*1.3. COVID-19 and Inflammation in the Elderly*

Inflammation is a complex and multifactorial phenomenon that involves several trigger mechanisms. An inflammatory state underlies a wide variety of diseases, pain, stress, and depression, and an exacerbated inflammatory response may drive the deleterious consequences of the infection [9,10].

Since pre-existing chronic inflammatory conditions such as hypertension, diabetes, obesity, cardiovascular disease, as well as autoimmune diseases also activate the RAS pathway, COVID-19 patients show a significant association between ACE2 deficiency and the clinical severity of these comorbidities. In addition, a decrease in ACE2 expression with age has clinical implications for the poor prognosis of elderly COVID-19 patients. Since the ACE2 gene is located on the X chromosome, the high male mortality rate in COVID-19 patients has been hypothesized to be related to the lower levels of ACE2 gene expression in male patients, so much so that the restoration of SARS-CoV-2-induced RAS imbalance has been suggested as an ideal clinical approach to slow the early progression of COVID-19 pathogenesis [11]. In addition, IL-6, which is one of the cytokines most expressed in the COVID-19 patient, is a multi-effective cytokine with both anti-inflammatory and pro-inflammatory roles. Elevated IL-6 level in COVID-19 patients is a predictor of higher mortality rates [10]. Moreover, IL-6 has been reported to facilitate CD147 expression [12].

In general, proinflammatory cytokines increase the expression of cell adhesion molecules on the surface of neutrophils and endothelial cells. This promotes intercellular interactions. Furthermore, the increased permeability of the pulmonary endothelium and the reduction in barrier protection attracts more neutrophils to the site of infection through endothelial penetration. Such dysregulation of the inflammatory immune response prevents the activation of the adaptive immune response [13,14].

In this perspective, it is very important to characterize the host–pathogen relationship, including immunoprotection correlates, such as COVID-19 virus-specific antibodies that limit disease and correlates of immune dysregulation, such as overproduction of cytokines that can promote disease.

It is known that a patient in old age suffers stressogenic conditions, both those linked to the action of the virus and those attributable to the awareness of the pathology, as well as the physiological conditions linked to the elderly state. Due to an age-altered immune system but also from rather frequent nutritional deficiencies, elderly people are particularly exposed to the risk of infection [15]. In addition, studies reported that visceral fat increases with age, and visceral fat inflammation increases the risk of COVID-19- related complications [16,17].

The semeiology of infections is sometimes atypical in the elderly and the signs and symptoms appear more discreetly than in young adults, leading to diagnostic and therapeutic delay that further aggravates the prognosis of infectious diseases in elderly patients.

Innate immunity serves at the first line of antiviral defence and the largest number of immune cells reside in the intestinal system. However, impaired immune responses in the elderly are responsible for many diseases, as well as increased susceptibility to infections. The response to COVID-19 includes various innate and adaptive traits, such as changes in the composition of dendritic cells and B cells and deeply altered T cell phenotypes that could impair immunoprotective T cells immunity [18]. Recent studies have highlighted the role of adaptive immunity like T cells and B cells in COVID-19. Laing et al. [18] showed reduced T cell immunity in COVID-19 patients. It has been suggested that immunological interventions targeting early predictive inflammatory markers would be more beneficial than those that block the late cytokine-related storm and therefore, very importantly, personalized therapeutic intervention would be required for each patient. Yet, an excessive quantity of neutrophils is associated with the course and severity of COVID-19 [19,20].

Recognition of pathogen-associated molecular patterns (PAMPs) by host pattern recognition receptors (PRRs) is the first step in activating the innate immune system against viral infection. These receptors include, among others, nucleotide-binding oligomerization

domain-like receptors (NODs), and toll-like receptors (TLRs). This virus-derived PAMP recognition by innate immune receptors activates a series of signalling cascades that ultimately lead to the activation of transcription factors such as nuclear factor-kappa B (NF-kB) and interferon regulatory factors.

COVID-19 patients show general lymphopenia, which is a significant reduction in the overall number of circulating lymphocytes in the blood [21]. In contrast, the monocytemacrophage system is significantly upregulated by SARS-CoV-2 infection. In general, monocytes are innate immune cells that participate in inflammatory responses, phagocytosis, antigen presentation, and a variety of other immune processes. Circulating monocytes pour into peripheral tissues to differentiate into macrophages or dendritic cells during inflammation. Thus, the upregulation of monocytes by SARS-CoV-2 infection may contribute to the improvement of proinflammatory processes. Neutrophils are also recruited to the site of infection through the circulation and permeabilization of the endothelial membranes adjacent to the site of infection [1–3]. However, due to lymphopenia, COVID-19 patients are more vulnerable to microbial infection. It has been speculated that the inability to eradicate SARS-CoV-2 infection due to its innate immune response antagonism hyper-inflates the innate immune system. This causes an excessive release of inflammatory cytokines to compensate for the depletion of the immune system due to SARS-CoV-2-induced lymphopenia. Finally, the overproduction of cytokines increases the membrane permeability of the capillary walls around the infected alveoli, causing pulmonary oedema, dyspnoea and hypoxemia. The introduction of plasma fluid into the alveoli as well as the loss of elasticity due to the reduced production of surfactant cause complications.

Importantly, SARS-CoV-2 primarily enters through the respiratory tract to infect humans, but it can also enter through the gastrointestinal tract [22].
