ACE2 polymorphisms have been previously linked to increased susceptibility to multiple diseases and are currently linked to SARS CoV-2 susceptibility and complications. Notably, ACE2 transcribed or regulated proteins include the activity of metaloproteinsase-2 and apelin-13 and 36, might be linked to abnormal immune responses and complications. Potential genetic or serological tests might be developed to detect the higher vulnerable groups to SARS CoV-2 complications and/or mortality. Moreover, we postulate that diabetic and obese patients suffer from exhausted and/or abnormally functioning apelinergic peptides that predispose them to a higher severe COVID-19 risk. Finally, infusion of apelin-13 to treat selected critical cases of COVID-19, especially those complaining of refractory advanced heart failure, might be considered for clinical trials. 

A peer reviewed published version at Expert Review of Anti-Infective Therapy : https://doi.org/10.1080/14787210.2021.1939683IntroductionMediators of immunity and inflammation are playing a crucial role in COVID-19 pathogenesis and complications as demonstrated by several genetic and clinical studies. Moreover, a weak, irregular, or inhibited early interferon response to SARS CoV-2 infection was shown to trigger an exaggerated inflammatory response leading to the COVID-19 associated mortality. Thus, repurposing of drugs that possess anti-inflammatory and/or immune-modulatory effects for COVID-19 is considered a rational approach.Areas coveredWe present a concise analysis and interpretations of selected studies that correlated COVID-19 with dysregulated interferon and inflammatory responses while reflecting on our academic and real-life experience using non-steroidal anti-inflammatory drugs, nitazoxanide and azithromycin for management of COVID-19. Moreover, we interpret the recent results that suggested a potential survival benefit of low dose aspirin and colchicine when used for COVID-19.Expert opinionNitazoxanide/azithromycin combination has been first hypothesized by the author and practiced by him and several researchers to benefit COVID-19 patients due to a potential ability to augment the natural interferon response as well as their positive immunomodulatory effects on several cytokines. Furthermore, NSAIDs, that were unfortunately almost globally avoided early in the COVID-19 era and still avoided in many developing ones or at best of second choice in the developed ones, have been early postulated and clinically practiced by the author to prevent or ameliorate COVID-19 complications and mortality due to their ability to prevent, constrain or reverse COVID-19 associated dysregulated immune and hyper-inflammatory responses through mitigating the formation of several inflammatory cytokines and pathways including the interleukin-6 amplifier and its NF-kB component, as well as modulation of a described monocytic immunological dysrhythmia, which is also known to trigger the COVID-19 cytokine storm. Finally, we repeat our previous call to adopt our observational study that used these drugs in sufficiently powered double blind randomized clinical trials as COVID-19 potential safe and economic cure might be available and unfortunately repeatedly ignored for one year.

A document by Mina Kelleni. Click on the document to view its contents.

Multiple reports all over the world are hypothesizing a possible relationship between BCG vaccination, and a lesser incidence of and mortality from COVID-191. China is considered as one of the heavily affected countries and it was the first to report COVID-19, the author will examine this hypothesis using China as an example.According to the WHO global tuberculosis report 20192, it’s stated that in 2018, among 180 countries for which data were collected, 153 countries have properly reported administration of BCG vaccination as a standard part of childhood immunization programmes, of which 113 reported coverage of ≥90% (Figure 1). In the same report, China has accomplished a 99% BCG vaccination coverage, to be considered as one of the top countries providing this coverage rate all over the world. Moreover, the reported estimates for the global BCG coverage according to the WHO monitoring system for vaccine-preventable diseases has revealed that BCG vaccination coverage in China to be either 99% or 100% for the years 2009 to 20183. Thus, we may reasonably consider that all children, currently 10 years old or younger and living in China, are efficiently covered and immunized by BCG vaccination.Interestingly, as of the 11th of February, 2020 the Chinese Center for Disease Control and Prevention has reported 416 laboratory-confirmed pediatric cases; aged 0–9 years4. Moreover, another study, published about one month later, has researched 2143 pediatric Chinese patients who were both laboratory-confirmed as well as suspected cases, and concluded that children at all ages appeared susceptible to COVID-19 and it’s also reported that the proportion of severe and critical cases was 10.6 %, 7.3%, 4.2% for the age group of <1, 1-5, 6-10, respectively. Noteworthy, this study has suggested that the majority of COVID-19 pediatric patients were less severe in their medical condition than adults’ cases because children are usually well cared for at home and might have relatively less opportunities to expose themselves to SARS CoV-25.Thus, basing on the above analysis, the author suggests that stating that BCG vaccination could prevent COVID-19 infection should be considered as a myth. Moreover, the author considers stating that countries which have adopted childhood BCG vaccination might be the reason for a lower morbidity or mortality of COVID-19 for adults immunized at birth, should be also considered as another myth, as revealed by the incidence of adults’ morbidity and mortality rates reported in China as well as several other countries that have adopted childhood BCG vaccination. However, BCG vaccination given once a month for three consecutive months has previously showed a benefit against adult upper respiratory tract infections in the elderly6 and it might prove the same benefits against COVID-19 if administered to unimmunized adults or re-administered to previously immunized adults waiting for the results of the undergoing clinical trials7. On the other hand, BCG vaccination might or might not have some ameliorative benefits for immunized children affected by COVID-19 and this suggested positive association is highly unlikely to be properly proved because of multiple confounding factors. Finally, please keep and remain vigilant till the world finds a cure for COVID-19, this is an evidence-based medicine piece of advice.Funding:NoneConflict of interests:NoneFinancial disclosure:None

This preprint has been peer reviewed, updated and published: https://link.springer.com/article/10.1007/s42399-021-00824-4 In this manuscript, we demonstrate a personal perspective that discusses the expectations versus the real word results and outcomes of three repurposed COVID-19 drugs; tocilizumab, remdesivir and favipiravir, which resembled the well-known metaphor; the good, the bad and the ugly, respectively. We wish that this manuscript might help other colleagues to consider the risk benefit ratio before a decision is made using any of these drugs.

Currently the main idea of this manuscript has been peer reviewed, updated and published: https://link.springer.com/article/10.1007/s42399-021-00824-4 and it has been also cited thereThis manuscript has been published on the 29 th of May 2020 by the honorable BMJ as a rapid response to a related article. However since a DOI has not been assigned and two subsequent manuscripts have cited it, I'm preprinting a copy wishing it might reach all the interested colleagues and researchers in an easier way. https://www.bmj.com/content/369/bmj.m2097/rrhttps://www.youtube.com/watch?v=-g_8IguC9Lc

This preprint has been peer reviewed, updated and published: https://link.springer.com/article/10.1007/s42399-021-00824-4  On the same day the results of the RECOVERY study was published; July 17, 2020, we have submitted a letter to New England Journal of Medicine (NEJM, ID 20-25534) representing some concerns about this study and its status was with editor until November 29, 2020 on which a withdrawal request has been sent to NEJM and was promptly accepted on the following day. Notably, four emails were sent to NEJM, once every month wondering about this unprecedent delay in publishing a short letter and the response was that the editor has been contacted on multiple occasions but he/she is busy because of the large number of COVID-19 related submissions.  

The pathogenesis of Coronavirus disease 2019 is still obscure, indeed it’s only few months since it has been first reported on December 2019, yet the need for exploration of possible mechanisms, suggestion of new drugs should never be delayed. In this communication, the author proposes an integrated pathophysiological as well as pharmacological COVID-19 approach to recommend using anti-inflammatory drugs, other than glucocorticoids, suggesting ibuprofen as an example, to be added to his recently published suggested COVID-19 early management protocol. A possible explanation for the potential failure of hydroxychloroquine for COVID-19 is also explained according to the suggested concept. The author is fully aware of the ibuprofen contradictory hypothesis; as discussed and argued against in this report.

A peer-reviewed article of this Preprint also exists. Journal: InflammopharmacologyDOI:  https://doi.org/10.1007/s10787-020-00755-x This article discusses from a pharmacological point of view, the points of weakness in a correspondence published at the Lancet Respiratory Medicine that has suggested a hypothesis relating ACEIs, ARBs and ibuprofen to be associated with a higher risk for COVID-19 infection and complications. This article also explains some unfortunate mistakes that have been made by some who have adopted this hypothesis and decided to unwisely recommend against these important drugs.