In a recent study published in the Journal of Interferon & Cytokine Researchresearchers compared the cytokine storms of pandemic influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections.
Study: Comparison of the cytokine storms of COVID-19 and pandemic flu† Image Credit: NIAID
Background
Emerging respiratory viruses pose a serious health risk because they have the potential to cause large-scale outbreaks. The SARS-CoV-2 pandemic has resulted in millions of serious infections and fatalities worldwide over the past two years. Vaccination against Coronavirus 2019 (COVID-19) disease and natural infection have been shown to provide protective immune responses against SARS-CoV-2, but the parameters influencing morbidity are not well understood.
Matching the immune fingerprints of SARS-CoV-2 infections with those of other serious respiratory infections, such as pandemic flu, could help resolve current debates about the reasons behind their serious manifestations. As a result, finding similarities in the immunopathology of two diseases could lead to immunotherapy targets that address shared pathogenic processes. Meanwhile, identifying different traits that distinguish each infection could lead to the discovery of specific immune modifications that aid the development of diagnostic and personalized therapies for each case.
About the study
In the current study, the researchers summarize immunopathological elements of pandemic flu and COVID-19, considering cytokine storms as the underlying cause of morbidity. The team analyzed differences and similarities in the cytokine signatures of both infections to identify compounds more attractive for translational drug and drug development.
This review examines cytokine storm syndromes (CSS) observed during influenza and COVID-19 to identify conserved immunopathogenic processes underlying severe disease. In addition, the researchers provide the theoretical basis for future research on certain cytokine systems involved in the pathogenesis of COVID-19 by emphasizing different immune features in severe SARS-CoV-2 infection, with potential immunotherapy targets.
Mechanisms behind the cytokine storm of sepsis. Sepsis is an exaggerated immune response triggered by a local or systemic infection. Individuals with this condition exhibit elevated levels of cytokines in the bloodstream (hypercytokinemia), a phenomenon called “cytokine storm.” The mechanisms driving the progression of a normal immune response against a pathogen to sepsis are being investigated. Clinical and demographic features of affected individuals, along with genetic factors that promote excessive immune activation or influence the regulatory mechanisms of the immune system, may contribute to the pathobiology of sepsis. The exuberant production of cytokines leads to deleterious effects on local cells, activation and increased endothelium permeability and microthrombosis. Hypercytokinemia is also associated with many anti-inflammatory mechanisms that stop immune cell functions (immunoparalysis). Together, these changes (cytokine storm + immunoparalysis) result in the development of organ failure without curing the infection. Understanding the pathogenesis of sepsis is critical to addressing other serious infections such as COVID-19 and pandemic flu. The artworks used in this figure have been 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. In addition, both diseases increase the levels of cytokines with different roles.
The elevated cytokines such as interferon (IFN-β) and IFN-α have antiviral properties, and tumor necrosis factor α (TNFα), interleukin 22 (IL-22) and IL-12) have inflammatory characteristics in severe SARS-CoV-2 and influenza infections . Furthermore, IL-10 has regulatory functions and fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) have angiogenic properties. In addition, cytokines, such as chemokine (CXC motif) ligand 8 (CXCL8), CXCL10, CXCL9, chemokine (CC motif) ligand 2 (CCL2), CCL5 and CCL4 harbor chemoattractant characteristics. Furthermore, granulocyte colony stimulating factor (G-CSF), PDGF and FGF exhibit growth factor characteristics.
Therefore, the authors noted that pathogenic processes such as increased innate immune stimulation, microvascular dysfunction and monocyte or neutrophil chemotaxis may be relevant during the COVID-19 and influenza diseases. Using the information presented in this review, it is possible to conclude that the CSS of severe COVID-19 and influenza was similar, implying that similar pathogenic pathways could be used for therapeutic applications.
Certainly, both viruses were recognized by identical pattern recognition receptors (PRRs), activate similar signaling pathways and require similar adaptive and innate immune elements for protection. Elevated inflammasome- and PRR-induced cytokines, including IL-1, TNF and IL-6, were seen in the CS of severe COVID-19 and influenza, indicating a chronic innate inflammatory cascade that was detrimental to the host. Hypothetically, addressing these compounds could reduce their immunological and vascular effects, which is important in the pathophysiology of sepsis, reducing inflammation and restoring balance to the extrapulmonary organs and lungs.
The cytokine storm profiles of pandemic flu and COVID-19. (A) Cytokines, chemokines and growth factors that are frequently 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 artworks used in this figure have been 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 flu. Elevated levels of type 1 T helper (Th1) cytokines plus IL-2, a proliferation-inducing ligand (APRIL), soluble tumor necrosis factor receptor 2 (sTNF-R2), sTNF-R1, CXCL17, and surfactant protein D (SP-D) in patients with severe flu. In addition, severe SARS-CoV-2 patients exhibit a polyfunctional Th2/Th1/Th17 immune activation pattern. According to the findings, SARS-CoV-2, not the influenza virus, produced a polyfunctional and abundant CS profile.
As a result, restoring a balanced immune response could be a viable target for host-directed therapy targeting some subsets of SARS-CoV-2 patients. The team proposes that the optimal COVID-19 immunotherapies should inhibit certain immune signaling pathways associated with hyperinflammation and restore beneficial immune homeostasis that enhances protective immunity in the subset of patients who produce polyfunctional cytokines.
The authors stated that more research was needed to confirm these immune features and determine the ideal time to provide specific immunotherapies based on the cytokine dynamics of these diseases (SARS-CoV-2 and influenza infections). They said future research should evaluate whether tezepelumab, which improves lung function and reduces exacerbations and eosinophilia in people with uncontrolled asthma, could improve COVID-19 outcomes.
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