Unraveling the relationship between ACTH and cortisol levels in COVID-19 infections: A meta-analysis

This systematic review was conducted in accordance with the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) (S1 Checklist. PRISMA 2020 checklist.) [11]. We searched multiple databases including PubMed, Web of Science, Embase, and Cochrane Library, without any language restrictions, from their earliest inception until May 2023. Our search strategy included the use of keywords and Medical Subject Headings (MeSH) terms related to “COVID-19” or “SARS-CoV-2”, “ACTH”, and “cortisol”. In addition, we conducted manual cross-referencing of the included articles to supplement the electronic search. The full-text articles were independently reviewed and duplicates were eliminated to ensure eligibility. Any discrepancies between reviewers were resolved through consensus. By following the PRISMA guidelines, we aimed to ensure the quality and transparency of our systematic review and meta-analysis.

To evaluate the quality of the selected studies, we employed the Newcastle-Ottawa Quality Assessment Scale (NOS) [12]. This scale assesses each study across three dimensions: selection, comparability, and exposure, with a total possible score ranging from 0 to 9. Studies achieving NOS scores of 6 or higher were deemed to be of high quality [12]. The NOS score of each study is presented in Table 1.

We conducted an initial search across four databases and retrieved a total of 287 articles published up until May 2023 (as illustrated in Fig 1). Following the removal of duplicate articles, 158 papers were assessed based on their titles and abstracts. The full text of the remaining 90 articles was then reviewed for eligibility for inclusion in our meta-analyses, resulting in the exclusion of 81 articles for reasons such as being case reports, abstracts, letters, or editorials. Finally, nine studies that met our inclusion criteria were selected for analysis, and Table 1 summarizes the key characteristics of these studies [13–21]. Fig 1 provides a visual depiction of the number of articles included and excluded at each stage of our evaluation process, together with the reasons why certain studies were excluded. Overall, the combination of Fig 1 and Table 1 provides readers with a comprehensive understanding of our evaluation process and the studies that we ultimately included in our meta-analyses.

This meta-analysis comprised nine articles, involving a total of 914 patients. The sample sizes of the included studies ranged from 30 to 235 subjects, and their quality ratings ranged from six to nine stars. Of the included studies, seven evaluated patients with ACTH, while six evaluated patients with cortisol. Table 1 presents a concise summary of the key features of each of the studies included in this meta-analysis. All of the studies were published between 2020 and 2022 and consisted of three cohort studies, four case-control studies, and two cross-sectional study. These studies were conducted in diverse geographic locations, with three from Turkey, two from India, Iran and one each from China, and Greece.

Our meta-analysis revealed a statistically significant increase in serum cortisol concentrations among COVID-19 patients compared to controls (weighted mean difference [WMD]: 3.46; 95% confidence interval [CI]: 2.29 to 4.62) (Fig 2). The studies included in the analysis show heterogeneity (I² = 62.6%). Regarding serum ACTH concentrations, our overall analysis did not demonstrate a statistically significant difference between COVID-19 patients and controls (WMD: 1.58; 95% CI: -5.79 to 8.94) (Fig 3). The significance of these findings may suggest that COVID-19 patients experience a dysregulation in cortisol levels, which could potentially contribute to the pathophysiology and clinical manifestations of the disease. We also conducted tests for publication bias, including Begger’s test, Egger’s test (data not shown), and funnel plot analysis, and all the tests indicated the absence of publication bias (Fig 4A and 4B). Additionally, the sensitivity analyses we performed indicated the robustness of our conclusions (Fig 4C and 4D). Our findings suggest that serum cortisol levels may be elevated in COVID-19 patients, while serum ACTH concentrations may not be significantly affected. These results were consistent across different sensitivity analyses and publication bias tests, further supporting their validity.

To the best of our knowledge, this study represents the first comprehensive meta-analysis investigating the association of ACTH and cortisol levels with COVID-19 infection in humans. We identified and analyzed 9 relevant studies, which collectively included 914 patients of all ages. Our findings indicate a significant association between elevated cortisol levels, suggesting a possible mechanism underlying COVID-19 infection-induced risk in the infected patients. This is consistent with previous finding that cortisol is used for acute respiratory infections [22].

In the context of the growing evidence surrounding hormonal disturbances in COVID-19, the study by Ramezani et al. (2020) is particularly noteworthy [21]. Their research concentrated on the relationship between anxiety, cortisol levels, and COVID-19 outcomes. They discovered that patients who died from COVID-19 had significantly higher cortisol levels compared to those who recovered. Additionally, their findings revealed a positive correlation between cortisol levels and scores on the Hospital Anxiety and Depression Scale (HADS), suggesting that stress and anxiety might induce higher cortisol levels, which in turn could serve as a prognostic marker in COVID-19. This study sheds light on the intricate connection between psychological factors and physiological responses in the course of COVID-19. The stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in elevated cortisol levels, could potentially worsen inflammatory responses and affect the severity of the disease. These findings underscore the importance of incorporating psychological interventions and stress management into the comprehensive care of COVID-19 patients.

Firstly, stress levels can significantly impact metabolic, cardiovascular, and immune systems by elevating cortisol levels. Additionally, under stressful conditions, cortisol metabolism and cortisol-binding globulin (CBG) metabolism can be inhibited, leading to increased cortisol activity [23]. Additionally, elevated cortisol levels in COVID-19 patients could also be attributed to heightened stress and fear of mortality related to the pandemic [24].

Secondly, elevated cortisol levels in COVID-19 patients could be attributed to proinflammatory cytokine IL-6. Previous studies have suggested that IL-6 acts like an ACTH-like stimulus for the glucocorticoid-secreting adrenal fasciculus [25], which could result in increased cortisol secretion under prolonged stressful circumstances [26]. Researchers have also identified the expression of IL-6 and IL-6 receptors in primary cultures of human adrenal cells deficient in macrophages (CD68-positive cells), mainly in the reticular zone but also within the fascicular zone and in individual cells in the glomerular zone and medulla [27].

Our analysis found no significant differences in the circulating levels of ACTH between COVID-19 patients and controls. Interestingly, some researchers have proposed an intriguing hypothesis that suggests SARS-CoV expresses an amino acid sequence that shares molecular homology with ACTH. As a result, it may block the stress-induced cortisol response in the host by producing antibodies against ACTH [28]. These variations might be attributed to the virus’s direct impact on the HPA axis or secondary effects due to systemic inflammation [29, 30]. Such findings suggest a complex interplay between the virus and the endocrine system, impacting both the course of the disease and the patient’s response to treatment. Therefore, a nuanced understanding of ACTH levels and their implications in COVID-19 is crucial for developing effective therapeutic strategies and managing patient care more effectively.