Counter-Regulatory Hormonal and Stress Systems in Patients With COVID-19

The COVID-19 pandemic is associated with a highly variable presentation, ranging from patients who are asymptomatic or experience only mild symptoms to others with acute respiratory syndrome (ARDS) who require ventilatory support and carry a high risk of severe adverse outcomes and mortality. The most vulnerable population are older adults, usually people with chronic medical conditions and more often men than women.. Nevertheless, infection with SARS-CoV-2 can have deadly consequences even among those without any clear pre-existing medical conditions. Differences in adaptive immune responses and ensuing inflammatory reactions are proposed to contribute to the variable vulnerability to severe disease among patients infected with SARS-CoV-19. It is also possible that inter-individual differences in responsiveness of counter-regulatory hormonal and stress systems may further contribute to variable outcomes in infected patients, and that this may involve modulation of inflammatory responses. The hypothalamo-pituitary adrenal (HPA) axis in particular is a critical regulator of adaptive responses of metabolic and immune systems to various stressors, including. Sex-differences and age-related declines in adrenal cortical production of glucocorticoids and androgens as well as responsiveness of the HPA axis and immune function to stressors are particularly in older men. Such factors may contribute to the high morbidity associated with SARS-CoV-2 infection in elderly males.Among other important hormonal counter-regulatory systems, the renin angiotensin aldosterone system (RAAS) is prominently and directly impacted by SARS-CoV-2. Specifically both SARS-CoV-2 and SARS-CoV angiotensin-converting enzyme 2 (ACE2) to gain entry into cells. Tissue distrubtions of ACE2 match to viral distributions and systemic-wide impacts of SARS-CoV-2 or SARS-CoV beyond the lungs to kidneys, pancreas heart and other tissues. Studies in rats have shown that ACE2 is expressed in substantially higher amounts in alveolar epithelium, bronchiolar epithelium, endothelium and smooth muscle cells of pulmonary vessels of younger than older animals and among the latter group in higher amounts in females than males. Should the same apply to humans such differences may underly the predominance of symptomatic and more severe infections with both SARS-CoV-2 and SARS-CoV in older than younger patients, particularly male

The evidence outlined above altogether favors the possibility that inbalance of the RAAS involving upregulated ACE and and angiotensin II and downregulated ACE2 and angiotensin 1-7 might be involved in the susceptibility of SARS-CoV-2 infected patients to more severe outcomes. Given links between the RAAS and the HPA axis with inflammatory processes \[38-40\], it is also possible that alterations in adrenal steroidal systems might further contribute to the highly variable responses to SARS-CoV-2 infection. This clinical protocol will therefore examine RAAS and the HPA stress system in SARS-CoV-2 infected patients with the objective of identifying differences in these counter-regulatory hormonal and stress systems that might explain progression to more severe disease in infected patients. With this and associated patient data (e.g., age, sex, comorbidities, medications) the plan is to also include application of artificial intelligence-based machine learning approaches to develop algorithms for prognostic prediction of disease outcomes. Given the forecasted numbers of deaths and secondary impacts on health even amongst those not infected, as well as the estimated more than one trillion dollar hit to the world economy, it is clearly important to identify effective treatments that may also be relevant to possible future outbreaks resistant to vacines developed based on the current pandemic. With this in mind the associated data should better facilitate identification of disease mechanisms that underly the more severe clinical phenotypes, thereby enabling educated identification of most appropriate therapeutic approaches for successful management of infected patients. Finally there is some evidence from the earlier SARS-CoV epidemic that infection with these coronaviruses may have health consequences well beyond the acute infection stage. By long-term follow-up, that also allows for inclusion of additional patients at follow-up, this protocol will further address concerns about chronic impacts on health among patients infected with the virus.