Recent Advances in Imported Malaria Pathogenesis, Diagnosis, and Management.

Purpose of Review: Malaria is an important human parasitic disease affecting the population of tropical, subtropical regions as well as travelers to these areas.The purpose of this article is to provide clinicians practicing in non-endemic areas with a comprehensive overview of the recent data on microbiologic and pathophysiologic features of five Plasmodium parasites, clinical presentation of uncomplicated and severe cases, modern diagnostic methods, and treatment of malaria. Recent Findings: Employment of robust surveillance programs, rapid diagnostic tests, highly active artemisinin-based therapy, and the first malaria vaccine have led to decline in malaria incidence; however, emerging drug resistance, disruptions due to the COVID-19 pandemic, and other socio-economic factors have stalled the progress. Summary: Clinicians practicing in non-endemic areas such as the United States should consider a diagnosis of malaria in returning travelers presenting with fever, utilize rapid diagnostic tests if available at their practice locations in addition to microscopy, and timely initiate guideline-directed management as delays in treatment can lead to poor clinical outcomes.

The CARAMAL study could not assess the effectiveness of rectal artesunate in treating suspected severe malaria.

CARAMAL was a large observational study which recorded mortality in children with suspected severe malaria before and after the roll-out of rectal artesunate in Nigeria, Uganda and the Democratic Republic of the Congo. The results of CARAMAL have had a huge impact on public health policy leading to a World Health Organization moratorium on the roll-out of rectal artesunate. The conclusion reported in the abstract uses strong causal language, stating that "pre-referral RAS [rectal artesunate suppositories] had no beneficial effect on child survival". We argue that this causal interpretation of the study results is not justified. Data from the CARAMAL study inform chiefly on the strengths and weaknesses of referral systems in these three countries and do not inform reliably as to the beneficial effect of providing access to a known life-saving treatment.

Outcomes of childhood severe malaria: a comparative of study pre-COVID-19 and COVID-19 periods.

BACKGROUND: The collateral damages from measures adopted to mitigate the coronavirus disease 2019 (COVID-19) pandemic have been projected to negatively impact malaria in sub-Saharan Africa. Herein, we compare the prevalence and outcomes of childhood severe malaria during the pre-COVID-19 and COVID-19 periods at a tertiary health facility in Nigeria. METHODS: This was a retrospective review of cases of severe malaria admitted from 1st January to 31st December 2019 (pre-COVID-19 period) and 1st January to 31st December 2020 (COVID-19 period). We extracted relevant information, including demographics, the duration of symptoms before presentation, forms of severe malaria, and outcomes of hospitalization (discharged or death). RESULTS: In the pre-COVID-19 period, there were a total of 2312 admissions to the EPU and 1685 in the COVID-19 period, representing a decline of 27%. In contrast, there were 263 and 292 severe malaria admissions in the pre-COVID-19 and COVID-19 periods, respectively, representing an 11% increase in the absolute number of cases. The prevalence rates were 11.4% in the pre-COVID-19 period and 17.3% in the COVID-19 period, representing an increase of 52% in the percentage differences. The mortality rate in the COVID-19 period was higher than the pre-COVID-19 period ([10.3%; 30/292 vs. 2.3%; 6/263], p 0.001). The death rate increased by 350% during the COVID-19 period. The odds ratio (OR) of a child dying from severe malaria in the COVID-19 era was 4.9 [95% confidence interval (CI): 2.008 to 11.982]. In the COVID-19 era, presentation at a health facility was also delayed (p = 0.029), as were the odds of multiple features of severe malaria manifestations (OR-1.9, 95% CI, 1.107 to 3.269; p = 0.020). CONCLUSION: This study shows that the prevalence of severe childhood malaria increased by as much as 11.0%, with a disproportionate increase in mortality compared to the pre-pandemic level. Most children with severe malaria presented late with multiple features of severe malaria, probably contributing to the poor hospitalization outcomes (death) observed in this study.

Increased imported severe Plasmodium falciparum malaria involving hyperparasitaemia (>10%) in a UK hospital following relaxation of COVID-19 restrictions compared to the pre-pandemic period.

We identified and compared patients diagnosed with Plasmodium falciparum malaria at a large hospital in London, UK prior to the COVID-19 pandemic versus following relaxation of COVID-19-associated restrictions. We found that parasitaemias, rates of hyperpasitaemia and severe malaria were significantly higher in the period post-relaxation of COVID-19 restrictions.

The spectrum of clinical biomarkers in severe malaria and new avenues for exploration.

Globally, malaria is a public health concern, with severe malaria (SM) contributing a major share of the disease burden in malaria endemic countries. In this context, identification and validation of SM biomarkers are essential in clinical practice. Some biomarkers (C-reactive protein, angiopoietin 2, angiopoietin-2/1 ratio, platelet count, histidine-rich protein 2) have yielded interesting results in the prognosis of Plasmodium falciparum severe malaria, but for severe P. vivax and P. knowlesi malaria, similar evidence is missing. The validation of these biomarkers is hindered by several factors such as low sample size, paucity of evidence-evaluating studies, suboptimal values of sensitivity/specificity, poor clinical practicality of measurement methods, mixed Plasmodium infections, and good clinical value of the biomarkers for concurrent infections (pneumonia and current COVID-19 pandemic). Most of these biomarkers are non-specific to pathogens as they are related to host response and hence should be regarded as prognostic/predictive biomarkers that complement but do not replace pathogen biomarkers for clinical evaluation of SM patients. This review highlights the importance of research on diagnostic/predictive/therapeutic biomarkers, neglected malaria species, and clinical practicality of measurement methods in future studies. Finally, the importance of omics technologies for faster identification/validation of SM biomarkers is also included.

Readiness of the Kenyan public health sector to provide pre-referral care for severe paediatric malaria.

OBJECTIVE: To assess readiness among primary public health facilities in Kenya to provide pre-referral antimalarials for severe malaria. METHODS: Nine national surveys of randomly selected primary public health facilities undertaken bi-annually between 2017 and 2021 were analysed. The outcomes included the availability of pre-referral antimalarial drugs at the health facilities and health worker knowledge of recommended pre-referral treatment for severe malaria. RESULTS: A total of 1540 health workers from 1355 health facilities were interviewed. Injectable artesunate was available at 46%, injectable quinine at 7%, and artemether at 3% of the health facilities. None of the facilities had rectal artesunate suppositories in stock. A total of 960 (62%) health workers were trained on the use of injectable artesunate. 73% of the health workers who had ever referred a child with severe malaria were aware that artesunate was the recommended treatment, 49% said that intramuscular injection was the preferred route of administration, and 60% stated the correct dose. The overall knowledge level of the treatment policy was low at 21% and only slightly higher among trained than untrained health workers (24% vs 14%; p < 0.001) and those with access to guidelines versus those without access (29% vs 17%; p < 0.001). CONCLUSIONS: The readiness of primary health facilities and health workers to deliver appropriate pre-referral care to children with complicated malaria in Kenya is inadequate. Further investments are required to ensure (a) availability of nationally recommended pre-referral antimalarials; (b) appropriate training and supervision in their administration, and (c) monitoring of the entire referral process.

Autoimmune Dysfunction Due to Severe Malaria.

Despite advances in treatment and prevention, malaria still carries significant morbidity and mortality. Cases of malaria in the United States are rare and cases of severe malaria, mostly attributable to Plasmodium falciparum, are even more uncommon. With the coronavirus disease 2019 (COVID-19) pandemic, there have been distractions in evaluation and diagnosis leading to a rise in cases and deaths. We present a case of autoimmune dysregulation and blackwater fever secondary to severe malaria, requiring multiple courses of antimalarial therapy. Careful travel history and prompt recognition and treatment facilitates improved patient survival and recovery.

Neurological Complications of Malaria.

PURPOSE OF REVIEW: To discuss the neurological complications and pathophysiology of organ damage following malaria infection. RECENT FINDINGS: The principal advancement made in malaria research has been a better understanding of the pathogenesis of cerebral malaria (CM), the most dreaded neurological complication generally caused by Plasmodium falciparum infection. However, no definitive treatment has yet been evolved other than the use of antimalarial drugs and supportive care. The development of severe cerebral edema in CM results from two distinct pathophysiologic mechanisms. First, the development of "sticky" red blood cells (RBCs) leads to cytoadherence, where red blood cells (RBCs) get stuck to the endothelial walls and between themselves, resulting in clogging of the brain microvasculature with resultant hypoxemia and cerebral edema. In addition, the P. falciparum-infected erythrocyte membrane protein 1 (PfEMP1) molecules protrude from the raised knob structures on the RBCs walls and are in themselves made of a combination of human and parasite proteins in a tight complex. Antibodies to surfins, rifins, and stevors from the parasite are also located in the RBC membrane. On the human microvascular side, a range of molecules involved in host-parasite interactions, including CD36 and intracellular adhesion molecule 1, is activated during interaction with other molecules such as endothelial protein C receptor and thrombospondin. As a result, an inflammatory response occurs with the dysregulated release of cytokines (TNF, interleukins 1 and 10) which damage the blood-brain barrier (BBB), causing plasma leakage and brain edema. This second mechanism of CNS injury often involves multiple organs in adult patients in endemic areas but remains localized only to the central nervous system (CNS) among African children. Neurological sequelae may follow both P. falciparum and P. vivax infections. The major brain pathology of CM is brain edema with diffuse brain swelling resulting from the combined effects of reduced perfusion and hypoxemia of cerebral neurons due to blockage of the microvasculature by parasitized RBCs as well as the neurotoxic effect of released cytokines from a hyper-acute immune host reaction. A plethora of additional neurological manifestations have been associated with malaria, including posterior reversible encephalopathy syndrome (PRES), reversible cerebral vasoconstriction syndrome (RCVS), malarial retinopathy, post-malarial neurological syndrome (PMNS), acute disseminated encephalomyelitis (ADEM), Guillain-Barré syndrome (GBS), and cerebellar ataxia. Lastly, the impact of the COVID-19 pandemic on worldwide malaria control programs and the possible threat from co-infections is briefly discussed.

Factors Associated with Prolonged Hospital Length of Stay in Adults with Imported Falciparum Malaria-An Observational Study from a Tertiary Care University Hospital in Berlin, Germany.

Outcome of falciparum malaria is largely influenced by the standard of care provided, which in turn depends on the available medical resources. Worldwide, the COVID-19 pandemic has had a major impact on the availability of these resources, even in resource-rich healthcare systems such as Germany's. The present study aimed to determine the under-explored factors associated with hospital length of stay (LOS) in imported falciparum malaria to identify potential targets for improving management. This retrospective observational study used multivariate Cox proportional hazard regression with time to discharge as an endpoint for adults hospitalized between 2001 and 2015 with imported falciparum malaria in the Charité University Hospital, Berlin. The median LOS of the 535 cases enrolled was 3 days (inter-quartile range, IQR, 3-4 days). The likelihood of being discharged by day 3 strongly decreased with severe malaria (hazard ratio, HR, 0.274; 95% Confidence interval, 95%CI: 0.190-0.396) and by 40% with each additional presenting complication (HR, 0.595; 95%CI: 0.510-0.694). The 55 (10.3%) severe cases required a median LOS of 7 days (IQR, 5-12 days). In multivariate analysis, occurrence of shock (adjusted HR, aHR, 0.438; 95%CI 0.220-0.873), acute pulmonary oedema or acute respiratory distress syndrome (aHR, 0.450; 95%CI: 0.223-0.874), and the need for renal replacement therapy (aHR, 0.170; 95%CI: 0.063-0.461) were independently associated with LOS. All patients survived to discharge. This study illustrates that favourable outcomes can be achieved with high-standard care in imported falciparum malaria. Early recognition of disease severity together with targeted supportive care can lead to avoidance of manifest organ failure, thereby potentially decreasing LOS and alleviating pressure on bed capacities.

Identifying prognostic factors of severe metabolic acidosis and uraemia in African children with severe falciparum malaria: a secondary analysis of a randomized trial.

BACKGROUND: Severe metabolic acidosis and acute kidney injury are major causes of mortality in children with severe malaria but are often underdiagnosed in low resource settings. METHODS: A retrospective analysis of the 'Artesunate versus quinine in the treatment of severe falciparum malaria in African children' (AQUAMAT) trial was conducted to identify clinical features of severe metabolic acidosis and uraemia in 5425 children from nine African countries. Separate models were fitted for uraemia and severe metabolic acidosis. Separate univariable and multivariable logistic regression were performed to identify prognostic factors for severe metabolic acidosis and uraemia. Both analyses adjusted for the trial arm. A forward selection approach was used for model building of the logistic models and a threshold of 5% statistical significance was used for inclusion of variables into the final logistic model. Model performance was assessed through calibration, discrimination, and internal validation with bootstrapping. RESULTS: There were 2296 children identified with severe metabolic acidosis and 1110 with uraemia. Prognostic features of severe metabolic acidosis among them were deep breathing (OR: 3.94, CI 2.51-6.2), hypoglycaemia (OR: 5.16, CI 2.74-9.75), coma (OR: 1.72 CI 1.17-2.51), respiratory distress (OR: 1.46, CI 1.02-2.1) and prostration (OR: 1.88 CI 1.35-2.59). Features associated with uraemia were coma (3.18, CI 2.36-4.27), Prostration (OR: 1.78 CI 1.37-2.30), decompensated shock (OR: 1.89, CI 1.31-2.74), black water fever (CI 1.58. CI 1.09-2.27), jaundice (OR: 3.46 CI 2.21-5.43), severe anaemia (OR: 1.77, CI 1.36-2.29) and hypoglycaemia (OR: 2.77, CI 2.22-3.46) CONCLUSION: Clinical and laboratory parameters representing contributors and consequences of severe metabolic acidosis and uraemia were independently associated with these outcomes. The model can be useful for identifying patients at high risk of these complications where laboratory assessments are not routinely available.

The Indirect Costs of the SARS-CoV-2 Pandemic: A Case of Severe Malaria in Brooklyn.

Severe malaria due to the infection of Plasmodium falciparum is a critical infection that may lead to multisystem abnormalities if not promptly and adequately treated. We present a case of severe malaria in a patient recently repatriated from Conakry, Guinea, West Africa, marooned during the recent coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the direct costs of the SARS-CoV-2 pandemic and its indirect effect on neighboring industries have been analyzed, the indirect costs of other ailments in medicine have yet to be fully established. This case explores the ramifications of the SARS-CoV-2 pandemic on what would otherwise have been routine prophylaxis of malaria in a traveler. Given the pandemic, the healthcare industry has had fundamental changes that have impacted access to healthcare, particularly in the outpatient setting.

Weighted gene co-expression network analysis and drug-gene interaction bioinformatics uncover key genes associated with various presentations of malaria infection in African children and major drug candidates.

Malaria is a fatal parasitic disease with unelucidated pathogenetic mechanism. Herein, we aimed to uncover genes associated with different clinical aspects of malaria based on the GSE1124 dataset that is publicly accessible by using WGCNA. We obtained 16 co-expression modules and their correlations with clinical features. Using the MCODE tool, we identified THEM4, STYX, VPS36, LCOR, KIAA1143, EEA1, RAPGEF6, LOC439994, ZBTB33, PTPN22, ESCO1, and KLF3 as hub genes positively associated with Plasmodium falciparum infection (ASPF). These hub genes were involved in the biological processes of endosomal transport, regulation of natural killer cell proliferation, and KEGG pathways of endocytosis and fatty acid elongation. For the purple module negatively correlated with ASPF, we identified 19 hub genes that were involved in the biological processes of positive regulation of cellular protein catabolic process and KEGG pathways of other glycan degradation. For the salmon module positively correlated with severe malaria anemia (SMA), we identified 17 hub genes that were among those driving the biological processes of positive regulation of erythrocyte differentiation. For the brown module positively correlated with cerebral malaria (CM), we identified eight hub genes and these genes participated in phagolysosome assembly and positive regulation of exosomal secretion, and animal mitophagy pathway. For the tan module negatively correlated with CM, we identified four hub genes that were involved in CD8-positive, alpha-beta T cell differentiation and notching signaling pathway. These findings may provide new insights into the pathogenesis of malaria and help define new diagnostic and therapeutic approaches for malaria patients.