Erythropoietin (EPO) is the main mediator of erythropoiesis and an important tissue protective hormone that appears to mediate an ancestral neuroprotective innate immune response mechanism at an early age. When the young brain is threatened-prematurity, neonatal hyperbilirubinemia, malaria- EPO is hyper-secreted disproportionately to any concurrent anemic stimuli. Under eons of severe malarial selection pressure, neuroprotective EPO augmenting genetic determinants such as the various hemoglobinopathies, and the angiotensin converting enzyme (ACE) I/D polymorphism, have been positively selected. When malarial and other cerebral threats abate and the young child survives to adulthood, EPO subsides. Sustained high ACE and angiotensin II (Ang II) levels through the ACE D allele in adulthood may then become detrimental as witnessed by epidemiological studies. The ubiquitous renin angiotensin system (RAS) influences the α-klotho/fibroblast growth factor 23 (FGF23) circuitry, and both are interconnected with EPO. Here we propose that at a young age, EPO augmenting genetic determinants through ACE D allele elevated Ang II levels in some or HbE/beta thalassemia in others would increase EPO levels and shield against coronavirus disease 2019, akin to protection from malaria and dengue fever. Human evolution may use ACE2 as a "bait" for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to gain cellular entry in order to trigger an ACE/ACE2 imbalance and stimulate EPO hypersecretion using tissue RAS, uncoupled from hemoglobin levels. In subjects without EPO augmenting genetic determinants at any age, ACE2 binding and internalization upon SARS-CoV-2 entry would trigger an ACE/ACE2 imbalance, and Ang II oversecretion leading to protective EPO stimulation. In children, low nasal ACE2 Levels would beneficially augment this imbalance, especially for those without protective genetic determinants. On the other hand, in predisposed adults with the ACE D allele, ACE/ACE2 imbalance, may lead to uncontrolled RAS overactivity and an Ang II induced proinflammatory state and immune dysregulation, with interleukin 6 (IL-6), plasminogen activator inhibitor, and FGF23 elevations. IL-6 induced EPO suppression, aggravated through co-morbidities such as hypertension, diabetes, obesity, and RAS pharmacological interventions may potentially lead to acute respiratory distress syndrome, cytokine storm and/or autoimmunity. HbE/beta thalassemia carriers would enjoy protection at any age as their EPO stimulation is uncoupled from the RAS system. The timely use of rhEPO, EPO analogs, acetylsalicylic acid, bioactive lipids, or FGF23 antagonists in genetically predisposed individuals may counteract those detrimental effects.

Age and genotype dependent erythropoietin protection in COVID-19

The Malaria-High Blood Pressure Hypothesis: Revisited.

Despite clinical and pathological distinctions between malaria and hypertension, accumulated epidemiological and evolutionary evidence indicate the need of deeper understanding how severe malaria contributes to elevated hypertension risk. Malaria is said to exert strong selection pressure on the host genome, thus selecting certain genetic polymorphisms. Few candidate polymorphisms have also been reported in the RAS (ACE I/D and ACE2 rs2106809) that are shown to increase angiotensin II (ang II) levels in a combinatorial manner. The raised ang II has some antiplasmodial actions in addition to protecting against severe/cerebral malaria. It is hypothesized that RAS polymorphisms may have been naturally selected over time in the malaria-endemic areas in such a way that hypertension, or the risk thereof, is higher in such areas as compared to non-malaria endemic areas. The purpose of this review is to gain deeper insights into various sparse evidence linking malaria and hypertension and suggesting a way forward.

Evolutionary trilogy of malaria, angiotensin II and hypertension: deeper insights and the way forward.

In malaria-endemic countries, the burden of hypertension is on the rise. Although malaria and hypertension seem to have no direct link, several studies in recent years support their possible link. Three bioactive molecules such as angiotensin II (Ang II), bradykinin (BK) and sphingosine 1-phosphate (S1P) are crucial in regulating blood pressure. While the increased level of Ang II and S1P are responsible for inducing hypertension, BK is arthero-protective and anti-hypertensive. Therefore, in the present review, based on available literatures we highlight the present knowledge on the production and bioavailability of these molecules, the mechanism of their regulation of hypertension, and patho-physiological role in malaria. Further, a possible link between malaria and hypertension is hypothesized through various arguments based on experimental evidence. Understanding of their mechanisms of blood pressure regulation during malaria infection may open up avenues for drug therapeutics and management of malaria in co-morbidity with hypertension.

Malaria link of hypertension: a hidden syndicate of angiotensin II, bradykinin and sphingosine 1-phosphate.

Background: The use of malaria infection prevalence among febrile patients is a valuable epidemiological surveillance tool. In this study, a cross sectional study was conducted among febrile patients in selected government Hospitals in Ondo State for malaria prevalence. Results: Plasmodium falciparum is the only encountered malaria parasite with prevalence values of 82.72% (426/515) and 80.19% (413/515) were obtained for microscopy and RDTs respectively. The prevalence of malaria among the males (86.59%) was higher than the females (80.65%), all age groups in this study were vulnerable with highest infection rate of 89.66% among age group 11-20 years. The parasites densities ranged between 209 and 22310 parasites/μl with a mean parasitaemia of 5522.17 ± 183.30 parasites/μl. The prevalence of malaria among the febrile participants that have taken antimalarial drug before visiting the hospital is 82.94% (389/469) with the mean parasitaemia of 4615.21 ± 188.14 parasites/μl while among the participants that have taken herbs before visiting the hospital the prevalence is 85.03% (142/167) with the mean parasitaemia of 4913.81 ± 330.20 parasites/μl. Conclusion: There was high prevalence of malaria among febrile patients and this fi nding will help improve the diagnosis and treatment of other febrile (non-malaria) infections, limit antimalarial usage to only malaria parasite-based test true positives and serve as a guide to combat malaria drug resistance in the study area.

https://www.scireslit.com/PublicHealth/AJEPH-ID40.pdf

Prevalence of Malaria among Febrile Patients attending Government Hospitals in Ondo State, South-West Nigeria

Background: Peptides of the renin angiotensin aldosterone system (RAAS) have been implicated in the pathogenesis of malaria infection; however, available data are limited. Thus, this study was aimed at determining the association between hypertension and activity of angiotensin converting enzyme (ACE) in malaria patients attending Sheikh Muhammad Jiddah General Hospital, Kano State, Nigeria. Materials and Methods: Four hundred and fifty consenting adults (300 malaria positive and 150 control participants) were evaluated. Data on sociodemographic characteristics were obtained using a questionnaire. ACE level was determined as described by Cushman and Cheung (1971) and blood pressure (BP) was evaluated using standard methods. Statistical Analysis: ACE activity and BP were expressed as mean ± SEM. Comparison between groups was carried out using one-way analysis of variance. Pearson's Chi-square (χ2) test was employed to establish association between Plasmodium infection, hypertension, sex, age, educational, and occupational status. P <0.05 was regarded as statistically significant. Results: A total of 300 (66.6%) patients tested positive for malaria, of which 60 (20%) were hypertensive. The prevalence differed significantly by gender, age group, and occupational status. The serum ACE activity was significantly lower in male (1.54 ± 1.04 μmol/min/ml) and female (2.01 ± 1.29 μmol/min/ml) patients with malaria compared to controls (7.09 ± 2.42 and 7.48 ± 2.42 μmol/min/ml, for males and females, respectively); and this further decreased with severity of infection. Moreover, the ACE activity of malaria patients with hypertension (11.67 ± 0.5 and 10.60 ± 0.40 μmol/min/ml) was significantly higher than nonhypertensive (3.20 ± 1.31 and 3.16 ± 0.74 μmol/min/ml) male and female patients, respectively. Conclusions: There was a significant association between the activity of ACE and hypertension in malaria infection, showing that ACE might play a significant role in the outcome of malaria.

Association of hypertension and activity of angiotensin converting enzyme in malaria patients attending Sheik Muhammad Jidda General Hospital, Kano State, Nigeria

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Association of hypertension and activity of angiotensin converting enzyme in malaria patients attending Sheik Muhammad Jidda General Hospital, Kano State, Nigeria