Dampening COVID-19 Inflammatory Cytokines Increases Survival Rate

30% of patients with COVID-19 infection in ICU would develop ARDS with characteristic severe lung edema, dyspnea, hypoxemia, and about 65% of these patients with ARDS died. Typical treatment of ARDS is based on pharmacologic modulation of the innate immune system, and it is administered to understand that ARDS is a syndrome of hyper-inflammation. Although inflammation is a protective innate immune response against viral insult, exaggerated inflammation or persistent inflammatory ABSTRACT Unchecked-activation of immune responses leads to excessive expression of NF-kB, which further leads to multi organ failure at the site of viral infection and systemic level. Several studies showed that elevated expression of NF-kB related genes further amplifies inflammatory soluble cytokine/chemokines worsening the COVID infection. Although the prospective of counteracting cytokines flood is compelling, a significant limitation depends on understanding the immune signaling pathways triggered by COVID. Thus, finding more clues about the immune system’s role in COVID-19 management may prevent the transition from mild to severe stages.


Introduction
In the last two decades, severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) caused severe respiratory diseases in endemic areas. However, the most recent coronavirus epidemic dwarfs SARS and MERS in its social, medical, and economic impact. Discovered in December 2019 in Wuhan, Hubei province, China, this highly contagious respiratory syndrome was given an acronym of COVID-19 (coronavirus disease 2019) to stands for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Essentially, COVID-19 is a respiratory illness with the lung as the target organ. Severe and irreparable structural and functional damage to the lung is common, which phenotypically results in acute respiratory distress syndrome (ARDS). What sets COVID-19 apart from SARS-CoV and MERS are its contagious nature, ability to survive on inanimate objects for prolonged times, rapid disease progression, and non-responsiveness to conventional anti-viral therapies. Till November 2020, COVID-19 has caused 62,363,527 active cases and 1,456,687 confirmed deaths in 220 countries [1]. These numbers are projected to rise unless an effective vaccine is globally and strategically implemented promptly. Even if the vaccine is made universally available, therapeutic alternatives to treat existing infection and its clinical sequel will be the key to win the ongoing fight against COVID-19.
About 30% of patients with COVID-19 infection in ICU would develop ARDS with characteristic severe lung edema, dyspnea, hypoxemia, and about 65% of these patients with ARDS died.
Typical treatment of ARDS is based on pharmacologic modulation of the innate immune system, and it is administered to understand that ARDS is a syndrome of hyper-inflammation. Although inflammation is a protective innate immune response against viral insult, exaggerated inflammation or persistent inflammatory feed-forward loop is highly damaging to the lung and contributes to its failure [2]. However, ARDS is a heterogeneous manifestation because different patients can respond differently to the same treatment; thus, efforts have been made to segregate patients into subgroups depending on clinical outcomes [3]. Moreover, COVID-19 patients with ARDS eventually develop multi-organ failure.
Unfortunately, there is no definite and clinically validated drug for ARDS capable of reducing either short-term distress or longterm mortality in COVID-19 patients. SARS-CoV-2 uses angiotensin converting enzyme II (ACE2) as its entry receptor with the help of transmembrane serine protease 2 (TMPRSS2), suggesting ACE2, and TMPRSS2 as potential therapeutic targets for COVID-19 [4,5].

Putative Anti-Inflammatory Targets for ARDS Associated with COVID-19
At the causal level, ARDS is viewed as a cytokine release syndrome (CRS). The central signaling mechanism involved in creating cytokine storms is the hyper-activated nuclear factorkappa B (NFκB) pathway [6]. Therefore, attention has been focused on restraining or attenuating the magnitude and duration of NFκB-mediated signaling. In a recent intriguing report, Sohn, et al. implicated S100A9, an alarmin and Toll-like receptor 4 (TLR4) ligand for the activation of NFκB pathway in COVID-19 patients [7].

Glucocorticoids (GCs) Restrain Inflammatory Response in COVID-19 Patients
Glucocorticoids are potent anti-inflammatory and immunosuppressive agents. Their use has been recommended for severe cases of COVID-19 [11], and positive outcomes have of transcription (Jak-STAT) pathway [14,15]. The Jak-STAT pathway is activated when cytokines bind their cell surface receptor, which leads to the phosphorylation-dependent activation of STAT proteins [14]. Multiple ligands can activate individual STAT proteins, and specific cytokines can also preferentially activate particular STATs.
For example, interleukin-6 (IL-6) preferentially activates STAT3, whereas IFNγ preferentially activates STAT1. It's been reported that GCs and IL-6-STAT3 axis synergizes with each other. Bagca and Avci recently reviewed the potential of inhibition of the Jak-STAT pathway by ruxolitinib to treat COVID-19 [16]. On the other hand, Meyer, et al. described a combined use of GCs and ruxolitinib for fighting cytokine storm [17], which could also be applicable in COVID-19 [18].

Interleukin (IL)-6 as a Target for Dampening the Hyperactive Immune System in COVID-19
Emerging clinical trial data suggest that immunomodulatory drugs can reduce the cytokine storm. IL-6 is a pro-inflammatory cytokine produced by several cell types, and its production is elevated COVID-19 affected lung tissue [19,20]. It has been rationalized that inhibition of IL-6 or its effects may alter the course of COVID-19. The impact of IL-6 could be inhibited either by antibodies against IL-6 or its receptor (IL-6R). The Food and Drug Administration-approved monoclonal antibodies against IL-6R include sarilumab and tocilizumab, whereas siltuximab is a monoclonal antibody against IL-6. The complete list of such antibodies at various stages of clinical trials is given in Table 1. A recent retrospective study found that tocilizumab decreased C-reactive protein in most of the patients [21]. Another retrospective study demonstrated that tocilizumab effectively controlled the severity of COVID-19 symptoms such as fever, respiratory illness [22]. Levilimab is another antibody against IL-6R, which is currently in clinical testing against COVID-19 [23]. The Russian Federation registered levilimab (marked under the name Ilsira) to control cytokine storm associated with COVID-19 [24]. Despite these initial successes, the composite data from various trials have not been promising so far, which led the COVID-19 Treatment Guidelines Panel to recommend against the use of anti-IL-6 receptor monoclonal antibodies or anti-IL-6 monoclonal antibody for the treatment of COVID-19, except in a clinical trial (Table 1).

Blocking Upstream Regulators of NFκB Pathway
A recent study from Korea showed that toll-like receptor (TLR) 4-mediated inflammatory signaling pathways, which mimic pathogenesis of bacterial sepsis, were highly upregulated in peripheral blood mononuclear cells (PBMCs) from COVID-19 patients, compared with healthy controls [7]. Among the most highly increased inflammatory mediators, S100A9, a TLR4 ligand, was found as a biomarker, suggesting TLR4 signaling may contribute to COVID-19 inflammation. Curcumin-like chalcones were reported to modulate MD2-TLR4 binding nullified TLR4 activation and sequentially inhibited NF-kB activation [37,38], suggesting these MD2 modulators can be used therapeutic purposes through targeting TLR4-mediated inflammation. Several small molecules reported as NF-κB inhibitors, such as diphenyldihaloketones (DDKs), namely EF24 and CLEFMA may be helpful in controlling "cytokine storm". EF24 shown to affect several functions of DCs, besides reduces NF-κB activation and suppresses pro-inflammatory cytokine secretion [39][40][41][42].

Authors Contribution
B Chidipi and V Eada are designed this concept and wrote this paper.

Consent for Publication
Not applicable.