Comparing the Cytokine Storms of COVID-19 and Pandemic Influenza

Abstract

Emerging respiratory viruses are major health threats due to their potential to cause massive outbreaks. Over the past 2 years, the coronavirus disease 2019 (COVID-19) pandemic has caused millions of cases of severe infection and deaths worldwide. Although natural and vaccine-induced protective immune mechanisms against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been increasingly identified, the factors that determine morbimortality are less clear. Comparing the immune signatures of COVID-19 and other severe respiratory infections such as the pandemic influenza might help dissipate current controversies about the origin of their severe manifestations. As such, identifying homologies in the immunopathology of both diseases could provide targets for immunotherapy directed to block shared pathogenic mechanisms. Meanwhile, finding unique characteristics that differentiate each infection could shed light on specific immune alterations exploitable for diagnostic and individualized therapeutics for each case. In this study, we summarize immunopathological aspects of COVID-19 and pandemic influenza from the perspective of cytokine storms as the driving force underlying morbidity. Thereby, we analyze similarities and differences in the cytokine profiles of both infections, aiming to bring forward those molecules more attractive for translational medicine and drug development.

Keywords: COVID-19; SARS-CoV-2; cytokine storm; cytokines; flu; influenza.

FIG. 1.

Mechanisms behind the cytokine storm of sepsis. Sepsis is an exaggerated immune reaction elicited by local or systemic infection. Individuals with this condition display elevated levels of cytokines in the circulation (hypercytokinemia), a phenomenon named “cytokine storm.” The mechanisms driving the progression from a normal immune response against a pathogen to sepsis are under investigation. Clinical and demographic features of affected persons, together with genetic factors promoting an excessive immune activation or affecting the regulatory mechanisms of the immune system, might contribute to the pathobiology of sepsis. The exuberant production of cytokines leads to harmful effects on local cells, activation, and increased permeability of the endothelium, and microthrombosis. Hypercytokinemia is also accompanied by many anti-inflammatory mechanisms that arrest immune cell functions (immunoparalysis). Together, these alterations (cytokine storm + immunoparalysis) result in the development of organ failure without clearing the infection. Understanding the pathogenesis of sepsis is crucial to approaching other severe infections such as COVID-19 and pandemic influenza. The art pieces used in this figure were modified from Biorender, licensed under a Creative Commons Attribution 3.0 Unported License. COVID-19, coronavirus disease 2019.

FIG. 2.

Immune mechanisms implicated in the defense against SARS-CoV-2 and influenza. (A) Innate humoral factors present in the lumen of the lower airways block viruses before they attach the underlying epithelium. Mucins and surfactant proteins A and D are important for host defenses against influenza virus and SARS-CoV-2. Mannose-binding lectin has also shown to neutralize SARS-CoV-2. (B) The innate immune response against these viruses begins with recognizing PAMPs by host PRRs. TLR3, TLR7, RIG-1, and the NLRP3 inflammasome participate in the early recognition of influenza and SARS-CoV-2, eliciting the production of cytokines, chemokines, and interferons. TLR2 and TLR4 may also participate in the defense against SARS-CoV-2, but the evidence is still scarce. (C) The innate phase of the immune response against influenza and SARS-CoV-2 comprehends an ample range of mechanisms, including the chemotaxis of monocytes, neutrophils, other granulocytes, and neutrophil degranulation and NETosis, phagocytosis of viral particles and infected cells, and cytotoxicity by NK cells. Some populations of NK cells with adaptive properties (NKG2C⁺) might also expand during COVID-19. (D) Dendritic cells link innate and adaptive immunity by presenting antigens at local lymph nodes and secreting cytokines that shape the functional fate of B and T cells. B cells produce neutralizing antibodies that mediate complement activation and antibody-dependent cellular cytotoxicity. CD8⁺ T cells kill infected cells by perforin and granzyme degranulation or via the Fas/FasL signaling pathway. CD4⁺ T cells produce cytokines to orchestrate all the other mechanisms described. A balance between Th1 and Th2 responses might be crucial for antiviral immunity. The art pieces used in this figure were modified from Biorender, licensed under a Creative Commons Attribution 3.0 Unported License. NK, natural killer; NLRP3, NLR family pyrin domain containing 3 receptor; RIG-1, retinoic-acid-inducible gene 1; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TLR, Toll-like receptor.

FIG. 3.

The cytokine storm profiles of pandemic influenza and COVID-19. (A) Cytokines, chemokines, and growth factors commonly or differentially elevated during severe influenza and COVID-19 were identified by retrospective analysis of independent studies. (B) Immune profiles distinguishing influenza from COVID-19 identified by parallel comparisons. The art pieces used in this figure were modified from Biorender, licensed under a Creative Commons Attribution 3.0 Unported License.