In a recent study published in the Journal of Interferon & Cytokine Research, researchers compared the cytokine storms of pandemic influenza and infections with severe acute respiratory syndrome with coronavirus 2 (SARS-CoV-2).
Study: Comparison of cytokine storms of 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 outbreaks. The SARS-CoV-2 pandemic has resulted in millions of severe 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 influencing the incidence are not well understood.
Comparing the immune footprints of SARS-CoV-2 infections with those of other severe respiratory infections, such as pandemic influenza, may help resolve the ongoing debate about the causes behind their severe manifestations. As a result, the discovery of similarities in the immunopathology of two diseases can lead to immunotherapy goals that target shared pathogenic processes. Meanwhile, the identification of individual traits that distinguish each infection can lead to the discovery of specific immune modifications that help develop diagnostic and personalized therapies for each case.
About the study
In the present study, researchers summarize the immunopathological elements of pandemic influenza and COVID-19, looking at cytokine storms as a major cause of morbidity. The team analyzed the differences and similarities in the cytokine signatures of the two infections to identify compounds that are more attractive for drug development and translation drugs.
This review examines cytokine storm syndromes (CSS) observed during influenza and COVID-19 to identify persistent immunopathogenic processes that underlie severe disease. In addition, the researchers provide a theoretical basis for future research on certain cytokine systems involved in the pathogenesis of COVID-19, highlighting individual 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 response caused by a local or systemic infection. People with this condition show elevated levels of cytokines in the bloodstream (hypercytokineemia), a phenomenon called “cytokine storm”. The mechanisms driving the progression from a normal immune response against a pathogen to sepsis are under investigation. The clinical and demographic characteristics of those affected, together with genetic factors that promote excessive immune activation or affect the regulatory mechanisms of the immune system, may contribute to the pathobiology of sepsis. Abundant cytokine production leads to detrimental effects on local cells, activation and increased endothelial permeability and microthrombosis. Hypercytokineemia is also accompanied by many anti-inflammatory mechanisms that stop the function of immune cells (immunoparalysis). Together, these changes (cytokine storm + immunopolysis) lead to the development of organ failure without clearing the infection. Understanding the pathogenesis of sepsis is critical to the approach to other severe infections such as COVID-19 and pandemic influenza. The artwork used in this figure has been modified by Biorender (licensed under the 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 characteristics of severe COVID-19 and influenza. In addition, both diseases increase cytokine levels with different roles.
Elevated cytokines such as interferon β (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. In addition, IL-10 has regulatory functions, and fibroblast growth factor (FGF) and platelet 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 have chemoattractant traits. In addition, granulocyte colony stimulating factor (G-CSF), PDGF and FGF exhibit growth factor characteristics.
Therefore, the authors note that pathogenic processes such as increased innate immune stimulation, microvascular dysfunction, and chemotaxis of monocytes or neutrophils may be relevant during 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 is similar, suggesting comparable pathogenic pathways that can be used for therapeutic applications.
Of course, both viruses are recognized by identical pattern recognition receptors (PRRs), activate similar signaling pathways, and require comparable adaptive and innate immune defense elements. Elevated inflammation and PRR-induced cytokines, including IL-1, TNF and IL-6, have been observed in the CS of severe COVID-19 and influenza, suggesting a chronic congenital inflammatory cascade that is detrimental to the host. Hypothetically, dealing with these compounds may reduce their immunological and vascular effects, important for the pathophysiology of sepsis, relieving inflammation and allowing extrapulmonary organs and lungs to regain balance.
The cytokine storm profiles of pandemic influenza and COVID-19. (A) Cytokines, chemokines, and growth factors, often or differently 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 artwork used in this figure has been modified by Biorender (licensed under the Creative Commons Attribution 3.0 Unported License.
Conversely, there was a mismatch in the immune fingerprint of COVID-19 and influenza. Elevated levels of cytokines type 1 T helper (Th1) plus IL-2, proliferation-inducing ligand (APRIL), soluble tumor necrosis factor receptor 2 (sTNF-R2), sTNF-R2, sTNF-R1, CXCL17 and surfactant protein D (SP-D) in severe patients with influenza. In addition, patients with severe SARS-CoV-2 show a multifunctional model of immune activation of Th2 / Th1 / Th17. According to the findings, SARS-CoV-2, not the influenza virus, causes a multifunctional and abundant CS profile.
As a result, restoring a balanced immune response may be a viable goal for host-targeted therapy targeting certain subgroups of patients with SARS-CoV-2. The team suggests the optimal immunotherapeutic agents for COVID-19 to inhibit certain immune signaling pathways associated with hyperinflammation and to restore beneficial immune homeostasis that enhances protective immunity in a subset of patients who produce polyfunctional cytokines.
The authors stated that more research is needed to confirm these immune characteristics and to determine the ideal time to provide specific immunotherapies based on the cytokine dynamics of these diseases (SARS-CoV-2 and influenza infections). They mentioned that future research should evaluate whether tezepelumab, which improves lung function and reduces exacerbations and eosinophilia in people with uncontrolled asthma, could improve COVID-19 results.
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