The effect of genetically proxied IL-6 signalling on severe malaria: A Mendelian randomisation analysis (preprint)

Introduction Severe malaria remains a deadly disease for many young children in low- and middle-income countries. Levels of Interleukin-6 (IL-6) have been shown to identify cases of severe malaria and associate with severity, but it is unknown if this association is causal, or whether manipulation of IL-6 might alter outcomes in severe malaria. Methods A single nucleotide polymorphism (SNP, rs2228145) in the IL-6 receptor ( IL6R) was chosen as a genetic variant that is known to alter IL-6 signalling. We measured the association between the minor allele of this SNP (C) and C-reactive protein (CRP) levels, a marker of IL-6 signalling in the non-European ancestry population recruited to UK Biobank. We then took this forward as an instrument to perform Mendelian randomisation (MR) in MalariaGEN, a large cohort study of patients with severe malaria at eleven worldwide sites. As a secondary approach, we identified cis protein quantitative trait loci ( cis -pQTL) for IL6R itself and other markers of IL-6 signalling in a recently published GWAS of the plasma proteome performed in African Americans. We then performed MR using these instruments in the African MalariaGEN sites (9/11). Analyses were performed at each site, and meta-analysed using inverse variance weighting. Additional analyses were performed for specific sub-phenotypes of severe malaria: cerebral malaria and severe malarial anaemia. Results The minor allele (C) of rs2228145 was associated with decreased CRP across all tested continental ancestries in UK Biobank. There was no evidence of heterogeneity of effect and a large overall effect (beta -0.11 per standard deviation of normalised CRP per C allele, p = 7.55 × 10 −255 ) In Mendelian randomisation studies using this SNP, we did not identify an effect of decreased IL-6 signalling on severe malaria case status (Odds ratio 1.14, 95% CI 0.56 – 2.34, p = 0.713). Estimates of the association with any severe malaria sub-phenotype were similarly null although there was significant imprecision in all estimates. Using an alternative instrument ( cis -pQTLs for IL6R ), which included 3 SNPS (including rs2228145), we identified the same null effect, but with greater precision (Odds ratio 1.02, 95% CI 0.95 – 1.10), and no effect on any severe malaria subtypes. Conclusions Mendelian randomisation analyses using a SNP in the IL-6 receptor known to alter IL-6 signalling do not support a causal role for IL-6 signalling in the development of severe malaria, or any severe malaria sub-phenotype. This result suggests IL-6 may not be causal for severe outcomes in malaria, and that therapeutic manipulation of IL-6 may not be a suitable treatment for severe malaria.

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.

The epidemiology of severe malaria at Manhiça District Hospital, Mozambique: a retrospective analysis of 20 years of malaria admissions surveillance data.

BACKGROUND: Most malaria burden estimates rely on modelling infection prevalence to case incidence data, with insufficient attention having been paid to the changing clinical presentation of severe disease and its relationship with changing transmission intensity. We present 20 years of longitudinal surveillance data to contribute to the understanding of the relationship between malaria transmission and the burden and clinical presentation of severe malaria and to inform policy. METHODS: This retrospective analysis of clinical surveillance hospital data included all children younger than 15 years admitted with malaria to Manhiça District Hospital (MDH), Mozambique, from July 1, 1997, to June 30, 2017. Case fatality ratios (CFRs) were calculated as the number of patients who died having a specific diagnosis or syndrome divided by the total number of patients with known outcome admitted with that diagnosis or syndrome. FINDINGS: Over the study period, 32 138 children were admitted to MDH with a malaria diagnosis. Malaria accounted for a large proportion of admissions, ranging from 4083 (76·9%) of 5307 admissions in 2000-01 to 706 (27·5%) of 2568 admissions in 2010-11. Since 2000-02, the absolute and relative number of malaria admissions and deaths presented a decreasing trend. The age pattern of patients with malaria shifted to older ages with a median age of 1·7 years (IQR 0·9-3·0) in 1997-2006 and 2·6 years (IQR 1·3-4·4) in 2006-17, although most malaria deaths (60-88% in 2009-17) still occurred in children younger than 5 years. The clinical presentation of severe malaria changed, with an increase in cerebral malaria and a decrease in severe anaemia and respiratory distress, leading to similar yearly cases for the three syndromes. CFRs for severe malaria fluctuated between 1·1% (2 of 186 in 2014-15) and 7·2% (11 of 152 in 2010-11), varying by severe malaria syndrome (3·3% [70 of 2105] for severe anaemia, 5·1% [191 of 3777] for respiratory distress, and 14·8% [72 of 487] for cerebral malaria). Overall malaria CFRs (1·8% [543 of 30 163]) did not vary by age group. INTERPRETATION: Despite the unprecedented scale up of malaria control tools, malaria still represented around 30-40% of paediatric hospital admissions in 2006-17. The age shift towards older children was not accompanied by an increase in severe malaria or deaths; however, control programmes should consider adapting their high-risk target groups to include older children. Malaria remains a leading cause of disease and health-care system use and the massive unfinished malaria control agenda warrants intensified efforts. FUNDING: Spanish Agency for International Cooperation and Development.

Pandemic-related delay of falciparum malaria diagnosis in a traveller leading to cerebral malaria.

We report the case of a 29-year-old male in whom COVID-19 concerns led to a delayed diagnosis of falciparum malaria. The patient developed symptoms of cerebral malaria with cytotoxic lesions of the corpus callosum in magnetic resonance imaging.

COVID-19 and Malaria Co-Infection; Same Coin But Different Faces? (preprint)

Background: As the COVID-19 pandemic spreads rapidly around the world, urgent action is needed to combat the new coronavirus, while other deadly diseases such as malaria cannot be ignored. The impact of the coronavirus on countries affected by malaria and, where possible, contribute to a successful response to COVID-19. Our aim is to assess the possible link between malaria and COVID-19. Methods: This is a retrospective cohort study conducted among adult Sudanese COVID-19 patients admitted to the Universal and Ombada hospitals in a period (4th of April 2020 to the 15th of January 2021) . 87 of the patients were included . Results: Among the 87 patients 64.9 % were males while 35.6 were females. 27.6 % had a positive blood film. 64.7% of the malaria patients had P. falciprum while 35.3% had P. vivax. 52.9% of the patients showed positive RT-PCR for COVID-19 with 52.9 % showed positive CT findings. Generalized fatigability was observed in 52.9 % of the patients with malaria followed by headache, nausea, fever with chills, fever with shivering, vomiting and diarrhea in 42.5%, 36.8%, 20.7%,12.6%, 9.2%, and 9.2% respectively. In COVID-19 patients 85.1% had fever and generalized fatigability, followed by cough, headache, SOB, sore throat, myalgia, chest pain, and diarrhea. 13.79 %of malaria patients had malarial pneumonitis, followed by pulmonary edema, choleric malaria, thrombocytopenia and malaria induced hepatitis in 10.39 %, 9.2 %, 9.19 %, and 6.9% respectively. 8.4% had cerebral malaria while 1.1% had cerebellar syndromes. 44.8 % had ARDS, 17.2% had heart failure, 8% had pulmonary embolism, 8% had stroke, 3.9% had encephalitis and 1.1% had convulsions. Conclusion: Malaria and COVID-19 have a possible link that they both share similar presentations and complications.Funding Information: There was no funding.Declaration of Interests: All authors declare that there are no conflicts of interest.Ethics Approval Statement: Ethical approval was obtained from the state ministry of health, Khartoum state . Both written and verbal consents were taken from the participants. Privacy and protection of the participant’s files and information were of the highest priority.

COVID-19 and Malaria Co-infection; Same coin but different faces? (preprint)

Background: As the COVID-19 pandemic spreads rapidly around the world, urgent action is needed to combat the new coronavirus, while other deadly diseases such as malaria cannot be ignored. The impact of the coronavirus on countries affected by malaria and, where possible, contribute to a successful response to COVID19. Our aim is to assess the possible link between Malaria and COVID-19 . Methods: : This is a descriptive retrospective cross sectional study which was conducted among adult Sudanese COVID-19 patients admitted to the Universal and Ombada hospitals in the period (4th of April 2020 to the 15th of January, 2020). A total number of 87 patients were included. Results: : Among the 87 patients 64.9 % were males while 35.6 were females. 27.6 % had a positive blood film. 64.7% of the malaria patients had p.falciparum while 35.3% had p.vivax. 52.9% of the patients showed positive RT-PCR for COVID-19 with 52.9 % showed positive CT findings . Generalized fatigability was observed in 52.9 % of the patients with malaria followed by headache, nausea, fever with chills, fever with shivering, vomiting and diarrhea in 42.5%, 36.8%, 20.7%, 12.6%, 9.2% and 9.2% respectively. In COVID-19 patients 85.1% had fever and generalized fatigability, followed by cough, headache, SOB , sore throat ,myalgia, chest pain and diarrhea. 13.79 % of malaria patients had malarial pneumonitis, followed by pulmonary edema, choleric malaria, thrombocytopenia and malaria induced hepatitis in 10.39 %, 9.2 %, 9.19 % and 6.9% respectively. 8.4% had cerebral malaria while 1.1% had cerebellar syndromes. 44.8 % had acute respiratory distress syndrome, 17.2% had heart failure, 8% had pulmonary embolism, 8% had stroke, 3.9% had encephalitis and 1.1% had convulsions. Conclusion: Malaria and COVID-19 have a possible link that they both share similar presentations and complications.