substitution (P = 0.0037; odds ratio, 1.95; 95% confidence interval, 1.2 to 3.0) and a single unique haplotype defined by “C-b-Asp” (P corrected = 0.0024) for protection against cerebral malaria. Further, the median plasma level of nitrite-nitrate was found to be increased in individuals with the Glu298→Asp substitution and was significantly higher in the mild malaria group (P ≤ 0.0001), but the increase was not significant in the severe malaria group (P = 0.0528). These findings suggest that the Glu298→Asp substitution and the “C-b-Asp” haplotype may enhance eNOS expression and NO production, which leads to protection against cerebral malaria. These findings may increase our understanding of the pathogenesis of malaria.

scholarly journals Effect of health seeking behaviour of caregivers on severe malaria outcome in under-fives seen in a tertiary health institution in Nigeria

2020 ◽  
Vol 54 (3) ◽  
pp. 156-163
Author(s):  
Damian Nwaneri ◽  
Ayebo Sadoh
Keyword(s):  
Social Class ◽  
Cerebral Malaria ◽  
Severe Malaria ◽  
Cross Sectional Study ◽  
Severe Anaemia ◽  
World Health ◽  
Health Seeking Behaviour ◽  
Health Seeking ◽  
Cross Sectional ◽  
Health Institution

Background: Recognition of the symptoms and seeking prompt treatment in a health facility is a major means of reducing morbidity and prevention of mortality from severe malaria in under-fives.Objectives: To document the effect of health-seeking behaviour of caregivers and severe malaria outcome in underfives seen in a tertiary health institution in Nigeria.Design: A descriptive cross-sectional study carried out from July 2012 – June 2013. Data were obtained using a researcher-administered questionnaire.Subjects: Caregivers and children (6 – 59 months) who presented with features of severe malaria according to World Health Organization criteria.Results: Of the 120 caregivers mean [SD] age (31.4 [7.0] years) /child pairs (24 [14.7] months), 35 (29%) caregivers had appropriate health-seeking behaviour. The commonest place visited for initial healthcare before presentation was the patent medicine vendors by 87 (73%) caregivers. Seventy-seven per cent of caregivers who did not have appropriate health-seeking behaviour were from the lower family social class (p = 0.03). Caregivers whose children presented with severe anaemia were significantly more likely to have appropriate health-seeking behaviour (p = 0.00). The mortality rate of severe malaria was 15 per 1000; of which 94% were children whose caregivers did not have appropriate health-seeking behaviour. Age younger than 2 years (p = 0.02), cerebral malaria (p = 0.01) and jaundice (p = 0.03) significantly predicted mortality in the children irrespective of the caregivers’ health-seeking behaviour status.Conclusion: Less than a third of the caregivers had appropriate health-seeking behaviour for their under-fives with severe malaria, and the majority of these were from the lower family social class. Cerebral malaria and jaundice significantly predicted mortality in children with severe malaria irrespective of caregivers’ health-seeking behaviour status.Keywords: behaviour, caregivers, severe malaria, health-seeking, outcomeFunding: The study was self-sponsored by the authors

scholarly journals A Novel Role for Von Willebrand Factor in the Pathogenesis of Experimental Cerebral Malaria

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 97-97
Author(s):  
Niamh O'Regan ◽  
Kristina Gegenbauer ◽  
Jamie O'Sullivan ◽  
Alister Craig ◽  
Padraic Fallon ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Severe Malaria ◽  
Falciparum Malaria ◽  
Murine Model ◽  
Fold Increase ◽  
Clinical Progression ◽  
Direct Role ◽  
Experimental Cerebral Malaria ◽  
Independent Mechanism ◽  
Consistent Feature

Abstract Cerebral malaria (CM) is a major cause of death in young children in sub-Saharan Africa. Although the pathogenesis of this condition remains poorly understood, Plasmodium falciparum infection results in adhesion of infected erythrocytes (IE) to microvascular endothelium, and acute endothelial cell (EC) activation. Recent studies have shown that plasma VWF:Ag and VWF propeptide levels are markedly elevated in children with severe falciparum malaria. Moreover elevated VWF:Ag levels inversely correlate with clinical outcomes. In addition, circulating ultra-large VWF multimers have also been observed in children with severe malaria. Importantly, platelet-decorated UL-VWF strings have been shown to recruit trophozoite-stage falciparum-IE to EC surfaces in shear-based assays. Collectively, these emerging data suggest that VWF may play a novel role in the pathogenesis of CM. To further investigate this hypothesis, we utilized an established murine model of experimental CM which involves wild type (WT) C57BL/6J mice infected with Plasmodium berghei ANKA. In brief, WT C57Bl/6J mice were inoculated with 2x106P. berghei ANKA via I.P. injection. These mice typically developed CM and died within 6-8 days. In keeping with findings in children with falciparum malaria, acute EC activation was also an early and consistent feature in the murine model of CM. Mean plasma VWF:Ag levels were significantly elevated from Day+3 in infected mice compared to controls (Day +3 1.8 fold increase; Day +5 2.5 fold increase; p<0.01). In addition, plasma angiopoietin-2 and osteoprotegerin levels were also both significantly elevated from Day +3 and Day +5 respectively in mice infected with P. berghei. Interestingly, despite the fact that murine plasma ADAMTS13 activity levels were not significantly reduced, pathological ultra-large VWF multimers (UL-VWF) were also observed in murine plasma from Day +3 following P. berghei inoculation. Cumulatively these findings suggest that early marked elevation in VWF:Ag levels, and the appearance of pathological UL-VWF multimers in the plasma, represent hallmarks of both human and murine severe malaria infection. To determine whether VWF plays a direct role in modulating the pathogenesis of CM in vivo, we further investigated P. berghei infection in VWF-/- C57BL/6J mice. Importantly, although there was no difference in blood parasitaemia levels, overall survival was significantly prolonged in VWF-/- mice compared to wild type mice (6 versus 7.25 days; p=0.0106). Moreover, a significant delay in malaria clinical progression in the VWF-/- mice was also observed using a previously validated clinical scoring algorithm for experimental cerebral malaria. (Amante et al, Am J Path 2007). Recent studies have demonstrated that platelets may play a direct role in modulating malaria parasite killing. Consequently, to investigate potential mechanisms through which VWF-/- mice are protected against experimental CM, daily platelet counts were determined in WT and VWF-/- mice following infection. In keeping with observations in human patients infected with falciparum malaria, significant thrombocytopenia was also a consistent feature in the murine model. For example, by Day +4 following inoculation of WT mice mean platelet count had fallen by 71.6 ± 26 %. Interestingly however, significant thrombocytopenia was also observed in VWF-/- mice infected with P. berghei (84.2 ± 9 %). Despite the significant differences in clinical progression and overall survival no significant differences in platelet counts were observed between VWF-/- and WT mice at any time point. These findings suggest that VWF-/-mice are protected against CM through a platelet-independent mechanism. In conclusion, we demonstrate that early and consistent EC activation is a feature of the murine model of experimental CM similar to previous findings of children infected with P. falciparum. In addition, our findings show that marked elevation of VWF:Ag, and the appearance of pathological UL-VWF multimers in the plasma, both represent hallmarks of human and murine severe malaria infection. Finally, we report that VWF-/- mice exhibit significantly prolonged survival against CM, and that this effect is mediated through a platelet-independent mechanism. Given the significant morbidity and mortality associated with CM, these novel data have direct translational significance. Disclosures No relevant conflicts of interest to declare.

scholarly journals 963. Whole Blood Transcriptome Analysis Reveals Differences in Erythropoiesis and Neurologically Relevant Pathways Between Cerebral Malaria and Severe Malarial Anemia

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S35-S35
Author(s):  
Srinivas Nallandhighal ◽  
Gregory Park ◽  
Yen-Yi Ho ◽  
Robert Opoka ◽  
Chandy John ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cerebral Malaria ◽  
Severe Malaria ◽  
Whole Blood ◽  
Heme Oxygenase 1 ◽  
Specific Gene ◽  
Severe Malarial Anemia ◽  
Specific Gene Expression ◽  
Blood Transcriptome ◽  
Malarial Anemia

Abstract Background Plasmodium falciparum malaria can rapidly progress to severe disease that can lead to death if left untreated. Severe malaria cases commonly present as severe malarial anemia (SMA), defined in children as hemoglobin (Hb) &lt;5 g/dL with parasitemia, or as cerebral malaria (CM), which manifests as parasitemia with acute neurological deficits and has an inpatient mortality rate of ~20%. The molecular and cellular processes that lead to CM and SMA are unclear. Methods In a cross-sectional study, we compared genome-wide transcription profiles of whole blood obtained from Ugandan children with acute CM (n = 17) or SMA (n = 17) and community children without P. falciparum infection (n = 12) who were enrolled in a parent cohort study of severe malaria. We determined the relationships between gene expression, hematological indices, and plasma biomarkers, including inflammatory cytokines. Results Both CM and SMA demonstrated enrichment of dendritic cell activation, inflammatory/TLR/chemokines, monocyte, and neutrophil modules but depletion of lymphocyte modules. Neurodegenerative disease and neuroinflammation pathways were enriched in CM. Increased Nrf2 pathway gene expression corresponded with increased plasma heme oxygenase-1 and the heme catabolite bilirubin in a manner specific to children with both SMA and sickle cell disease. Reticulocyte-specific gene expression was markedly decreased in CM relative to SMA despite higher Hb levels and appropriate increases in plasma erythropoietin. Viral sensing/interferon regulatory factor (IRF) 2 module (M111) expression and plasma IP-10 levels both negatively correlated with reticulocyte-specific signatures, but only M111 expression independently predicted decreased reticulocyte-specific gene expression after controlling for leukocyte count, Hb level, parasitemia, and clinical syndrome by multiple regression. Conclusion Differences in the blood transcriptome of CM and SMA relate to neurologically relevant pathways and erythropoiesis. Erythropoietic suppression during severe malaria is more pronounced during CM versus SMA and is positively associated with IRF2 blood signatures. Future studies are needed to validate these findings. Disclosures All authors: No reported disclosures.

INCREASED SERUM PHOSPHOLIPASE A2 ACTIVITY IN MALAWIAN CHILDREN WITH FALCIPARUM MALARIA

PEDIATRICS ◽  
1995 ◽  
Vol 96 (1) ◽  
pp. 125-125
Author(s):  
P Vadas ◽  
TE Taylor ◽  
L Chimsuku
Keyword(s):  
Mortality Rate ◽  
Phospholipase A2 ◽  
Cerebral Malaria ◽  
Severe Malaria ◽  
Falciparum Malaria ◽  
Neurological Status ◽  
Pla2 Activity ◽  
Multisystem Disease ◽  
The Mean

Malaria is a multisystem disease with a mortality rate of 5 to 30% even with optimal treatment. Earlier studies have shown increased circulating levels of TNF in the plasma of patients as an independent predictor of severe or fatal disease. TNF has already been shown to facilitate the release of proinflammatory enzyme phospholipase A2 from various cells in vitro. Because both TNF and PLA2 are increased in patients with septicemia and because TNF levels are already shown to be increased in patients with malaria, the authors studied the relationship between TNF levels, severity of disease, and PLA2 activity. Seventy-five children (age 3 months to 10 years) with severe malaria due to Plasmodium falciparum and 34 controls (age 2 to 5 years) taking part in the malaria survey at a school in the same region in Malawi were included in the study. The children were afebrile and aparasitemic. Many of these children had cerebral malaria with coma. Twenty patients had uncomplicated falciparum malaria and 55 had cerebral malaria. Ten of them (all with cerebral malaria) died. In addition to examining the children, particularly for neurological status, laboratory studies obtained included the blood count, hematocrit, leukocyte count, thick blood smears for quantitative evaluation of parasitemia, and measurement of PLA2 activity. Mean plasma PLA2 activity in 34 healthy controls was 424 U/mL, whereas in the 75 patients with malaria the mean value was 53 804 U/mL. In the 45 children who were available for follow-up 1 month later after treatment the mean plasma PLA2 activity was 2546 U/mL. The high mean plasma level was not different between children with cerebral malaria and those with uncomplicated malaria. However the PLA2 activity in 28 children with profound coma was much higher than in other patients with malaria. The initial plasma PLA2 activity was predictive of outcome. Patients who had levels higher than 60 000 U/mL had a higher mortality rate (33%) compared with those with values less than 60 000 U at (8.3%). There was also a significant correlation between TNF and plasma PLA2 activity. Pretreatment serum PLA2 activity also correlated with the intensity of parasitemia. The cerebral spinal fluid PLA2 activity was not elevated even in those patients with severe malaria. The biological role of this observation is unclear. However, selective inhibition of PLA2 may be a new target for future therapy because PLA2 is proinflammatory enzyme.

scholarly journals A HOSPITAL-BASED RETROSPECTIVE COMPARATIVE STUDY OF COMPLICATIONS, OUTCOMES, CLINICAL AND LABORATORY PARAMETERS OF MALARIA WITH AND WITHOUT NEUROLOGICAL INVOLVEMENT

2016 ◽  
Vol 9 (1) ◽  
pp. e2017006 ◽  
Author(s):  
Sohaib Ahmad ◽  
Nadia Shirazi ◽  
Nowneet Kumar Bhat ◽  
Minakshi Dhar ◽  
Garima Mittal ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Severe Malaria ◽  
Ventilatory Support ◽  
Neurological Complications ◽  
Adverse Outcomes ◽  
Neurological Involvement ◽  
Severe Thrombocytopenia ◽  
Laboratory Parameters ◽  
Retrospective Comparative Study ◽  
Demographic Attributes

Background & Objectives: Classically associated with Plasmodium falciparum, neurological complications in severe malaria is associated with increased morbidity and mortality. However, reports implicate the long considered benign Plasmodium vivax for causing severe malaria as well. We aimed to analyze the cerebral complications in malaria, and study if there is a specie-related difference in the presentation and outcomes.Methods: We retrospectively compared patients of malaria hospitalised from 2009-15, with (n=105) and without (n=1155) neurological involvement in terms of outcomes, complications, demographic attributes, clinical features, and laboratory parameters. Subsequently, the same parameters were studied in those with cerebral malaria due to mono-infections of vivax or falciparum and their co-infection.Results: Cerebral malaria was observed in 8.3% (58/696), 7.4% (38/513) and 17.6% (6/51) of vivax, falciparum and combined plasmodial infections respectively. Those with cerebral malaria had significantly (p<0.05) longer hospitalization, delayed defervescence, required mechanical ventilatory support and dialysis despite comparable levels of azotemia and renal insufficiency, and adverse outcomes compared to non-cerebral malaria. Severe thrombocytopenia, respiratory distress and mechanical ventilation were significantly (p<0.05) associated with P. vivax cerebral malaria.Conclusions:The plasmodial species were comparable in clinical and laboratory parameters and outcomes in cerebral malaria in isolation and in combination (p>0.05). P. vivax emerged as the predominant cause of cerebral malaria and its virulence was comparable to P. falciparum.

scholarly journals Differential kinetics of plasma procalcitonin levels in cerebral malaria in urban Senegalese patients according to disease outcome

2011 ◽  
Vol 2 (1) ◽  
pp. 22 ◽  
Author(s):  
Babacar Mbengue ◽  
Bacary Diatta ◽  
Birahim Niang ◽  
Ngor Diagne ◽  
Mamadou Ndiaye ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Severe Malaria ◽  
Fatal Outcome ◽  
Care Facility ◽  
Threshold Level ◽  
Serum Levels ◽  
Sub Saharan Africa ◽  
Serial Killer ◽  
Sub Saharan ◽  
Hôpital Principal

<em>P. falciparum</em> malaria continues as the serial killer of over a million lives yearly, mainly for children in sub-Saharan Africa. For severe malaria, we are still on the quest for a prognostic marker of fatal outcome. We analysed the association between serum levels of Procalcitonin (PCT), a marker of septic inflammation, and clinical outcome in Senegalese patients admitted with confirmed cerebral malaria in the intensive care facility of Hopital Principal. A total of 98 patients living in the hypoendemic urban area of Dakar, Senegal, were enrolled during transmission seasons. Levels of PCT were compared between surviving vs the 26.5 % fatal cases in blood samples of the 3 days following hospitalisation. Mean PCT levels were elevated in patients with active infection, with a large range of values (0.1 to 280 nanog per mL), significantly higher on day 0 in fatal cases than in surviving (53.6 vs 27.3; P=0.01). No exact individual threshold level could indicate occurrence of fatality, however mortality could be most accurately predicted by PCT level above 69 nanog per ML and there was a very clear different profile of evolution of PCT levels on the 3 days of observation decreasing early from day 1 in surviving patients (P&lt;10–3), contrary to fatal cases. These results indicate that PCT kinetic rather than intrinsic level could be of use to predict a reduced risk of fatality in patient with cerebral malaria and could serve as potential predicting marker for severe malaria.

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