Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an RNA virus responsible for a pandemic that causes asymptomatic or paucisymptomatic infection in most individuals but may be responsible for severe interstitial pneumonia, myocarditis, acute kidney injury, hepatitis, acute respiratory distress syndrome (ARDS), multiorgan failure (MOF), and death. 1 Patients with severe coronavirus disease (COVID-19) typically show signs of hyperinflammation characterized by an exuberant host immune response leading to a virus-driven cytokine release syndrome. 2 A hallmark of COVID-19 is lymphopenia, involving virtually all cell lineages, and a number of studies have provided evidence in support of altered innate and adaptive immune responses in COVID-19. 2 With respect to the latter, most studies focused on phenotypic and molecular T-cell alterations; however, little or no information is available for B cells, apart from the possible role of SARS-CoV-2-specific neutralizing antibodies in controlling the infection and clinical outcome. An altered distribution of B-cell subsets is usually observed in chronic viral infections, including hepatitis C and B 3, 4 and HIV. 5 In an effort to identify characteristic changes that may be associated with favorable or poor outcomes in patients with COVID-19, we studied peripheral blood B-cell subsets in 17 patients presenting with severe SARS-CoV-2 infection and interstitial pneumonia with a viral RNA-positive nasopharyngeal swab or bronchoalveolar lavage. All were admitted to the hospital because of severe dyspnea requiring at least a Venturi type of mask for oxygen ventilation. Four patients required a ventilation upgrade to continuous positive airway pressure with high positive end-expiratory pressure or transfer to the ICU and intubation. Ten of these patients died because of ARDS and/or MOF. Follow-up peripheral blood mononuclear cells were available from seven recovered patients~ 45 days after discharge. Seven convalescent (Conv) individuals who donated hyperimmune plasma because of serum high-titer neutralizing antibodies immediately after hospital discharge or after home quarantine were also investigated. Laboratory findings are reported in Supplementary Table 1. Thirteen clinically healthy, SARS-CoV-2 RNA-negative subjects of the same age group as the patients served as controls (HD). The study was approved by the Institutional Review Board of Fondazione IRCCS Policlinico San Matteo (prot. N. 20200038910). B cells (CD19+) were examined by flow cytometry (FACS Celesta, BD Bioscience, San Diego, CA, USA) and are shown as frequencies and absolute numbers that largely overlapped, with only a few exceptions. B cells were categorized according to the expression of CD21, CD27, and CD10 molecules as immature transitional (itBC, CD27−/CD10+), atypical memory (atMBC, CD21lo/CD27−/CD10−), activated memory (AMBC, CD21lo/CD27+/CD10−), classical memory (cMBC, CD21+/CD27+/CD10−), and naïve (nBC, CD21+/CD27−/C10−) cells (Fig. 1 a and Supplementary Fig. 1). Analysis of B-cell subsets revealed a characteristic and significant expansion of atMBC in terms of both frequencies and numbers, in patients with COVID-19 (CoV-2) compared with HD and Conv individuals (Fig. 1 b and Supplementary Fig. 2a). Importantly, the proportion of atMBC was significantly higher in patients who died than in those who survived (Fig. 1 b). Conversely, the proportions and numbers of cMBC were significantly reduced in patients with severe COVID-19 compared with HD and Conv individuals. There was no significant difference between survivors and deceased patients at admission …