Tackling the cytokine storm in COVID-19, challenges and hopes

Abstract

The outbreak of Coronavirus disease 2019 (COVID-19) is the current world health concern, presenting a public health dilemma with ascending morbidity and mortality rates exceeding any previous viral spread, without a standard effective treatment yet. SARS-CoV-2 infection is distinguished with multiple epidemiological and pathological features, one of them being the elevated levels of cytokine release, which in turn trigger an aberrant uncontrolled response known as "cytokine storm". This phenomenon contributes to severe acute respiratory distress syndrome (ARDS), leading to pneumonia and respiratory failure, which is considered a major contributor to COVID-19-associated fatality rates. Taking into account that the vast majority of the COVID-19 cases are aggravated by the respiratory and multiorgan failure triggered by the sustained release of cytokines, implementing therapeutics that alleviate or diminish the upregulated inflammatory response would provide a therapeutic advantage to COVID-19 patients. Indeed, dexamethasone, a widely available and inexpensive corticosteroid with anti-inflammatory effects, has shown a great promise in reducing mortality rates in COVID-19 patients. In this review, we have critically compared the clinical impact of several potential therapeutic agents that could block or interfere with the cytokine storm, such as IL-1 inhibitors, IL-6 inhibitors, mast cell targeting agents, and corticosteroids. This work focused on highlighting and contrasting the current success and limitations towards the involvement of these agents in future treatment protocols.

Keywords: COVID-19; Cytokine storm; Dexamethasone; Hydroxychloroquine; IL-1 inhibitors; IL-6 inhibitors; JAK inhibitors; Mast cell stabilizers.

Graphical abstract

Fig. 1

Schematic diagram depicting the potential target pathways to counteract the cytokine storm. Once the SARS-CoV-2 invades the pulmonary epithelial cells, immune cells, such as mast cells recognize the viral RNA by their receptors, such as Toll-like receptors (TLR). This interaction activates transcription factors, such as NF-kB and STAT to ignite an inflammatory program harboring the cytokine storm. Among the different inflammatory products are the interleukins IL-1β, IL-6 that can promote further inflammation by interacting with corresponding receptors. Both the interleukins and their receptors can be targeted by the mentioned agents. JAK/STAT and mast cells can also be blocked to attenuate the constitutive inflammatory activation.