From Cytokine Storm to Cytokine Breeze: Did Lessons Learned from Immunopathogenesis Improve Immunomodulatory Treatment of Moderate-to-Severe COVID-19?

Abstract

Complex immune response to infection has been highlighted, more than ever, during the COVID-19 pandemic. This review explores the immunomodulatory treatment of moderate-to-severe forms of this viral sepsis in the context of specific immunopathogenesis. Our objective is to analyze in detail the existing strategies for the use of immunomodulators in COVID-19. Immunomodulating therapy is very challenging; there are still underpowered or, in other ways, insufficient studies with inconclusive or conflicting results regarding a rationale for adding a second immunomodulatory drug to dexamethasone. Bearing in mind that a “cytokine storm” is not present in the majority of COVID-19 patients, it is to be expected that the path to the adequate choice of a second immunomodulatory drug is paved with uncertainty. Anakinra, a recombinant human IL-1 receptor antagonist, is a good choice in this setting. Yet, the latest update of the COVID-19 Treatment Guidelines Panel (31 May 2022) claims that there is insufficient evidence to recommend either for or against the use of anakinra for the treatment of COVID-19. EMA’s human medicines committee recommended extending the indication of anakinra to include treatment of COVID-19 in adult patients only recently (17 December 2021). It is obvious that this is still a work in progress, with few ongoing clinical trials. With over 6 million deaths from COVID-19, this is the right time to speed up this process. Our conclusion is that, during the course of COVID-19, the immune response is changing from the early phase to the late phase in individual patients, so immunomodulating therapy should be guided by individual responses at different time points.

CCR5/CXCR3 antagonist TAK-779 prevents diffuse alveolar damage of the lung in the murine model of the acute respiratory distress syndrome

“…In majority of clinical cases, innate and adaptive immunity overcomes SARS-CoV-2 infection; however, some patients develop a severe late stage, which promotes the cytokine storm and accelerates the deterioration of patients to the ARDS/DAD ( Rondovic et al, 2022 ). The main pathological effect may be caused by hypersensitivity reactions rather than the virus itself, as Zhenfei et al reported that formaldehyde-inactivated SARS-CoV-2 induces ARDS in human ACE2-transgenic mice ( Bi et al, 2021 ).…”

CCR5/CXCR3 antagonist TAK-779 prevents diffuse alveolar damage of the lung in murine model of the SARS-CoV-2-related acute respiratory distress syndrome

“…In majority of clinical cases innate and adaptive immunity overcomes SARS-CoV-2 infection, however, some patients develop a severe late stage, which promotes the cytokine storm and accelerates the deterioration of patients to the ARDS/DAD [56]. The main pathological effect may be caused by hypersensitivity reactions rather than virus itself, as study by Zhenfei et al reported that formaldehyde-inactivated SARS-CoV-2 induces ARDS in human ACE2-transgenic mice [57].…”

Updated Insights into the T Cell-Mediated Immune Response against SARS-CoV-2: A Step towards Efficient and Reliable Vaccines

“…It is quite obvious that the scientific community has sufficiently emphasized the importance of T-cell-mediated adaptive immune responses for the clearance of the virus and long-term antiviral immunity. However, it is important to consider that T-cell exhaustion can significantly contribute to the exaggerated release of the cytokines, commonly known as a cytokine storm, in severely infected patients with COVID-19 [ 35 , 36 , 128 , 129 ]. T-cell exhaustion is a condition in which CD8+ T cells might develop metabolic malfunctions.…”