Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

COVID-19: Comprehensive Synopsis of Suggested Pathophysiological Mechanisms and Repurposed Drugs

Version 1 : Received: 3 July 2020 / Approved: 7 July 2020 / Online: 7 July 2020 (02:50:55 CEST)

How to cite: Binkhorst, M.; Offringa, A.K.; van der Hoeven, J.G. COVID-19: Comprehensive Synopsis of Suggested Pathophysiological Mechanisms and Repurposed Drugs. Preprints 2020, 2020070108. Binkhorst, M.; Offringa, A.K.; van der Hoeven, J.G. COVID-19: Comprehensive Synopsis of Suggested Pathophysiological Mechanisms and Repurposed Drugs. Preprints 2020, 2020070108.


During the current COVID-19 pandemic caused by SARS-CoV-2, clinicians and scientists are working assiduously to unravel its pathophysiology and find effective treatments. An impressive number of papers has been published on SARS-CoV-2, exposing the complexity of the disease, the tendency of scientists to form hypotheses within their area of expertise, and the lack of orchestration of research. Hypotheses and research findings mainly complement each other, though sometimes controversies can be discerned among various theories and study results. Our overview aims to portray the ‘big picture’ of COVID-19, visualising the interwovenness of different pathophysiological pathways, with a focus on cytokine-induced pathology, the sequelae of ACE2 downregulation, and thrombosis associated with microvascular injury. It aids in overseeing the effects of repurposed drugs on intended targets, but also alerts to the (adverse) effects on interacting pathways. The overview shows how comorbidities probably increase susceptibility to (severe) COVID-19 and provides the possible pathophysiological origin of signs, symptoms, and biochemical abnormalities.


COVID-19; SARS-CoV-2; coronavirus; hypothesis; pathophysiology; drug repurposing


Medicine and Pharmacology, Pharmacy

Comments (4)

Comment 1
Received: 10 July 2020
Commenter: Anton Yuryev
The commenter has declared there is no conflict of interests.
Comment: Great article! We will make sure all drugs described in this review are present in Elsevier mechanistic models COVID19 describing COVID19 biology and infection cycle available at this link:
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Response 1 to Comment 1
Received: 10 July 2020
The commenter has declared there is no conflict of interests.
Comment: Thank you
Comment 2
Received: 12 July 2020
The commenter has declared there is no conflict of interests.
Comment: I would wholeheartedly like to compliment the authors with their relevant work in creating a bigger picture on the COVID-19 pathophysiology. Together with other systematic reviews, such as the excellent one of Wiersinga in JAMA July 10, this helps understanding the clinical pictures and probably enables more fruitful drug targeting.
In this bigger picture the authors rightly also mention comorbidity (as 'cardiovascular and renal disorders'), as these are probably playing a major role in determining disease severity and recovery potential (i.e. ' systemic resilience').

I would like to add two points of interest that may help to extend and clairify this bigger picture, so that it can also help to understand why older adults have the most serious COVID-19 disease trajectories.

First, also other comorbidities (e.g. obesity, COPD, diabetes), but also premorbid disabilities (e.g. cognitive decline, sarcopenia, malnutrition), and complications (e.g. delirium) are very likely to contribute to the overall pathophysiology. Moreover, aging mechanisms also interact with the immune system by mechanisms called immunosenescence and inflammaging (both via the innate and trained /adaptive immunity; see for example the special collection on COVID-19 in Aging-US and in Age& Aging; or the preprint of Mueller et al: doi: 10.20944/preprints202004.0548.v1). Without taking into account the aging mechanism and comorbidity related pathophyisology a figure, even the complex one pictured so nicely in this preprint paper, fails to clearly explain the major empirical characteristics in mortality and morbidity we now see at large scale globally. Also the focus of repurposing drugs asks for this extension, as drugs as resveratrol, and rapamycine (or other mTOR targeting drugs) may be intersting in this perspective (resveratrol is already in the graph).

Second, the methodology of developing a complex pathophysiological picture, from literature to praphics, may benefit from more formal methodology as deveoped by complexity science. In the current preprint paper it is not described how the data from the papers included (which do not seem to be part of a formal systemstic review methodology according to PRISMA guidelines) are combined in the complete interaction graph. Here, formally described and validated methodology such as 'mind mapping', 'group model building (GMB)', 'causal loop diagram (CLD) development', and 'system dynamics computational modeling' may be of great help. These methods now have a solid base in the domain called 'complexity science (see for example recent applications and descriptions of GMB and CLD in Complex systems and population health. Apostopoulos et al Oxford Univ press 2020). We succesfully applied these methods of more formally in CLD development on the domain of Alzheimer's dementia, which is now widely accepted as having a complex multifactorial pathophysiology instead of being a simple monocausal beta-amyloid related disorder (see Uleman J et al Mapping the Multicausality of Alzheimer's Disease through Group Model Building in: Geroscience 2020 In Press) .

However, these two points do not lessen my appreciation for the paper presented in this preprint, as in this pandemic we really need to join scientific insights interdisciplinary, in which this overarching graph may already be a major step forward.

Marcel Olde Rikkert, MD PhD
Professor in Geriatric Medicine
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Response 1 to Comment 2
Received: 12 July 2020
The commenter has declared there is no conflict of interests.
Comment: Dear colleague,
Thank you very much for your positive and helpful comments. Although we did mention 'aging' in the diagram, you are probably right that age-related comorbidities and processes, such as immunosenescence, deserve more attention in the delineation of SARS-CoV-2 induced pathophysiology, given the clearly increased vulnerability, morbidity, and mortality in older adults. Drugs acting on these mechanisms are indeed worthwhile considering. You are also absolutely right that we did not formally perform a systematic review according to befitting guidelines. From the first day that the WHO declared COVID-19 a pandemic, we did start collecting relevant papers on the pathophysiology of this disease by identifying peer reviewed articles and preprints on a daily basis. As can be seen on LinkedIn, it all started with an elaborate mind map created by the first author. We currently consider to update the picture with the most recent findings in the literature, this time assembled by more formal methods. However, there are two practical limitations that thwart our scientific endeavour to portray a scientifically sound and exhaustive overview: the enormous topicality of the subject matter - a systematic review performed today may already fail to include relevant contributions tomorrow - and the fact that choices have to be made in order to fit everything into one overview. Nonetheless, it would be nice to be able to update the overview once more using formal methodology and get it published after fast track peer review. Perhaps I might interest you to join us in this effort? Lastly, you are right again that we still need to enhance interdisciplinary collaboration in order to be capable of overseeing the whole picture. I would like to see more publications written by authors of diverse discliplines.

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