Phytotherapy for treatment of cytokine storm in COVID­19

Abstract

In 2020, a novel strain of coronavirus has led to a significant morbidity and mortality worldwide. As of the date of this writing, a total of 116 M cases has been diagnosed worldwide leading to 2.5 M deaths. The number of mortalities is directly correlated with the rise of innate immune cells (especially macrophages) in the lungs that secrete inflammatory cytokines (IL-1β and IL-6) leading to the development of "Cytokine Storm Syndrome" (CSS), multi-organ-failure and death. Given that currently the treatment of this condition is rare and release of effective vaccine might be months away, here, we review the plants and their pharmacologically active-compounds as potential phytopharmaceuticals for the virus induced inflammatory response. Experimental validation of the effectiveness of these natural compounds to prevent or reduce the cytokine storm might be beneficial as an adjunct treatment of SARS-CoV-2.

The Impacts of Anti-Inflammatory Agents on COVID-19 Cytokine Storm

“…The binding of high levels of IL-6 to sIL-6R subsequently leads to the production of more IL-6, IL-8, vascular endothelial growth factor, and CCL-2 [7]. Moreover, secretion of IL-1β and tumor necrosis factor-alpha (TNF-α) by neutrophils upregulates the NFκB signaling pathway, leading to the release of several cytokines, ranging from chemokines (CCL2, CCL3, CCL5, CXCL10), granulocyte-macrophage colony-stimulating factor (GM-CSF), and granulocyte colony-stimulating factor (G-CSF) [3,10]. TLRs also activate other signaling pathways, including Janus kinase (JAK)/signal transducer and activator of transcription (STAT), involved in antiviral response and the generation of several cytokines [11].…”

“…TLRs also activate other signaling pathways, including Janus kinase (JAK)/signal transducer and activator of transcription (STAT), involved in antiviral response and the generation of several cytokines [11]. These cytokines exacerbate the inflammatory response by attracting T-cells involved in the production of TNF-α and IFNs, which then activate dendritic and endothelial cells, inducing more cytokine production and resulting in cytokine release syndrome (CRS) or cytokine storm (CS) [10].…”

“…More so, IL-6 and IL-1β cause the recruitment of CD8+ T cells and neutrophils to the site of infection. These cells produce cytotoxic substances such as matrix-metalloproteinase (MMP), reactive oxygen species (ROS), and leukotriene that provoke tissue injury in the lung parenchyma of the host, thereby predisposing the host to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) [10]. TNF-α could also cause flu-like symptoms such as fever, malaise, and fatigue, as well as vascular leaking, heart failure, acute-phase protein synthesis, and lung damage [11].…”

“…The clinical features of CS could be assessed from deregulated levels of acute-phase proteins, biochemical indices, renal function indices, liver function indices, cardiac biomarkers, coagulation profile, cytokines, and chemokines, as well as hematological indices as shown in Table 1. The cytokine profile of COVID-19 patients has similarities with that of cytokine release syndrome patients having abnormal levels of inflammatory cytokines and chemokines (tumor necrosis factor-alpha (TNF-α), lymphopenia as well as chemokine ligand-2, CCL-3, and CXCL10, interleukin (IL-1 and IL-6) [10]. Early identification of the biochemical markers of a cytokine storm from serum chemistry and hematological indices will facilitate the use of an optimal drug for the management and treatment of COVID-19 severity, thereby avoiding CS-induced mortality.…”

“…These agents not only exert antiviral effects, thereby inhibiting replication of SARS-CoV-2, but also dampen excessive inflammation reaction through immune regulation. Remarkably, a plethora of studies have shown that phytoconstituents regulate levels of pro-inflammatory cytokines produced during the inflammatory condition [10]. The list of plant phytoconstituents that have demonstrated anti-inflammatory effects includes chlorogenic acid, quercetin, luteoloside, anthocyanins, gallic acid, myricetin, resveratrol, prodelphinidin, catechin, gallocatechin, stilbenoid, naringenin, procyanidins, and geranilated flavonoids [18].…”