Study Status: Completed
Recruit Status: Completed
Study Type: Interventional
Official Title: Counter-Regulatory Hormonal and Stress Systems in Patients With COVID-19
Brief Summary: 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 [1]. Presence of hypertension in particular, but also diabetes and coronary heart disease have been consistently identified as comorbidities associated with poor prognosis [2]. 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 [3,4]. 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 [5-7]. The hypothalamo-pituitary adrenal (HPA) axis in particular is a critical regulator of adaptive responses of metabolic and immune systems to various stressors, including [8-10]. 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 [11-13]. 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 [14]. The enzyme is located on cellular membranes of a wide range of tissues from oral mucosa, airway epithelia and pulmonary alveolar cells, kidney, enterocytes of the small intestine, beta cells of the endocrine pancreas, bladder, heart, vascular endothelium and certain cells in the central nervous system [15-18]. 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 [19].
ACE2 can also be measured in the circulation where it is found in increased plasma concentrations in hypertension, diabetes and kidney disease as well as sex specific correlations with its different genetic variants [20,21]. 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 [22]. 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 males.The above may seem counter-intuitive since it might seem that as a vehicle for cellular viral entry, increased expression of ACE2, would act to facilitate infection. Indeed, this has been proposed, also providing the basis for concerns and controversy about use of antihypertensive drugs that increase expression of ACE2 [23-25]. However, ACE2 has opposing actions to ist better known homologue angiotensin converting enzyme (ACE), which converts angiotensin I to angiotensin II. Specifically, ACE2 functions as a counter-regulatory component of the RAAS by metabolizing the vasoconstrictor, angiotensin II, to angiotensin 1-7. Angiotension 1-7, which can also be formed from sequential respective actions of ACE2 and ACE on angiotensin I and angiotensin1-9, is a vasodilator with organ-protective properties that oppose the actions of angiotensin II [25]. From studies of SARS-CoV in mice it has been determined that SARS coronovirus-induced lung injury is associated with reduced expression of ACE2; furthermore, both recombinant ACE2 and blocking angiotensin II type 1a receptors protect against lung injury, whereas ACE and angiotensin II promote SARS conovirus induced lung injury [26,27]. There is also abundant experimental evidence and some clinical support indicating that both ACE and angiotensin 1-7 have protective actions in a range of clinical conditions and associated pathologies such as diabetes, cardiovascular, kidney and respiratory diseases