To date no treatment protocol of proven efficacy was approved to manage COVID-19. We have developed a novel COVID-19 immunomodulatory protocol basing on our early pioneering article that justified repurposing of nitazoxanide/azithromycin combination for early cases of COVID-19 which was followed by two articles to justify addition of non-steroidal anti-inflammatory drugs to nitazoxanide/azithromycin. We are presenting a prospective telemedicine protocol that managed more than 50 documented COVID-19 patients while fully presenting a case series of 36 patients/legal guardians COVID-19 Arab patients including 12 confirmed by PCR and 23 diagnosed by other measures. The patients included 14 adult males including an immunocompromised patient, 15 adult females including one lactating, 3 pregnant patients including one confirmed by PCR as well as 4 children. All patients have received a short 5-day-regimen of NSAIDs (diclofenac potassium in most of cases, ibuprofen, lornoxicam, meloxicam, celecoxib, naproxen, ketoprofen or ketorolac)/nitazoxanide/azithromycin +/- cefoperazone either in full or in part as illustrated in the manuscript. The primary endpoint of this protocol was full relief of all serious COVID-19 clinical manifestations and it was fully achieved in all patients within two weeks. Most of the patients treated early have fully recovered during its described five days; the leucocytic/lymphocytic count was significantly improved for those with prior leucopenia/lymphopenia. No significant adverse effects were reported. A novel 5-day-protocol to safely and effectively cure COVID-19 using repurposed immunomodulatory safe and inexpensive FDA approved drugs is illustrated and we recommend performing sufficiently powered double blind randomized clinical trials against any current standard protocol.
Nucleic acid based - mRNA based and adenovirus vectored - vaccines, were first ever or first commercially ever approved for the public, respectively. However, these newly emergency approved types possess a potential risk to induce auto-immune diseases e.g., thrombocytopenia, myocarditis and immune induced thrombosis and thromboembolism that might be fatal and could reason for some of the post vaccination sudden death reports. Moreover, all SARS CoV-2 types of vaccines, depending on the spike protein immunogenicity, especially the conventional inactivated ones might increase the likelihood of COVID-19 severity upon re-infection through antibody dependent enhancement which might reason for the recently described abundance of hospital admissions within seven days of vaccination and might also reason for some of the serious adverse effects encountered with administration of convalescent plasma to COVID-19 patients as well as they might share in development of some lethal SARS CoV-2 variants. Importantly, we suggest that SARS CoV-2 mass vaccination campaigns were the worst ever decision made and that making these COVID-19 vaccines compulsory or administering them to children or pregnant participants might be considered as a crime against humanity to the extent that no prior companies- governmental agreements would ever secure impunity. Finally, a full informed personalized risk benefit ratio especially for some described high-risk groups must be secured while suggesting that the subunit vaccines are the least hazardous ones.
Nucleic acid based - mRNA based and adenovirus vectored - vaccines, were first ever or first commercially ever approved for the public, respectively. However, these newly emergency approved types possess a potential risk to induce auto-immune diseases e.g., thrombocytopenia, myocarditis and immune induced thrombosis and thromboembolism that might be fatal and could reason for some of the post vaccination sudden death reports. Moreover, all SARS CoV-2 types of vaccines, depending on the spike protein immunogenicity, especially the conventional inactivated ones might increase the likelihood of COVID-19 severity upon re-infection through antibody dependent enhancement which might reason for the recently described abundance of hospital admissions within seven days of vaccination and might also reason for some of the serious adverse effects encountered with administration of convalescent plasma to COVID-19 patients as well as they might share in development of some lethal SARS CoV-2 variants. Importantly, we suggest that SARS CoV-2 mass vaccination campaigns were the worst ever decision made and that making these COVID-19 vaccines compulsory or administering them to children or pregnant participants might be considered as a crime against humanity to the extent that no prior companies- governmental agreements would ever secure impunity. Finally, a full informed personalized risk benefit ratio especially for some described high-risk groups must be secured while suggesting that the subunit vaccines are the least hazardous ones.
A heavily updated version would be find here:https://www.authorea.com/users/318758/articles/522100-ace2-polymorphisms-reflected-on-the-immune-and-apelinergic-peptide-systems-potential-covid-19-tools-for-risk-stratification-and-therapyShort communicationThe apelinergic peptide system link with ACE2 polymorphisms: novel insights in COVID-19 managementMina T. Kelleni, MD, PhDAssistant Professor of Pharmacology, College of Medicine, Minia University, Egypt.Mobile: +201200382422drthabetpharm@yahoo.com, mina.kelleni@mu.edu.eghttps://orcid.org/0000-0001-6290-6025HighlightsACE2 polymorphisms have been previously linked to increased susceptibility to multiple diseases and are currently linked to SARS CoV-2 susceptibility and complicationsACE2 transcribed or regulated proteins including the activity of metaloproteinsase-2 and apelin-13 and 36 cleavage, might be linked to abnormal immune responses and complicationsA potential genetic or serological test might be developed to detect the higher vulnerable groups to SARS CoV-2 complications and/or mortality including health care professionalsInfusion of apelin-13 to treat critical cases of COVID-19, especially those complaining of advanced heart failure, might prove beneficialAbstract:Aiming to decrease the unexplained COVID-19 mortality in some young and otherwise healthy patients, including health care professionals, we hypothesize that ACE2 polymorphisms might be reflected through under/overexpression of ACE2 transcribed or regulated proteins including the activity of metaloproteinsase-2 and apelin-13 and 36 cleavage, leading to unexpected immune responses and complications. We might detect the higher vulnerable groups if a genetic test to detect potential associated variant ACE2 alleles, or a serological test to detect the suggested associated proteins, could be developed and linked to those cases of unexpected complications and/or mortality. Furthermore, basing on the same hypothesis, we suggest testing infusion of apelin-13 to treat critical cases of COVID-19, especially those complaining of advanced heart failure. Keywords:SARS CoV-2, COVID-19, ACE2 polymorphisms, apelin-13. Recent studies have demonstrated that the expression, polymorphism and/or mutations in the receptor binding domain of ACE2, the receptor of SARS CoV-2, could influence both the susceptibility of people and populations to SARS CoV-2 infection as well as the potential clinical manifestations and outcomes of COVID-19(Azer, 2020; Devaux, Rolain & Raoult, 2020; Hou et al., 2020; Khayat et al., 2020). As an example, a study showed that East Asian populations have a much higher  ACE2 allelic fraction in expression quantitative trait loci variants which may suggest different susceptibilities or response to SARS CoV-2 from other populations (Cao et al., 2020). Thus, thorough exploration of the relationship ACE2 polymorphisms with COVID-19 might help to save lives, especially those belonging to the minority of unexplainable complications and/or mortality of young patients, including health care professionals.  ACE2 polymorphisms and their induced mutations have been previously linked to enhanced susceptibility to heart diseases including coronary heart disease and myocardial infarction as have been revealed both clinically and experimentally(Wang et al., 2014; Yang et al., 2006). Importantly, the ACE2 rs4646188 variant was suggested as a potential and optimal genetic susceptibility marker for essential hypertension, dyslipidemia and its related ischemic stroke(Pan et al., 2018). Similarly, three other ACE2 variants (rs4240157, rs4646155, and rs4830542) were found to be associated with essential hypertension and hypertension-related atrial fibrillation and left atrial remodeling(Luo et al., 2019). Similarly, genetic variants in the ACE2 gene have been suggested to be associated with left ventricular mass, septal wall thickness and left ventricular hypertrophy in hemizygous men(Lieb et al., 2006) and genetic variants in the ACE2 gene were significantly associated with diastolic blood pressure responses to cold stress in the Chinese female population(Huang et al., 2012). Thus, ACE2 polymorphisms were logically suggested and later showed to be linked with SARS CoV-2 variable clinical manifestations and outcomes. Notably, a study showed that six out of ten eQTL variants in ACE2 have been associated with altered ACE2 tissue expression and linked with the need for hospitalization due to COVID-19, suggesting that ACE2 genotype may inform both COVID-19 risk stratification and the need for more intense therapy(Wooster, Nicholson, Sigurslid, Lino Cardenas & Malhotra, 2020). Furthermore, a significant ACE2‐mRNA expression was observed in the classical human monocyte subpopulation (CD14++CD16− cells)(Rutkowska-Zapała et al., 2015), thus, a variable immune response associated with some ACE2 variants might prove beneficial when thoroughly examined. Taken together, it is likely that ACE2 polymorphisms might explain at least some cases of the otherwise unexplained COVID-19 induced mortality encountered in some healthy adults/health care professionals(Kelleni). Moreover, several apelin peptides have been shown to inhibit human immunodeficiency virus into cells expressing the G protein coupled apelin receptor to which they act as endogenous ligands (Read et al., 2019; Zou, Liu, Haraguchi, Soda, Tatemoto & Hoshino, 2000) and apelin-13 has been shown to act as a  positive regulator of ACE2 mRNA transcription(Gheblawi et al., 2020). Similarly, it is well established that downregulation of ACE2 receptors triggers important inflammatory lesions in the respiratory tree and has been suggested to play a central role in the pathogenesis of SARS-CoV-2 infection(Verdecchia, Cavallini, Spanevello & Angeli, 2020). Moreover, a negative correlation between ACE2 expression and COVID‐19 fatality at both the population and molecular levels has been shown (Chen et al., 2020). Thus, we recommend exploring our suggested hypothesis to detect potential varian ACE2 alleles and their suggested over/underexpression or altered abnormal activity of some transcribed/regulated proteins including metallopeptidase-2 activity(Kuan et al., 2013) and apelin-13 and apelin-36 peptide cleavage (Gheblawi et al., 2020; Yang et al., 2017) wishing to develop potential genetic tests to detect variant ACE2 alleles as well as serological tests to detect the suggested abnormal levels or activities of the suggested and other associated proteins. Bronchoscopy/CT guided lung biopsies and autopsies might be considered to directly examine those markers to be compared in different groups of COVID-19 patients. Interestingly, apelin peptides were shown to ameliorate acute lung injury by several mechanisms that are also associated with COVID-19 associated acute respiratory distress syndrome(Saeedi Saravi & Beer, 2020) and apelin-13 continuous infusion at 1 mg/kg/d by an osmotic pump upregulated ACE2 expression, improved heart functions and reduced heart weight in AT1R-deficient mice under transverse aortic constriction(Sato et al., 2013) and we recommend to test apelin-13 infusion for critical cases of COVID-19, especially those complaining of advanced heart failure. Finally, we would like to recommend that the continuous exploration of this type of genetic research should never be abandoned even if a valid cure and/or vaccine has been developed, we should learn from this COVID-19 pandemic to prepare in the morning to what might newly arise before the end of the day.             Conflict of interests:The author has no conflicts of interest to declare.Funding/Financial disclosure:None.References: Azer SA (2020). COVID-19: pathophysiology, diagnosis, complications and investigational therapeutics. New Microbes and New Infections 37: 100738. Cao Y, Li L, Feng Z, Wan S, Huang P, Sun X, et al. (2020). Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discovery 6: 11. Chen J, Jiang Q, Xia X, Liu K, Yu Z, Tao W, et al. (2020). Individual variation of the SARS-CoV-2 receptor ACE2 gene expression and regulation. Aging Cell 19. Devaux CA, Rolain J-M, & Raoult D (2020). 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