The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of "inflame-aging"

Abstract

Purpose: Novel Coronavirus disease 2019 (COVID-19), is an acute respiratory distress syndrome (ARDS), which is emerged in Wuhan, and recently become worldwide pandemic. Strangely, ample evidences have been shown that the severity of COVID-19 infections varies widely from children (asymptomatic), adults (mild infection), as well as elderly adults (deadly critical). It has proven that COVID-19 infection in some elderly critical adults leads to a cytokine storm, which is characterized by severe systemic elevation of several pro-inflammatory cytokines. Then, a cytokine storm can induce edematous, ARDS, pneumonia, as well as multiple organ failure in aged patients. It is far from clear till now why cytokine storm induces in only COVID-19 elderly patients, and not in young patients. However, it seems that aging is associated with mild elevated levels of local and systemic pro-inflammatory cytokines, which is characterized by "inflamm-aging". It is highly likely that "inflamm-aging" is correlated to increased risk of a cytokine storm in some critical elderly patients with COVID-19 infection.

Methods: A systematic search in the literature was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, as well as Google Scholar pre-print database using all available MeSH terms for COVID-19, Coronavirus, SARS-CoV-2, senescent cell, cytokine storm, inflame-aging, ACE2 receptor, autophagy, and Vitamin D. Electronic database searches combined and duplicates were removed.

Results: The aim of the present review was to summarize experimental data and clinical observations that linked the pathophysiology mechanisms of "inflamm-aging", mild-grade inflammation, and cytokine storm in some elderly adults with severe COVID-19 infection.

Keywords: ACE2 receptor; Autophagy; COVID-19; Cytokine storm; Senescent cell; Vitamin D.

Fig. 1

Normal immunological responses in young adults with mild COVID-19 infection. Direct infection of the bronchi and bronchioles epithelium with COVID-19 particles turn on innate and cell-mediated immune responses. COVID-19 particles convert dendritic cells to mature form, antigen-presenting cells (APCs). The APCs migrates to the lymph node and presents the antigen in the form of the MHC complex to naïve T helper cells (Th0). Th0 cells become activated, proliferate and differentiated to other cells such as CD4⁺ (T helper lymphocytes) and CD8⁺ (cytotoxic T lymphocytes) cells. In healthy adults, due to sufficient vitamin D level, VD can decrease the expression of pro-inflammatory genes in immune cells. A balanced between pro-inflammatory and anti-inflammatory activity causes shut down of the immune system at the right moment

Fig. 2

The link between “inflame-aging” and cytokine storm in in elderly adults with severe COVID-19. Several aging-related factors may associate chronic inflammation to cytokine storm in elderly patients of COVID-19

Fig. 3

The role of alteration of mitophagy in “inflame-aging” and subsequent cytokine storm in elderly adults. The decline of mitophagy during aging, increased ROS production. On one hand, excess ROS production can activate and up-regulate intracellular Nod-like receptor type 3 (NLR3). NLRs over-activity increase expression of caspase-1, and pro-inflammatory cytokines, including IL-1β and IL-18, leading to pyroptosis (cell death) of immune cells. In other hand, the excess ROS production can increase the pro-inflammatory molecules release through activation of multiple transcription factors, including human polynucleotide phosphorylase (hPNPaseold-35), nuclear factor kappa B (NF-κB), activator protein 1 (AP-1), specificity protein 1 (Sp1), peroxisome proliferator-activated receptors (PPARs)

Fig. 4

The role of vitamin D content on pro-inflammatory cytokine release in young and elderly adults with COVID-19 infection. Following exposure to COVID-19 particles in young adults, sufficient vitamin D content increasing intracellular glutathione levels, suppressing excessive ROS production, suppressing NF-κB (nuclear factor kappa b) and p38 MAP kinase expression. In contrast, vitamin D deficiency in elderly adults leads to over-activity of p38 MAP kinase/ STAT (signal transducers and activator of transcription) and ROS/ NF-Κb pathways in the immune cells. So, elderly adults with severe COVID-19 infection cannot turn off their pro-inflammatory immune machine

Fig. 5

Disrupted immunological responses in elderly adults with severe COVID-19 infection. Several factors can un-controllable turn on the inflammatory machine in elderly adults with COVID-19, including (1) decreased ACE2 expression in alveolar cells, (2) decreased mitophagy and subsequently excess ROS production, (3) accumulation of senescent adipocyte cells in visceral white adipose tissue, (4), increased number of senescent immune cells, as well as (5) vitamin D deficiency. Hence, elderly adults with severe COVID-19 infection cannot shut down their pro-inflammatory immune response