We therefore investigated whether there was a significant variation of the previously identified immune parameters between patients who were admitted to the ICU (ICU patients) and those not admitted to the ICU (non-ICU patients) during the course of hospitalization. As shown in Physique 4A, ICU patients were characterized by a significant increase of neutrophils absolute figures and a significant decrease of lymphocytes absolute figures in the peripheral blood as compared with non-ICU patients. and exhibited a skewing of CD8+ T cells toward a terminally differentiated/senescent phenotype. In agreement, CD4+ T and CD8+ T, but also NK cells, displayed reduced antiviral cytokine production capability. Moreover, a reduced cytotoxic potential was recognized in patients with COVID-19, particularly in those who required rigorous care. The latter group of patients also showed increased serum IL-6 levels that inversely correlated to the frequency of granzyme ACexpressing NK cells. Off-label treatment with tocilizumab restored the cytotoxic potential of NK cells. CONCLUSION The association between IL-6 serum levels and the impairment of cytotoxic activity suggests the possibility that targeting this cytokine may restore antiviral mechanisms. FUNDING This study was supported by funds from your Department of Experimental and Clinical Medicine of University or college of Florence (the ex-60% fund and the Superiority Departments 2018C2022 Project) derived from Ministero dellIstruzione, dellUniversit e della Ricerca (Italy). (6). SARS-CoV-2 contamination clinically presents with fever, nonproductive cough, and respiratory distress that tends to be more common in adults than in children (10). Coronavirus access into host cells is usually mediated by the transmembrane spike (S) glycoprotein that forms homotrimers protruding from your viral surface (11). SARS-CoV and several SARS-related coronaviruses interact directly with angiotensin-converting enzyme 2 (ACE2) via the S protein to enter target cells (12, 13). It has been recently shown that ACE2 can also mediate SARS-CoV-2 S-dependent access into cells, thus representing a functional receptor for this newly emerged coronavirus (14). ACE2 is usually expressed in the respiratory tract, by mucosal epithelial cells, lung alveolar type 2 pneumocytes, and arterial and venous endothelial cells but also in other tissues, including the gastrointestinal tract, accounting for the moderate enteritis that sometimes is present in patients with COVID-19 (15, 16). Both innate and adaptive immune responses are critical for the control of viral infections. NK cells exert the primary control during acute viral infection, but cytotoxic CD8+ T lymphocytes (CTLs) are critical for long-term surveillance (17C20). The antiviral effects of NK and CD8+ T cells can be mediated by direct cytotoxicity or through the release of IFN-. IFN- is able to directly interfere with viral replication, as well as to indirectly affect viral clearance through the activation of Th1-mediated responses and through MHC class I pathway enhancement (21). Antiviral cytotoxic responses are mediated principally by perforin and granzymes. Recovery from viral infections requires the generation of effective antiviral responses that can eliminate, or at least control, the infecting pathogen. Severe viral infections may induce per se HBEGF immunopathology; however, dysregulated antiviral immune responses can contribute to tissue damage. Thus, it is important to understand the mechanisms regulating pathogen elimination, immunity, and pathology to prevent immune-mediated damage (22, 23). In trying to treat common infections, it is important to understand the mechanisms that regulate pathogen elimination, immunity, and pathology so that immune-mediated damage is prevented. The aim of the present study was to perform a deep immunophenotyping of ZM323881 PBMCs from patients affected by COVID-19 and to correlate these data with clinical parameters and outcomes. Results Clinical evaluation of patients with COVID-19. We evaluated 30 patients affected by COVID-19 who were admitted to Careggi University Hospital. SARS-CoV-2 infection was confirmed by positive reverse transcription real-time PCR on nasopharyngeal swab in accordance with WHO interim guidance (24). All specimens were retested and deemed positive for SARS-CoV-2 by the Italian NIH. The clinical characteristics of the 30 patients are shown in Supplemental Table 1 (supplemental material available online with this article; https://doi.org/10.1172/JCI138554DS1). The median age of the patients was 70 years (range 36C85 years), the mean age was 65.9 years, and 60% of the patients were male. The mean age was 67.9 years for men and 63 years for women. On the day of the immunological analysis, ZM323881 which was performed on average 9.2 days after the onset of the disease and 3.5 days after the hospital admission, the most common symptoms were fever (53%) and cough (40%), whereas diarrhea was an uncommon manifestation (3%). All patients presented with chest imaging abnormalities (Supplemental Table 1); the most frequent radiological findings were pulmonary consolidations (40%) and multiple, bilateral, patchy opacities (30%), compatible with interstitial pneumonia. Supplemental Table 2 reports laboratory results on the day of immunological analysis. Lymphocytopenia ZM323881 (median 830 cells/L) was ZM323881 present in 93% of the patients, with a median neutrophil/lymphocyte ratio of 7.3 and eosinopenia (median 20 cells/L) in 52% of patients. Almost all patients had elevation of acute-phase proteins: C-reactive protein (CRP, median 60.5 mg/L), fibrinogen (median 510 mg/dL), and ferritin (median 795 ng/mL). D-dimer (median 940 ng/mL) and lactate.