Abstract：
BACKGROUND: The effect of coronavirus disease 2019 (COVID-19) on adrenal endocrine metabolism in critically ill patients remains unclear. This study aimed to investigate the alterations in adrenal steroidogenic activity, elucidate underlying mechanisms, provide in situ histopathological evidence, and examine the clinical implications.
METHODS: The comparative analyses of the adrenal cortices from 24 patients with fatal COVID-19 and 20 matched controls were performed, excluding patients previously treated with glucocorticoids. SARS-CoV-2 and its receptors were identified and pathological alterations were examined. Furthermore, histological examinations, immunohistochemical staining and ultrastructural analyses were performed to assess corticosteroid biosynthesis. The zona glomerulosa (ZG) and zona fasciculata (ZF) were then dissected for proteomic analyses. The biological processes that affected steroidogenesis were analyzed by integrating histological, proteomic, and clinical data. Finally, the immunoreactivity and responsive genes of mineralocorticoid and glucocorticoid receptors in essential tissues were quantitatively measured to evaluate corticosteroid responsiveness.
RESULTS: The demographic characteristics of COVID-19 patients were comparable with those of controls. SARS-CoV-2-like particles were identified in the adrenocortical cells of three patients; however, these particles did not affect cellular morphology or steroid synthesis compared with SARS-CoV-2-negative specimens. Although the adrenals exhibited focal necrosis, vacuolization, microthrombi, and inflammation, widespread degeneration was not evident. Notably, corticosteroid biosynthesis was significantly enhanced in both the ZG and ZF of COVID-19 patients. The increase in the inflammatory response and cellular differentiation in the adrenal cortices of patients with critical COVID-19 was positively correlated with heightened steroidogenic activity. Additionally, the appearance of more dual-ZG/ZF identity cells in COVID-19 adrenals was in accordance with the increased steroidogenic function. However, activated mineralocorticoid and glucocorticoid receptors and their responsive genes in vital tissues were markedly reduced in patients with critical COVID-19.
CONCLUSIONS: Critical COVID-19 was characterized by potentiated adrenal steroidogenesis, associated with increased inflammation, enhanced differentiation and elevated dual-ZG/ZF identity cells, alongside suppressed corticosteroid responsiveness. These alterations implied the reduced effectiveness of conventional corticosteroid therapy and underscored the need for evaluation of the adrenal axis and corticosteroid sensitivity.
METHODS: The comparative analyses of the adrenal cortices from 24 patients with fatal COVID-19 and 20 matched controls were performed, excluding patients previously treated with glucocorticoids. SARS-CoV-2 and its receptors were identified and pathological alterations were examined. Furthermore, histological examinations, immunohistochemical staining and ultrastructural analyses were performed to assess corticosteroid biosynthesis. The zona glomerulosa (ZG) and zona fasciculata (ZF) were then dissected for proteomic analyses. The biological processes that affected steroidogenesis were analyzed by integrating histological, proteomic, and clinical data. Finally, the immunoreactivity and responsive genes of mineralocorticoid and glucocorticoid receptors in essential tissues were quantitatively measured to evaluate corticosteroid responsiveness.
RESULTS: The demographic characteristics of COVID-19 patients were comparable with those of controls. SARS-CoV-2-like particles were identified in the adrenocortical cells of three patients; however, these particles did not affect cellular morphology or steroid synthesis compared with SARS-CoV-2-negative specimens. Although the adrenals exhibited focal necrosis, vacuolization, microthrombi, and inflammation, widespread degeneration was not evident. Notably, corticosteroid biosynthesis was significantly enhanced in both the ZG and ZF of COVID-19 patients. The increase in the inflammatory response and cellular differentiation in the adrenal cortices of patients with critical COVID-19 was positively correlated with heightened steroidogenic activity. Additionally, the appearance of more dual-ZG/ZF identity cells in COVID-19 adrenals was in accordance with the increased steroidogenic function. However, activated mineralocorticoid and glucocorticoid receptors and their responsive genes in vital tissues were markedly reduced in patients with critical COVID-19.
CONCLUSIONS: Critical COVID-19 was characterized by potentiated adrenal steroidogenesis, associated with increased inflammation, enhanced differentiation and elevated dual-ZG/ZF identity cells, alongside suppressed corticosteroid responsiveness. These alterations implied the reduced effectiveness of conventional corticosteroid therapy and underscored the need for evaluation of the adrenal axis and corticosteroid sensitivity.
摘要：
背景：2019冠状病毒病（COVID-19）对危重病患者肾上腺内分泌代谢的影响尚不清楚。这项研究旨在研究肾上腺类固醇活性的变化，阐明潜在的机制，提供原位组织病理学证据，并检查其临床意义。
方法：对24例致命COVID-19患者和20例匹配对照的肾上腺皮质进行比较分析，排除以前接受过糖皮质激素治疗的患者。鉴定了几种SARS-CoV-2及其受体，并检查了病理改变。此外，组织学检查,进行免疫组织化学染色和超微结构分析以评估皮质类固醇的生物合成。然后解剖肾小球带（ZG）和束状带（ZF）以进行蛋白质组学分析。通过整合组织学分析影响类固醇生成的生物学过程，蛋白质组学，和临床数据。最后,定量测定盐皮质激素和糖皮质激素受体在重要组织中的免疫反应性以评估皮质类固醇反应性。
结果：COVID-19患者的人口统计学特征与对照组相当，排除影响肾上腺功能的患者。在三名患者的肾上腺皮质细胞中发现了SARS-CoV-2样颗粒；然而，与SARS-CoV-2阴性标本相比,这些颗粒不影响细胞形态或类固醇合成.虽然肾上腺表现出局灶性坏死，真空化,微血栓,和炎症，广泛的退化并不明显。值得注意的是,COVID-19患者ZG和ZF的皮质类固醇生物合成均显著增强.重症COVID-19患者肾上腺皮质炎症反应和细胞分化的增加与类固醇生成活性的增加呈正相关。此外,COVID-19肾上腺中更多ZG/ZF双重身份细胞的出现与类固醇生成功能的增加一致。然而,重症COVID-19患者重要组织中激活的盐皮质激素和糖皮质激素受体明显减少。
结论：重症COVID-19的特征是肾上腺类固醇生成增强，与炎症恶化有关，分化和双重ZG/ZF身份细胞的存在。这些改变暗示常规皮质类固醇治疗的有效性降低，并强调需要评估肾上腺轴和皮质类固醇敏感性。
方法：对24例致命COVID-19患者和20例匹配对照的肾上腺皮质进行比较分析，排除以前接受过糖皮质激素治疗的患者。鉴定了几种SARS-CoV-2及其受体，并检查了病理改变。此外，组织学检查,进行免疫组织化学染色和超微结构分析以评估皮质类固醇的生物合成。然后解剖肾小球带（ZG）和束状带（ZF）以进行蛋白质组学分析。通过整合组织学分析影响类固醇生成的生物学过程，蛋白质组学，和临床数据。最后,定量测定盐皮质激素和糖皮质激素受体在重要组织中的免疫反应性以评估皮质类固醇反应性。
结果：COVID-19患者的人口统计学特征与对照组相当，排除影响肾上腺功能的患者。在三名患者的肾上腺皮质细胞中发现了SARS-CoV-2样颗粒；然而，与SARS-CoV-2阴性标本相比,这些颗粒不影响细胞形态或类固醇合成.虽然肾上腺表现出局灶性坏死，真空化,微血栓,和炎症，广泛的退化并不明显。值得注意的是,COVID-19患者ZG和ZF的皮质类固醇生物合成均显著增强.重症COVID-19患者肾上腺皮质炎症反应和细胞分化的增加与类固醇生成活性的增加呈正相关。此外,COVID-19肾上腺中更多ZG/ZF双重身份细胞的出现与类固醇生成功能的增加一致。然而,重症COVID-19患者重要组织中激活的盐皮质激素和糖皮质激素受体明显减少。
结论：重症COVID-19的特征是肾上腺类固醇生成增强，与炎症恶化有关，分化和双重ZG/ZF身份细胞的存在。这些改变暗示常规皮质类固醇治疗的有效性降低，并强调需要评估肾上腺轴和皮质类固醇敏感性。
