Study: Comparing the Cytokine Storms of COVID-19 and Pandemic Influenza. Image Credit: NIAID

A comparison of SARS-CoV-2 and influenza cytokine storms

In a recent study published in the Journal of Interferon and Cytokine Researchresearchers compared the cytokine storms of pandemic influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections.

Study: Comparison of cytokine storms from COVID-19 and pandemic influenza. Image credit: NIAID

Background

Emerging respiratory viruses pose a serious health risk as they have the potential to create large-scale epidemics. The SARS-CoV-2 pandemic has resulted in millions of serious infections and deaths worldwide over the past two years. Vaccination against coronavirus disease 2019 (COVID-19) and natural infection have been shown to provide protective immune responses against SARS-CoV-2, but the parameters affecting morbidity are not well understood.

Matching the immune fingerprints of SARS-CoV-2 infections with those of other severe respiratory infections, such as pandemic influenza, could help settle current debates about the reasons for their severe manifestations. Accordingly, the discovery of similarities in the immunopathology of two diseases could lead to immunotherapy targets that address shared pathogenic processes. Meanwhile, identifying distinct traits that set each infection apart could lead to the discovery of specific immune modifications facilitating the development of diagnostic and personalized therapies for each case.

About the study

In the present study, the researchers summarize the immunopathological elements of pandemic influenza and COVID-19, considering cytokine storms as the underlying cause of morbidity. The team analyzed the differences and similarities in the cytokine signatures of the two infections to identify more attractive compounds for translational drug and drug development.

This review examines cytokine storm (SSC) observed during influenza and COVID-19 to identify conserved immunopathogenic processes that underlie severe disease. Additionally, researchers provide the theoretical foundation for future study of particular cytokine systems involved in the pathogenesis of COVID-19 with a focus on distinct immune characteristics in severe SARS-CoV-2 infection. , presenting potential targets for immunotherapy.

Mechanisms behind the cytokine storm of sepsis.  Sepsis is an exaggerated immune reaction caused by a local or systemic infection.  People with this disease have high levels of cytokines in the circulation (hypercytokinemia), a phenomenon called a Mechanisms behind the cytokine storm of sepsis. Sepsis is an exaggerated immune reaction caused by a local or systemic infection. People with this disease have high levels of cytokines in the circulation (hypercytokinemia), a phenomenon called a “cytokine storm.” The mechanisms underlying the progression of a normal immune response against a pathogen to sepsis are being investigated. The clinical and demographic characteristics of those affected, as well as genetic factors favoring excessive immune activation or affecting the regulatory mechanisms of the immune system, could 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 numerous anti-inflammatory mechanisms that shut down immune cell functions (immunoparalysis). Together, these alterations (cytokine storm + immunoparalysis) lead to the development of organ failure without eliminating the infection. Understanding the pathogenesis of sepsis is key to addressing other serious infections such as COVID-19 and pandemic influenza. The art pieces used in this figure were modified from Biorender (https://biorender.com/), licensed under a Creative Commons Attribution 3.0 Unported license. COVID-19, coronavirus disease 2019.

Results and conclusions

Overall, the data reported in this article illustrate significant differences and similarities in the immune signature of severe COVID-19 and influenza. Additionally, both diseases increase cytokine levels with varying roles.

Elevated cytokines such as interferon β (IFN-β) and IFN-α have antiviral characteristics, and tumor necrosis factor α (TNFα), interleukin 22 (IL-22), and IL- 12) have inflammatory features in severe SARS-CoV-2 and influenza infections. In addition, IL-10 has regulatory functions and fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) have angiogenic properties. Additionally, cytokines, such as chemokine (CXC motif) ligand 8 (CXCL8), CXCL10, CXCL9, chemokine (CC motif) ligand 2 (CCL2), CCL5, and CCL4 harbor chemoattractant traits. Also, granulocyte colony stimulating factor (G-CSF), PDGF, and FGF exhibit characteristics of growth factor.

Therefore, the authors noted that pathogenic processes such as increased innate immune stimulation, microvascular dysfunction, and monocyte or neutrophil chemotaxis might be relevant during COVID-19 and influenza-like illnesses. Using the information presented in this review, it is possible to conclude that the CSS of severe COVID-19 and influenza was similar, involving comparable pathogenic pathways that could be exploited for therapeutic applications.

Certainly, both viruses were recognized by identical pattern recognition receptors (PRRs), activate similar signaling pathways, and require comparable adaptive and innate immune elements to protect themselves. Elevated inflammasome and PRR-induced cytokines, including IL-1, TNF, and IL-6, were observed in severe COVID-19 and influenza CS, suggesting an innate inflammatory cascade chronic that was harmful to the host. In theory, processing these compounds could reduce their immunological and vascular impacts, important in the pathophysiology of sepsis, by relaxing inflammation and allowing extrapulmonary organs and the lungs to restore balance.

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.  Artwork used in this figure has been modified from Biorender (https://biorender.com/), licensed under a Creative Commons Attribution 3.0 Unported License.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 (https://biorender.com/), licensed under a Creative Commons Attribution 3.0 Unported license.

Conversely, there was a disparity in the immune fingerprint of COVID-19 and influenza. Increased levels of T helper cytokines type 1 (Th1) plus IL-2, proliferation-inducing ligand (APRIL), soluble tumor necrosis factor receptor 2 (sTNF-R2), sTNF-R1, CXCL17 and protein Surfactant D (SP-D) in severe influenza patients. Furthermore, patients with severe SARS-CoV-2 exhibit a polyfunctional Th2/Th1/Th17 immune activation pattern. According to the results, SARS-CoV-2, not the influenza virus, caused a polyfunctional and abundant CS profile.

Accordingly, restoring a balanced immune response might be a viable goal for host-directed therapy targeting certain subsets of SARS-CoV-2 patients. The team proposes that optimal COVID-19 immune therapeutics inhibits certain immune signaling pathways related to hyperinflammation and restores useful immune homeostasis that enhances protective immunity in the subset of patients who produce polyfunctional cytokines.

The authors said further studies are needed to confirm these immune characteristics and determine the ideal timing to provide specific immunotherapies based on the cytokine dynamics of these diseases (SARS-CoV-2 and influenza infections). They mentioned that future research should assess whether tezepelumab, which improves lung function and reduces exacerbations and eosinophilia in people with uncontrolled asthma, might improve COVID-19 outcomes.

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