INTRODUCTION
For the third time in two decades, an outbreak has been linked to the family of coronaviruses, causing a global pandemic leaving many countries in a state of despair(1). Acute respiratory syndrome coronavirus 2 (SARS-CoV2) is responsible for coronavirus 2019 (COVID-19), which became a pandemic in 2020(2). On January 7, 2020, a new coronavirus was extracted from pneumonia patients infected with the virus. In February 2020, the WHO identified the virus as the cause of COVID-19(3). Currently, RT-PCR testing for viral nucleic acid is the most common diagnostic method for COVID-19. Acute respiratory syndrome coronavirus 1 (SARS-CoV1) and SARS-CoV2—which were responsible for the SARS epidemic from 2002 to 2004, as well as the newer 2019 coronavirus (COVID-19)—all bind to the renin-angiotensin-aldosterone system (RAAS) via angiotensin-converting enzyme 2 (ACE2)(4). Patients on ACE inhibitors or angiotensin receptor blockers (ARB) could be at greater risk due to the mechanism by which SARS-CoV-2 enters the cell(5).
Clinical trials are underway to evaluate the safety and efficacy of RAAS modulators in treating COVID-19(4). The results of studies conducted so far on the role of this system in the pathophysiology of COVID-19 are diverse and contradictory and, like many other factors involved in the pathophysiology of this emerging disease, need more detailed study(6).
Often overlooked in consideration of the limited RAS, is aldosterone, which is a component of the wider RAAS. Antagonists of aldosterone have also been found to increase ACE2 levels in human macrophages. Aldosterone could be detrimental in COVID-19 infection by renal tubular actions to produce sodium retention, as well as by tissue actions, including endothelial alterations and immune system activation, resulting in pro-inflammatory actions(7).
In animal models, the use of spironolactone was an important drug in the prevention of pulmonary fibrosis. Through its dual action as a mineralocorticoid receptor (MR) antagonist and an androgenic inhibitor, spironolactone can provide significant benefits when used to treat COVID-19 infections. The primary effect of spironolactone in reducing pulmonary edema may also be beneficial in COVID-19 ARDS.
It has been shown that activation of MR in immune cells promotes the hyperinflammatory response. In macrophages, MR activation causes polarization towards the M1 pro-inflammatory phenotype. In CD4+ lymphocytes, the activation of the MR facilitates differentiation towards pro-inflammatory Th17 cells while enhancing Th17-mediated immunity influences dendritic cells’ functioning, which is crucial for immunological tolerance and homeostasis. It also induces cytotoxic IFNγ+-CD8+ T lymphocytes. This is particularly important since COVID-19 infections are characterized by a cytokine storm and hyperinflammatory state, with Th17 T cells increased and increased CD8+ cells cytotoxicity.
Large-scale epidemiological reports on COVID-19 have underlined that, apart from age and co-morbidities, additional risk factors include obesity, hypertension, and male gender, all of which have been associated with mineralocorticoid action(8). Glucocorticoids are widely used to treat various inflammatory lung diseases but are often associated with significant side effects. Published guidelines suggest that the systemic administration of low-dose, short-term glucocorticoids may be beneficial for COVID-19 patients for whom the disease progresses rapidly. However, the evidence is still limited.
In a systematic review, the efficacy and safety of glucocorticoids for the treatment of patients with COVID-19 were investigated. Twenty-three studies were reviewed, one of which was randomized controlled trial (RCT) and the other 22 of which were cohort studies. The total number of patients studied in these studies was 13,815. Studies have shown that in adults with COVID-19, the systemic use of glucocorticoids does not decrease mortality (RR= 2.00, 95% CI: 0.69 to 5.75, IU = 90.9%) or the course of lung inflammation (WMD= -1 days, 95 % CI: -2.91 to 0.91. Meanwhile, a significant decrease was observed in the duration of fevers. It was also found that systemic use of therapeutic glucocorticoids prolongs the length of hospital stay. The researchers concluded that glucocorticoid therapy reduced the duration of fever but did not reduce mortality, length of hospital stay, or absorption of lung inflammation.
The long-term use of high-dose glucocorticoids increases the risk of side effects such as co-infections. Therefore, routine use of systemic glucocorticoids is not recommended for patients with COVID-19. There are generally conflicting opinions about using glucocorticoids in the treatment of COVID-19 patients(9). ACE2 has also been shown to be expressed on adrenal gland endothelial cells. The dynamics of cortisol may have changed in patients with COVID-19. However, there are very few studies in this area.
COVID-19 may also affect the HPA axis. It has been shown that hypothalamic and pituitary tissues also express the ACE2 enzyme and, therefore, can be the target tissue of the virus. Measuring serum cortisol is one of the methods used to assess the status of the HPA activity axis and immune system activity during COVID-19(10).
Considering the importance of the HPA axis and RAAS in the pathophysiology of COVID-19, it is vital to evaluate and understand the mechanisms and systems involved in the pathophysiology of COVID-19 to better understand this disease and provide appropriate preventive and therapeutic solutions. However, diverse and sometimes contradictory results have been obtained from research on each of the mentioned factors in various previous studies. Therefore, our aim was to screen RAAS and the HPA (neuroendocrine stress) axis in COVID-19 suspicious outpatients tested for SARS-Co2 RT-PCR referred to 16-hour comprehensive health centers in Abadan.