key: cord-346291-qqy9ld94 authors: Noroozi, Rezvan; Branicki, Wojciech; Pyrc, Krzysztof; Łabaj, Paweł P.; Pośpiech, Ewelina; Taheri, Mohammad; Ghafouri-Fard, Soudeh title: Altered cytokine levels and immune responses in patients with SARS-CoV-2 infection and related conditions date: 2020-05-21 journal: Cytokine DOI: 10.1016/j.cyto.2020.155143 sha: doc_id: 346291 cord_uid: qqy9ld94 The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic in early 2020. The infection has been associated with a wide range of clinical symptoms. In the severely affected patients, it has caused dysregulation of immune responses including over-secretion of inflammatory cytokines and imbalances in the proportion of naïve helper T cells, memory helper T cells and regulatory T cells. Identification of the underlying mechanism of such aberrant function of immune system would help in the prediction of disease course and selection of susceptible patients for more intensive cares. In the current review, we summarize the results of studies which reported alterations in cytokine levels and immune cell functions in patients affected with SARS-CoV-2 and related viruses. Firstly, identified in an outbreak in Wuhan city of China, the novel coronavirus disease 2019 has caused a global pandemic in early 2020. Alternatively named as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus has been shown to induce various clinical manifestation in hosts ranging from asymptomatic conditions to severe symptoms including respiratory failure, shock, or multiorgan system dysfunction (1) Notably, this condition has been accompanied by a significant increase in the proportion of naïve helper T cells while reduction in memory helper T cells and regulatory T cells (5) . Based on the importance of immune responses in the determination of course of infection and the related complications, we performed a literature search to find the reported dysregulations in the levels of cytokines and immune cells in patients infected with SARS-CoV-19 and related viruses. A recent study in Chinese patients affected with SARS-CoV-2 has shown elevated plasma concentrations of IL-1B, IL-1RA, IL-7, IL-8, IL-9, IL-10, basic FGF, GCSF, GMCSF, IFN-γ, IFNγ-induced protein (IP)-10, monocyte chemotactic protein 1 (MCP1), MIP1A, MIP1B and TNF-α in both patients needed ICU admission and non-ICU patients compared with healthy controls at initial assessment. Notably, author reported significant over-production of IL-2, IL-7, IL-10, GCSF, IP-10, MCP1, MIP1A, and TNF-α in ICU patients compared with other group of SARS-CoV-2 infected persons (6) . Another study has demonstrated associations between severity of SARS-CoV-2 infection and levels of IL-2R, IL-6, IL-8, IL-10 and TNF-α. Moreover, disease severity was associated with both WBC and lymphocyte counts as well as quantities of neutrophils and eosinophils. Authors have suggested the IL-2R level >793.5U/mL, WBC>9.5*10^9/L or neutrophil count>7.305*10^9/L among parameters that indicate progression of SARS-CoV-19 infection to critical conditions. Thus, inflammatory responses were shown to be correlated with the severity of SARS-CoV-19. Besides, IL-6, TNF-α and IL-8 have been suggested as therapeutic targets (7) . A longitudinal study of cytokine levels and lymphocyte count in affected patients has revealed remarkable and continuous decreases in lymphocyte counts but elevations in neutrophil counts in severely infected cases compared with mild cases. Additionally, severely affected individuals had substantial reductions in T cells population, particularly CD8 + T cells, and upsurge in IL-6, IL-10, IL-2 and IFN-γ levels. Notably, T cell counts and cytokine concentrations in severe SARS-CoV-2 infected patients who stayed alive gradually returned to their levels in the mild cases. The most significant prognostic marker to show the course of infection has been the neutrophil-to-CD8+ T cell ratio (8) . IL-6 has also been among the up-regulated infection-related markers in the serum of patients with SARS-CoV-2 pneumonia (9) . Another study has demonstrated significant decrease in lymphocyte subsets both in severe and mild groups of patients with SARS-CoV-2 infection. Reduction in CD8 + T cells and increase in IL-6 levels were more prominent in the severely affected patients. Moreover, significant differences were detected between the severe and mild groups in CD4 + T, CD8 + T, IL-6 and IL-10 (7). Cellular immune responses to SARS-CoV infection have been previously assessed in an animal study. Animals were exposed to the virus through an intranasal route. Such viral administration resulted in induction of pneumonia which was accompanied by over-production of TNF-α, IL-6, CXCL10, CCL2, CCL3, and CCL5. Notably, increased cytokine and chemokine levels were associated with relocation of NK cells, macrophages, and plasmacytoid dendritic cells (pDC) into the lungs. The viral clearance was accompanied by another round of cytokine and chemokine release and an inflow of T lymphocytes occurred. Depletion studies showed the essential role of and IL-10 has been suggested as factors that predict severe course of the disorder (7). Taken together, the data presented above show some levels of similarity in the levels of proinflammatory cytokines particularly IL-6 and IL-10 as well as T cell subsets among different coronaviruses which indicate the role of these cytokines in the pathogenesis of infection-related complications. Future studies are needed to find the practical modalities to defend these aberrant responses and improve the clinical outcomes. Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19). 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The authors declare they have no conflict of interest.  SARS-CoV-2 causes dysregulation of immune responses in severely affected patients. It is associated with over-secretion of inflammatory cytokines and imbalances in the proportion of naïve Th cells, memory Th cells and Treg cells. Elevated levels of IL-6 and IL-10 predict severe course of the disorder. Levels of proinflammatory cytokines particularly IL-6 and IL-10 as well as T cell subsets are mostly similar between different coronaviruses.