The special issue of Neuroimmunomodulation on “COVID-19, Hormones and Brain” collects five comprehensive reviews on main topics of neuroendocrine immunology in the course of COVID-19. Durcan and colleagues reviewed the detrimental consequences of the virus on the hypothalamic-pituitary-adrenal (HPA) axis, reporting clinical, laboratory, and anatomical findings of early hypercortisolism and later hypo-cortisolism in COVID-19 [1]. Inflammatory response of the host is early triggered by SARS-CoV-2, resulting in activation of the HPA axis and production of endogenous cortisol. The authors analyzed different tests for the assessment of the HPA axis: basal adrenocorticotropic hormone (ACTH) and basal cortisol measurements, low-dose (1 μg) ACTH stimulation test, high-dose (250 μg) ACTH stimulation test, glucagon stimulation test, and insulin tolerance test [1]. Weighing the pros and cons, Duncan and colleagues suggest using basal cortisol measurements or low-dose ACTH stimulation test to identify cortisol insufficiency in COVID-19 patients, a clinical condition that is associated with an increased mortality [1].

Exogenous glucocorticoids have been widely used in the treatment of COVID-19, but their use should be reserved for patients with acute systemic inflammatory forms (cytokine storm) and for COVID-19 survivors who develop an adrenal insufficiency because of the disruption of the HPA axis [2]. In this case, glucocorticoids play the role of a “replacement therapy,” as already demonstrated in chronic inflammatory diseases [3].

The control of the inflammatory response is also the object of the review by Mubashshir and colleagues [4], who analyzed the role of melatonin supplementation in COVID-19 patients. Melatonin is usually classified as a pro-inflammatory hormone as it activates the circadian inflammatory response during the night [5]. However, melatonin can reduce the binding between SARS-CoV-2 and its main cellular receptor ACE-2, blocking angiotensin II activation (pro-inflammatory and pro-fibrotic) and promoting angiotensin 1–7 production (anti-inflammatory and anti-fibrotic) [4]. Moreover, melatonin can downregulate calmodulin, a protein that promotes the expression of ACE-2 on the surface of host cells. At last, anti-inflammatory (reduction of activation of NLRP3 inflammasome) and antioxidant (activation of catalase, superoxide dismutase, glutathione peroxidase) effects of melatonin have been reported, suggesting an ancillary role in the therapeutic management of COVID-19 patients, even if randomized placebo-controlled clinical trials are lacking [4].

Existing evidence supporting a neuroprotective role of vitamin D in the course of COVID-19 was collected by our research group in a review [6]. Vitamin D supplementation is another ancillary therapy that has been proposed against COVID-19 since the early phases of the pandemic [7]. Vitamin D is a secosteroid that plays immunoregulatory functions, downregulating activation of innate immunity (monocytes/macrophages, dendritic cells), and promoting anti-inflammatory activation of adaptive immunity (downregulation of Th1, Th17, and B cells with a prevalent Th2 response), reducing stimulation of the NF-kB pathway [7]. With regard to neuroprotection, vitamin D not only reduces the systemic inflammatory burden that damages the blood-brain barrier but also downregulates the expression of blood-brain barrier adhesion molecules and the release of pro-inflammatory cytokines by reactive astrocytes. Moreover, vitamin D promotes oligodendrogenesis, release of neurotrophic factors (i.e., brain-derived neurotrophic factor and nerve growth factor), and shift of microglial cells from M1 pro-inflammatory to M2 anti-inflammatory phenotype [6].

Furthermore, Joaquim and colleagues reviewed neurological manifestations of COVID-19 that included deficits in executive/visuospatial functions (i.e., rapid visual attention, immediate recall, information processing speed), working memory, verbal learning, language, orientation, and abstraction [8]. Interestingly, the authors highlighted how cognitive impairment was not linked only to the acute phase of SARS-CoV-2 infection. However, cognitive dysfunctions frequently occurred in COVID-19 survivors, even in the absence of predisposing risk factor, becoming part of the characteristic symptoms of long-COVID [9].

At last, also Karkala and colleagues [10] reviewed mechanisms of SARS-CoV-2 neuropsychiatric damage, focusing on COVID-19-related sleep and mental pathologies (i.e., new-onset psychosis). Sleep disorders (insomnia in sleep onset, maintenance, and nocturnal awakening) were reported in up to 75% of COVID-19 patients and were aggravated in patients suffering from respiratory distress [10]. SARS-CoV-2 can directly infect epithelial cells of the olfactory bulb that express ACE2 and astrocytes that express neuropilin-1 (another surface receptor for the virus). Astrocyte damage results in reduced production of lactate and glutamine, which is detrimental to the survival of neurons and the plasticity of synapses, leading to the aforementioned sleep disorders and neuropsychiatric consequences [10].

In conclusion, the current special issue of Neuroimmunomodulation underlines the interconnections between SARS-CoV-2 infection, reactive inflammation, as well as endogenous hormone production and brain networks, with important highlights and less considered aspects for clinical and therapeutic management of COVID-19 patients.

The authors are members of the European Alliance of Associations for Rheumatology (EULAR) Study Group on Neuro Endocrine Immunology of the Rheumatic Diseases (NEIRD) and thank it for the continuous cultural support.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

M.C. conceptualized the structure of the manuscript, wrote the paper, and critically reviewed the final version. E.G. collected data and co-wrote the paper. Both the authors approved the current version of the manuscript.

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