Do we know enough to find an adjunctive therapy for cerebral malaria in African children?

Cerebral malaria is the deadliest complication of malaria, a febrile infectious disease caused by Plasmodium parasite. Any of the five human Plasmodium species can cause disease, but, for unknown reasons, in approximately 2 million cases each year P. falciparum progresses to severe disease, ultimately resulting in half a million deaths. The majority of these deaths are in children under the age of five. Currently, there is no way to predict which child will progress to severe disease and there are no adjunctive therapies to halt the symptoms after onset. Herein, we discuss what is known about the disease mechanism of one form of severe malaria, cerebral malaria, and how we might exploit this understanding to rescue children in the throes of cerebral disease.

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A Study on Relationship of Thrombocytopenia and Likelihood of Severe Malaria in Patients Admitted With Malaria in a Tertiary Care Hospital of Dakshina Kannada

Asian Journal of Medicine and Health ◽

10.9734/ajmah/2019/v14i330104 ◽

2019 ◽

pp. 1-7

Author(s):

Mukhtarahmed Bendigeri ◽

Apoorva Panchakshare ◽

Nazir Attar ◽

Prakruthi Jaladhar

Keyword(s):

Renal Failure ◽

Cerebral Malaria ◽

Severe Malaria ◽

Hepatic Dysfunction ◽

Severe Disease ◽

Tertiary Care ◽

Plasmodium Species ◽

Malarial Parasite ◽

Severe Thrombocytopenia ◽

Care Hospital

Background: Malaria continues to be a huge socioeconomic burden despite various measures taken to curb the spread worldwide. It is also a global concern and more so in countries with a resource-limited setting. This inspired us to look at variables that could represent a severe disease in those limited settings, one such parameter being thrombocytopenia in malaria. Aims and Objectives: To find the relationship between thrombocytopenia and renal failure, hepatic dysfunction and cerebral malaria (severe malaria) and to identify if thrombocytopenia on the first day of admission increases the likelihood of severe malaria. Methods: The study included 85 patients admitted in Yenepoya medical college hospital with fever and peripheral smear or malarial parasite fluorescent test (MPFT) positive for Plasmodium species. Results: A total of 85 patients were included in the study. It was noted that the patients with profound thrombocytopenia (<20,000/ml) on day 1 were more commonly associated with manifestations of severe malaria-like cerebral malaria, renal failure, and jaundice. Platelet count of <50,000/ml was associated with increased incidence of renal failure, hepatic dysfunction, and cerebral malaria and increased mortality by an odds ratio of 4.37 on multivariate analysis. Conclusions: It was noted in our study that the presence of thrombocytopenia in a case of acute febrile illness increases the probability of malaria. This finding along with clinical suspicion of malaria should entail early treatment initiation. We have also noted that the presence of profound and severe thrombocytopenia was found to have a statistically significant correlation with cerebral malaria, renal failure and jaundice, and increased mortality.

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Meta-analysis ofPlasmodium falciparumvarSignatures Contributing to Severe Malaria in African Children and Indian Adults

mBio ◽

10.1128/mbio.00217-19 ◽

2019 ◽

Vol 10 (2) ◽

Cited By ~ 6

Author(s):

Fergal Duffy ◽

Maria Bernabeu ◽

Prasad H. Babar ◽

Anne Kessler ◽

Christian W. Wang ◽

...

Keyword(s):

Cerebral Malaria ◽

Severe Malaria ◽

Disease Severity ◽

Clinical Presentation ◽

Meta Analysis ◽

Clinical Syndrome ◽

Contributing Factors ◽

Content Type ◽

African Children ◽

Group A

ABSTRACTThe clinical presentation of severePlasmodium falciparummalaria differs between children and adults, but the mechanistic basis for this remains unclear. Contributing factors to disease severity include total parasite biomass and the diverse cytoadhesive properties mediated by the polymorphicvargene parasite ligand family displayed on infected erythrocytes. To explore these factors, we performed a multicohort analysis of the contribution ofvarexpression and parasite biomass to severe malaria in two previously published pediatric cohorts in Tanzania and Malawi and an adult cohort in India. Machine learning analysis revealed independent and complementary roles forvaradhesion types and parasite biomass in adult and pediatric severe malaria and showed that similarvarprofiles, including upregulation of group A and DC8var, predict severe malaria in adults and children. Among adults, patients with multiorgan complications presented infections with significantly higher parasite biomass without significant differences invaradhesion types. Conversely, pediatric patients with specific complications showed distinctvarsignatures. Cerebral malaria patients showed broadly increased expression ofvargenes, in particular group A and DC8var, while children with severe malaria anemia were classified based on high transcription of DC8varonly. This study represents the first large multisite meta-analysis ofvarexpression, and it demonstrates the presence of commonvarprofiles in severe malaria patients of different ages across distant geographical sites, as well as syndrome-specific disease signatures. The complex associations between parasite biomass,varadhesion type, and clinical presentation revealed here represent the most comprehensive picture so far of the relationship between cytoadhesion, parasite load, and clinical syndrome.IMPORTANCEP. falciparummalaria can cause multiple disease complications that differ by patient age. Previous studies have attempted to address the roles of parasite adhesion and biomass in disease severity; however, these studies have been limited to single geographical sites, and there is limited understanding of how parasite adhesion and biomass interact to influence disease manifestations. In this meta-analysis, we compared parasite disease determinants in African children and Indian adults. This study demonstrates that parasite biomass and specific subsets ofvargenes are independently associated with detrimental outcomes in both childhood and adult malaria. We also explored how parasitevaradhesion types and biomass play different roles in the development of specific severe malaria pathologies, including childhood cerebral malaria and multiorgan complications in adults. This work represents the largest study to date of the role of bothvaradhesion types and biomass in severe malaria.

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Gradual acquisition of immunity to severe malaria with increasing exposure

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2014.2657 ◽

2015 ◽

Vol 282 (1801) ◽

pp. 20142657 ◽

Cited By ~ 50

Author(s):

Jamie T. Griffin ◽

T. Déirdre Hollingsworth ◽

Hugh Reyburn ◽

Chris J. Drakeley ◽

Eleanor M. Riley ◽

...

Keyword(s):

Mathematical Model ◽

Plasmodium Falciparum ◽

Cerebral Malaria ◽

Severe Malaria ◽

Severe Disease ◽

Age Distribution ◽

Physiological Changes ◽

Careful Monitoring ◽

African Countries ◽

Multiple Episodes

Previous analyses have suggested that immunity to non-cerebral severe malaria due to Plasmodium falciparum is acquired after only a few infections, whereas longitudinal studies show that some children experience multiple episodes of severe disease, suggesting that immunity may not be acquired so quickly. We fitted a mathematical model for the acquisition and loss of immunity to severe disease to the age distribution of severe malaria cases stratified by symptoms from a range of transmission settings in Tanzania, combined with data from several African countries on the age distribution and overall incidence of severe malaria. We found that immunity to severe disease was acquired more gradually with exposure than previously thought. The model also suggests that physiological changes, rather than exposure, may alter the symptoms of disease with increasing age, suggesting that a later age at infection would be associated with a higher proportion of cases presenting with cerebral malaria regardless of exposure. This has consequences for the expected pattern of severe disease as transmission changes. Careful monitoring of the decline in immunity associated with reduced transmission will therefore be needed to ensure rebound epidemics of severe and fatal malaria are avoided.

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Faculty of 1000 evaluation for Endoglin in African children with Plasmodium falciparum malaria: a novel player in severe malaria pathogenesis?

F1000 - Post-publication peer review of the biomedical literature ◽

10.3410/f.1691966.1198069 ◽

2010 ◽

Author(s):

Charles Newton ◽

Samson Gwer

Keyword(s):

Plasmodium Falciparum ◽

Severe Malaria ◽

Falciparum Malaria ◽

Plasmodium Falciparum Malaria ◽

African Children

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

BMC Medicine ◽

10.1186/s12916-021-02033-1 ◽

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.

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Molecular markers of anti-malarial drug resistance in Central, West and East African children with severe malaria

Malaria Journal ◽

10.1186/s12936-017-1868-y ◽

2017 ◽

Vol 16 (1) ◽

Cited By ~ 11

Author(s):

Christian N. Nguetse ◽

Ayola Akim Adegnika ◽

Tsiri Agbenyega ◽

Bernhards R. Ogutu ◽

Sanjeev Krishna ◽

...

Keyword(s):

Drug Resistance ◽

Molecular Markers ◽

Severe Malaria ◽

East African ◽

African Children

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Effective Adjunctive Therapy by an Innate Defense Regulatory Peptide in a Preclinical Model of Severe Malaria

Science Translational Medicine ◽

10.1126/scitranslmed.3003515 ◽

2012 ◽

Vol 4 (135) ◽

pp. 135ra64-135ra64 ◽

Cited By ~ 65

Author(s):

A. H. Achtman ◽

S. Pilat ◽

C. W. Law ◽

D. J. Lynn ◽

L. Janot ◽

...

Keyword(s):

Severe Malaria ◽

Adjunctive Therapy ◽

Preclinical Model ◽

Regulatory Peptide ◽

Innate Defense

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Identifying targets of protective antibodies against severe malaria in Papua, Indonesia using locally expressed domains of Plasmodium falciparum Erythrocyte Membrane Protein 1.

Infection and Immunity ◽

10.1128/iai.00435-21 ◽

2021 ◽

Author(s):

Janavi S Rambhatla ◽

Gerry Q Tonkin-Hill ◽

Eizo Takashima ◽

Takafumi Tsuboi ◽

Rintis Noviyanti ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Membrane Protein ◽

Severe Malaria ◽

Erythrocyte Membrane ◽

Uncomplicated Malaria ◽

Igg Antibodies ◽

Erythrocyte Membrane Protein ◽

African Children ◽

Genes Encoding ◽

Malaria Severity

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), a diverse family of multi-domain proteins expressed on the surface of malaria-infected erythrocytes, is an important target of protective immunity against malaria. Our group recently studied transcription of the var genes encoding PfEMP1 in individuals from Papua, Indonesia with severe or uncomplicated malaria. We cloned and expressed domains from 32 PfEMP1s including 22 that were upregulated in severe malaria and 10 that were upregulated in uncomplicated malaria, using a wheat germ cell-free expression system. We used Luminex technology to measure IgG antibodies to these 32 domains and control proteins in 63 individuals (11 children). At presentation to hospital, levels of antibodies to PfEMP1 domains were either higher in uncomplicated malaria or were not significantly different between groups. Using principal components analysis, antibodies to three of 32 domains were highly discriminatory between groups. These included two domains upregulated in severe malaria, a DBLβ13 domain and a CIDRα1.6 domain (which has been previously implicated in severe malaria pathogenesis), and a DBLδ domain that was upregulated in uncomplicated malaria. Antibody to control non-PfEMP1 antigens did not differ with disease severity. Antibodies to PfEMP1 domains differ with malaria severity. Lack of antibodies to locally expressed PfEMP1 types, including both domains previously associated with severe malaria and newly identified targets, may in part explain malaria severity in Papuan adults. Importance Severe Plasmodium falciparum malaria kills many African children, and lack of antibody immunity predisposes to severe disease. A critical antibody target is the P. falciparum erythrocyte membrane 1 (PfEMP1) family of multidomain proteins, which are expressed on the infected erythrocyte surface and mediate parasite sequestration in deep organs. We previously identified var genes encoding PfEMP1 that were differentially expressed between severe and uncomplicated malaria in Papua, Indonesia. Here, we have expressed domains from 32 of these PfEMP1s and measured IgG antibody responses to them in Papuan adults and children. Using Principal Component Analysis, IgG antibodies to three domains distinguished between severe and uncomplicated malaria and were higher in uncomplicated malaria. Domains included CIDRα1.6, implicated in severe malaria; a DBLβ13 domain; and a DBLδ domain of unknown function. Immunity to locally relevant PfEMP1 domains may protect from severe malaria. Targets of immunity show important overlap between Asian adults and African children.

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