Toward a big picture of COVID-19.

The paper aims to illustrate and explain the problems and opportunities for improvement in Covid management that become evident when taking a systems perspective. Critical time delays occurred in the regulation of the pandemic that the management cycle of political cybernetics makes explicit. In general, the executive management of the pandemic in global, regional, and national organizations was unprepared in detecting and responding to the onset of the waves and making appropriate decisions towards differential instead of general lockdowns based on available data. This was further complicated by the mutants of SARS-CoV2 that perpetuated the high dynamics of the pandemic. In addition, the diversity of medical specialisms, without appropriate big picture thinking, led to an imbalanced response that failed to appreciate the role of virology and epidemiology compared to clinical and public health-related issues. In consequence, laboratory experts suggested everyday regulations for the citizens without taking into account wider considerations for empirical research. There was an insufficient effort made for proposed treatment studies using existing agents based on the established understanding of essential physiology and the role of local and systemic chronic inflammation. In contrast, driven by media popularization, drugs that later proved beneficial were put in doubt and other drugs that lacked benefit and potentially caused harm were driven to clinical trials and utilization. Person-centered systems view backed by scientific knowledge and established data would have set better priorities. Finally, we need to take a step back and consider the Corona crisis pandemic in the context of the unidimensional utility-driven handling of natural ecosystems by the culture of industrialized countries. This ever-accelerating destruction of life spaces for species drives adaptations are the basis of zoonoses. There is strong evidence that future pandemics should be faced with a more systemic socio-ecological conceptual framework that also reflects the fatal impact of human civilization on natural ecosystems, no matter if SARS CoV2 is a zoonosis or a laboratory accident. It is critical for the future of our species that we collectively learn from this experience, address limitations in our perspectives, enhance our system-based science and bolster global, regional, and national crisis management. The impact of climate change and biodiversity loss has crossed the horizon and is now clearly in full sight.

The interacting physiology of COVID-19 and the renin-angiotensin-aldosterone system: Key agents for treatment.

SARS-CoV-2 interacting with its receptor, angiotensin-converting enzyme 2 (ACE2), turns the host response to viral infection into a dysregulated uncontrolled inflammatory response. This is because ACE2 limits the production of the peptide angiotensin II (Ang II) and SARS-CoV-2, through the destruction of ACE2, allows the uncontrolled production of Ang II. Recovery from trauma requires activation of both a tissue response to injury and activation of a whole-body response to maintain tissue perfusion. Tissue and circulating renin-angiotensin systems (RASs) play an essential role in the host response to infection and injury because of the actions of Ang II, mediated via its AT1 receptor. Both tissue and circulating arms of the renin angiotensin aldosterone system's (RAAS) response to injury need to be regulated. The effects of Ang II and the steroid hormone, aldosterone, on fluid and electrolyte homeostasis and on the circulation are controlled by elaborate feedback networks that respond to alterations in the composition and volume of fluids within the circulatory system. The role of Ang II in the tissue response to injury is however, controlled mainly by its metabolism and conversion to Ang-(1-7) by the enzyme ACE2. Ang-(1-7) has effects that are contrary to Ang II-AT1 R mediated effects. Thus, destruction of ACE2 by SARS-CoV-2 results in loss of control of the pro-inflammatory actions of Ang II and tissue destruction. Therefore, it is the response of the host to SARS-CoV-2 that is responsible for the pathogenesis of COVID-19.

The Lung, the Heart, the Novel Coronavirus, and the Renin-Angiotensin System; The Need for Clinical Trials.

Angiotensin-converting enzyme 2 (ACE2) is the receptor for COVID-19 (SARs-CoV-2). ACE2 protects the lung and heart from acute respiratory distress syndrome (ARDS) and acute myocarditis and arrhythmias, because it breaks down Angiotensin II, which has inflammatory effects in the lung and heart as well as in the kidney. When SARS-CoV-2 binds to ACE2, it suppresses it, so this protective action of ACE2 is lost. Death from COVID-19 is due to ARDS and also heart failure and acute cardiac injury. Drugs that prevent the inflammatory actions of Angiotensin II (i.e., Angiotensin receptor blockers, ARBs) prevent acute lung injury caused by SARS-CoV. Clinical trials are underway to test the risks and benefits of ARBs and angiotensin-converting enzyme inhibitors (ACEIs) in COVID-19 patients requiring hospitalization. Other potential treatments are also discussed.