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Cortisol is a key element in acute stress including a severe infection. However, in coronavirus-associated disease, 20% of subjects experience hypocortisolemia due to direct or immune damage of pituitary and adrenal glands. One extreme form of adrenal insufficiency is found in 2∕3 of cases with viral and post-viral adrenal infarction (AI) (with∕without adrenal hemorrhage) that is mostly associated with a severe coronavirus disease 2019 (COVID-19) infection; it requires prompt glucocorticoid intervention. Some reports are incidental findings at computed tomography (CT)∕magnetic resonance imaging (MRI) scans for non-adrenal complications like pulmonary spreading and others are seen on post-mortem analysis. This is a review of PubMed-accessible, English papers focusing on AI in addition to the infection, between March 1, 2020 and November 1, 2021. Exclusion criteria were acute adrenal insufficiency without the histopathological (HP) and∕or imaging report of adrenal enlargement, necrosis, etc., respective adrenal failure due to pituitary causes, or non-COVID-19-related adrenal events. We identified a total of 84 patients (different levels of statistical evidence), as follows: a retrospective study on 51 individuals, two post-mortem studies comprising nine, respectively 12 patients, a case series of five subjects, seven single-case reports. HP aspects include necrosis associated with ischemia, cortical lipid degeneration (+/- focal adrenalitis), and infarcts at the level of adrenal cortex, blood clot into vessels, acute fibrinoid necrosis in arterioles and capsules, as well as subendothelial vacuolization. Collateral potential contributors to adrenal damage are thrombotic events, coagulation anomalies, antiphospholipid syndrome, endothelial dysfunction, severe COVID-19 infection with multiorgan failure, etc. Clinical picture is variable from acute primary adrenal insufficiency to asymptomatic or mild evolution, even a retrospective diagnostic; it may be a part of long COVID-19 syndrome; glucocorticoid therapy for non-adrenal considerations might mask cortisol deficient status due to AI∕hemorrhage. Despite its rarity, the COVID-19-associated AI/hemorrhage represents a challenging new chapter, a condition that is essential to be recognized due to its gravity since prompt intervention with glucocorticoid replacement is lifesaving.

Major depressive disorder (MDD) is beyond doubt a common, disabling, and costly condition. MDD associates hypothalamic-pituitary-adrenal (HPA) axis alterations. We sought to investigate two candidate variants which could have a role in the genetic susceptibility for stress or corticoid-induced MDD: glucocorticoid receptor (GR) - nuclear receptor subfamily 3 group C member 1 (NR3C1) rs41423247 and brain-derived neurotrophic factor rs6265 BDNF:c.442GA Val66Met. We enrolled 82 Romanian subjects, 1:2 male to female ratio, 53.54±8.98 years old, diagnosed with an episode of major depression at the Clinical Neuropsychiatry Hospital in Craiova, Romania, and 286 healthy controls, 34.28±16.34 years old. All subjects were genotyped using specific ThermoFisher Scientific assays on a ViiA™ 7 real-time polymerase chain reaction (PCR) system. The impact of certain genetic variants may be ethnic-specific. In our Romanian cohort, rs41423247 NR3C1:c.1184+646CG has a minor allele frequency of 29.2%, and rs6265 BDNF:c.442GA of 22.2%. Neither reached significance in our study, under any of the association models - dominant, recessive, or allelic. Interpretation of our negative findings requires caution: literature provides arguably more evidence for the association between the analyzed polymorphisms; our study has sample size challenges, from which refined phenotyping limitations derive.