Mixed storm in SARS-CoV-2 infection: A narrative review and new term in the Covid-19 era.

Coronavirus disease 2019 (Covid-19) is caused by a novel severe acute respiratory syndrome coronavirus virus type 2 (SARS-CoV-2) leading to the global pandemic worldwide. Systemic complications in Covid-19 are mainly related to the direct SARS-CoV-2 cytopathic effects, associated hyperinflammation, hypercytokinemia, and the development of cytokine storm (CS). As well, Covid-19 complications are developed due to the propagation of oxidative and thrombotic events which may progress to a severe state called oxidative storm and thrombotic storm (TS), respectively. In addition, inflammatory and lipid storms are also developed in Covid-19 due to the activation of inflammatory cells and the release of bioactive lipids correspondingly. Therefore, the present narrative review aimed to elucidate the interrelated relationship between different storm types in Covid-19 and the development of the mixed storm (MS). In conclusion, SARS-CoV-2 infection induces various storm types including CS, inflammatory storm, lipid storm, TS and oxidative storm. These storms are not developing alone since there is a close relationship between them. Therefore, the MS seems to be more appropriate to be related to severe Covid-19 than CS, since it develops in Covid-19 due to the intricate interface between reactive oxygen species, proinflammatory cytokines, complement activation, coagulation disorders, and activated inflammatory signaling pathway.

Integrating single-cell sequencing data with GWAS summary statistics reveals CD16+monocytes and memory CD8+T cells involved in severe COVID-19.

BACKGROUND: Understanding the host genetic architecture and viral immunity contributes to the development of effective vaccines and therapeutics for controlling the COVID-19 pandemic. Alterations of immune responses in peripheral blood mononuclear cells play a crucial role in the detrimental progression of COVID-19. However, the effects of host genetic factors on immune responses for severe COVID-19 remain largely unknown. METHODS: We constructed a computational framework to characterize the host genetics that influence immune cell subpopulations for severe COVID-19 by integrating GWAS summary statistics (N = 969,689 samples) with four independent scRNA-seq datasets containing healthy controls and patients with mild, moderate, and severe symptom (N = 606,534 cells). We collected 10 predefined gene sets including inflammatory and cytokine genes to calculate cell state score for evaluating the immunological features of individual immune cells. RESULTS: We found that 34 risk genes were significantly associated with severe COVID-19, and the number of highly expressed genes increased with the severity of COVID-19. Three cell subtypes that are CD16+monocytes, megakaryocytes, and memory CD8+T cells were significantly enriched by COVID-19-related genetic association signals. Notably, three causal risk genes of CCR1, CXCR6, and ABO were highly expressed in these three cell types, respectively. CCR1+CD16+monocytes and ABO+ megakaryocytes with significantly up-regulated genes, including S100A12, S100A8, S100A9, and IFITM1, confer higher risk to the dysregulated immune response among severe patients. CXCR6+ memory CD8+ T cells exhibit a notable polyfunctionality including elevation of proliferation, migration, and chemotaxis. Moreover, we observed an increase in cell-cell interactions of both CCR1+ CD16+monocytes and CXCR6+ memory CD8+T cells in severe patients compared to normal controls among both PBMCs and lung tissues. The enhanced interactions of CXCR6+ memory CD8+T cells with epithelial cells facilitate the recruitment of this specific population of T cells to airways, promoting CD8+T cell-mediated immunity against COVID-19 infection. CONCLUSIONS: We uncover a major genetics-modulated immunological shift between mild and severe infection, including an elevated expression of genetics-risk genes, increase in inflammatory cytokines, and of functional immune cell subsets aggravating disease severity, which provides novel insights into parsing the host genetic determinants that influence peripheral immune cells in severe COVID-19.

Complex Pathophysiological Mechanisms and the Propose of the Three-Dimensional Schedule For Future COVID-19 Treatment.

At present, the global COVID-19 epidemic is still in a state of anxiety, and increasing the cure rate of critically ill patients is an important means to defeat the virus. From an immune perspective, ARDS driven by an inflammatory storm is still the direct cause of death in severe COVID-19 patients. Although some experience has been gained in the treatment of COVID-19, and intensive COVID-19 vaccination has been carried out recently, it is still effective to save lives to develop more effective programs to alleviate the inflammatory storm and ARDS in patients with SARS-CoV-2 or emerging variants of SARS-CoV-2. In reorganizing the ARDS-related inflammatory storm formation program in COVID-19 patients, we highlighted the importance of the vicious circle of inflammatory cytokines and inflammatory cell death, which is aggravated by blood circulation to form multi-system inflammation. Summarizes the interlocking and crisscrossing of inflammatory response and inflammatory cell death mechanisms including NETs, pyrolysis, apoptosis and PANoptosis in severe COVID-19. More importantly, in response to the inflammatory storm formation program we described, and on the premise of following ethical and clinical experimental norms, we propose a three-dimensional integrated program for future research based on boosting antiviral immune response at the initial stage, inhibiting inflammatory cytokine signaling at the exacerbation stage and inhibiting cell death before it's worse to prevent and alleviate ARDS.

Dysimmunity and inflammatory storm: Watch out for bone lesions in COVID-19 infection.

At the end of 2019, a new kind of pneumonia which was proven to be supported by novel coronaviruses named SARS-CoV-2 emerges and it seems to be more complicate in its clinical course and management. Related researches have demonstrated that SARS-CoV-2 serves roles in respiratory, intestinal and neuronal diseases. Given the growing cases of COVID-19, analyzing the relevance between COVID-19 and fragile patients who suffer from bone destruction is entirely indispensable. Accordingly, the recapitulatory commentary is necessary to advance our knowledge on COVID-19 and orthopedics. In this article, we particularly clarify the possible relationship between the newly COVID-19 infection and bone lesions from the standpoints of dysimmunity and inflammatory storm.

Why tocilizumab could be an effective treatment for severe COVID-19?

A severe pneumonia-associated respiratory syndrome caused by a new coronavirus was identified in December 2019 (COVID-19), spread rapidly and has become a world-wide public health challenge. About 25% of COVID-19 patients experienced severe complications including acute respiratory distress syndrome (ARDS), and even progressed into an intensive care unit (ICU) admission and died. The exploration for the mortality causes and advancing novel therapeutic development of severe COVID-19 is crucial at the moment. The biopsy samples analysis at autopsy suggested that increased alveolar exudate caused by aberrant host immune response and inflammatory cytokine storm probably impedes alveolar gas exchange and contributes to the high mortality of severe COVID-19 patients. Our research has identified that pathogenic T cells and inflammatory monocytes incite inflammatory storm with large amount of interleukin 6, therefore monoclonal antibody that targets the IL-6 pathways may potentially curb inflammatory storm. Moreover, Tocilizumab treatment that blocking IL-6 receptors showed inspiring clinical results including temperature returned to normal quickly and respiratory function improved. Therefore, we suggest that Tocilizumab is an effective treatment in severe patients of COVID-19 to calm the inflammatory storm and reduce mortality.