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Although CD4+CD25+FOXP3+ regulatory T (TREG) cells have been studied in patients with COVID-19, changes in the TREG cell population have not been longitudinally examined during the course of COVID-19. In this study, we longitudinally investigated the quantitative and qualitative changes in the TREG cell population in patients with COVID-19. We found that the frequencies of total TREG cells and CD45RA−FOXP3hi activated TREG cells were significantly increased 15–28 d postsymptom onset in severe patients, but not in mild patients. TREG cells from severe patients exhibited not only increased proliferation but also enhanced apoptosis, suggesting functional derangement of the TREG cell population during severe COVID-19. The suppressive functions of the TREG cell population did not differ between patients with severe versus mild COVID-19. The frequency of TREG cells inversely correlated with SARS-CoV-2–specific cytokine production by CD4+ T cells and their polyfunctionality in patients with mild disease, suggesting that TREG cells are major regulators of virus-specific CD4+ T cell responses during mild COVID-19. However, such correlations were not observed in patients with severe disease. Thus, in this study, we describe distinctive changes in the TREG cell population in patients with severe and mild COVID-19. Our study provides a deep understanding of host immune responses upon SARS-CoV-2 infection in regard to TREG cells.

Background Our understanding of adaptive immune responses in COVID-19 patients is rapidly evolving, but information on the innate immune responses by natural killer (NK) cells is still insufficient. Objective We aimed to examine the phenotypic and functional status of NK cells and their changes during the course of mild and severe COVID-19. Methods We performed RNA sequencing (RNA-seq) and flow cytometric analysis of NK cells from patients with mild and severe COVID-19 at multiple time points in the course of the disease using cryopreserved peripheral blood mononuclear cells (PBMCs). Results In RNA-seq analysis, the NK cells exhibited distinctive features compared to healthy donors, with significant enrichment of pro-inflammatory cytokine-mediated signaling pathways. Intriguingly, we found that the unconventional CD56dimCD16neg (uCD56dim) NK cell population expanded in cryopreserved PBMCs from COVID-19 patients regardless of disease severity, accompanied by decreased NK cell cytotoxicity. The NK cell population was rapidly normalized alongside the disappearance of uCD56dim NK cells and the recovery of NK cell cytotoxicity in mild COVID-19 patients, but this occurred slowly in severe COVID-19 patients. Conclusion The current longitudinal study provides a deep understanding of the NK cell biology in COVID-19., Graphical abstract

Despite the worldwide effect of the Coronavirus disease 2019 (COVID-19) pandemic, the underlying mechanisms of fatal viral pneumonia remain elusive. Here, we show that critical COVID-19 is associated with enhanced eosinophil-mediated inflammation when compared to non-critical cases. In addition, we confirm increased Th2-biased adaptive immune responses, accompanying overt complement activation, in the critical group. Moreover, enhanced antibody responses and complement activation is associated with disease pathogenesis as evidenced by formation of immune complexes and membrane attack complexes in airways and vasculature of lung biopsies from six fatal cases, as well as by enhanced hallmark gene set signatures of FcγR signaling and complement activation in myeloid cells of respiratory specimens from critical COVID-19 patients. These results suggest that SARS-CoV-2 infection may drive specific innate immune responses, including eosinophil-mediated inflammation, and subsequent pulmonary pathogenesis via enhanced Th2-biased immune responses, which might be crucial drivers of critical disease in COVID-19 patients., Graphical Abstract, Kim et al. find that critical COVID-19 is associated with enhanced eosinophil-mediated inflammation when compared to non-critical cases. Increased Th2-biased immune responses, accompanying overt complement activation, are seen in the critical group. These findings suggest that enhanced eosinophil-mediated inflammation and dysregulated humoral responses might be drivers of severe COVID-19.

Despite the worldwide effect of the Coronavirus disease 2019 (COVID-19) pandemic, the underlying mechanisms of fatal viral pneumonia remain elusive. Here, we conducted kinetic profiling of respiratory leukocytes and associated inflammatory mediators to show that severe COVID-19 is associated with delayed but enhanced eosinophilic inflammation when compared to mild cases. In addition, we confirmed increased Th2-biased adaptive immune responses, accompanying overt complement activation, in the severe group. Moreover, enhanced antibody responses and complement activation was associated with disease pathogenesis as evidenced by formation of immune complexes and membrane attack complexes in airways and vasculature of lung biopsies from a fatal case, as well as by enhanced hallmark gene set signatures of FcgR signaling and complement activation in myeloid cells of respiratory specimens from severe COVID-19 patients. We also observed expression of viral antigen in lung epithelial and endothelial cells without producing viruses during late stage of COVID-19, indicating abortive viral infection which may further fuel antibody responses and aggravate immune-complex-mediated inflammation. These results suggest that SARS-CoV-2 infection may drive scripted specific innate immune responses, including eosinophilic inflammation, and subsequent pulmonary pathogenesis via enhanced Th2-biased immune responses, which might be crucial drivers of severe pneumonia in COVID-19 patients.

Observational studies of the ongoing coronavirus disease 2019 (COVID-19) outbreak suggest that a cytokine storm is involved in the pathogenesis of severe illness. However, the molecular mechanisms underlying the altered pathological inflammation in COVID-19 are largely unknown. We report here that toll-like receptor (TLR) 4-mediated inflammatory signaling molecules are upregulated in peripheral blood mononuclear cells (PBMCs) from COVID-19 patients, compared with healthy controls. Among the most highly increased inflammatory mediators in severe/critically ill patients, S100A9, an alarmin and TLR4 ligand, was found as a noteworthy biomarker, because it inversely correlated with the serum albumin levels. These data support a link between TLR4 signaling and pathological inflammation during COVID-19 and contribute to develop therapeutic approaches through targeting TLR4-mediated inflammation.

Background The fatality rate of patients with coronavirus disease 2019 (COVID-19) varies among countries owing to demographics, patient comorbidities, surge capacity of healthcare systems, and the quality of medical care. We assessed the clinical outcomes of patients with COVID-19 during the first wave of the epidemic in Korea. Methods Using a modified World Health Organization clinical record form, we obtained clinical data for 3,060 patients with COVID-19 treated at 55 hospitals in Korea. Disease severity scores were defined as: 1) no limitation of daily activities; 2) limitation of daily activities but no need for supplemental oxygen; 3) supplemental oxygen via nasal cannula; 4) supplemental oxygen via facial mask; 5) non-invasive mechanical ventilation; 6) invasive mechanical ventilation; 7) multi-organ failure or extracorporeal membrane oxygenation therapy; and 8) death. Recovery was defined as a severity score of 1 or 2, or discharge and release from isolation. Results The median age of the patients was 43 years of age; 43.6% were male. The median time from illness onset to admission was 5 days. Of the patients with a disease severity score of 3–4 on admission, 65 (71.5%) of the 91 patients recovered, and 7 (7.7%) died due to illness by day 28. Of the patients with disease severity scores of 5–7, 7 (19.5%) of the 36 patients recovered, and 8 (22.2%) died due to illness by day 28. None of the 1,324 patients who were < 50 years of age died; in contrast, the fatality rate due to illness by day 28 was 0.5% (2/375), 0.9% (2/215), 5.8% (6/104), and 14.0% (7/50) for the patients aged 50–59, 60–69, 70–79, and ≥ 80 years of age, respectively. Conclusion In Korea, almost all patients of < 50 years of age with COVID-19 recovered without supplemental oxygen. In patients of ≥ 50 years of age, the fatality rate increased with age, reaching 14% in patients of ≥ 80 years of age., Graphical Abstract

Background Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This disease, which is quickly spreading worldwide, has high potential for infection and causes rapid progression of lung lesions, resulting in a high mortality rate. This study aimed to investigate the effects of SARS-CoV-2 infection on renal function in patients with COVID-19. Methods From February 21 to April 24, 2020, 66 patients diagnosed with COVID-19 at Chungnam National University Hospital were analyzed; all patients underwent routine urinalysis and were tested for serum creatinine, urine protein to creatinine ratio (PCR), and urine albumin to creatinine ratio (ACR). Results Acute kidney injury (AKI) occurred in 3 (4.5%) of the 66 patients, and 1 patient with AKI stage 3 underwent hemodialysis. Upon follow-up, all 3 patients recovered normal renal function. Compared with patients with mild COVID-19, AKI (n = 3) occurred in patients with severe COVID-19, of whom both urine PCR and ACR were markedly increased. Conclusion The incidence of AKI was not high in COVID-19 patients. The lower mortality rate in SARS-CoV-2 infection compared with previous Middle East respiratory syndrome and SARS-CoV infections is thought to be associated with a low incidence of dysfunction in organs other than the lungs., Graphical Abstract

Background Observational studies of the ongoing coronavirus disease 2019 (COVID-19) outbreak suggest that a ‘cytokine storm’ is involved in the pathogenesis of severe illness. However, the molecular mechanisms underlying the altered pathological inflammation in COVID-19 are largely unknown. We report here that toll-like receptor (TLR) 4-mediated inflammatory signaling molecules are upregulated in peripheral blood mononuclear cells (PBMCs) from COVID-19 patients, compared with healthy controls (HC). Methods A total of 48 subjects including 28 COVID-19 patients (8 severe/critical vs. 20 mild/moderate cases) admitted to Chungnam National University Hospital, and age/sex-matched 20 HC were enrolled in this study. PBMCs from the subjects were processed for nCounter Human Immunology gene expression assay to analyze the immune related transcriptome profiles. Recombinant proteins of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were used to stimulate the PBMCs and monocyte-derived macrophages, and real-time polymerase chain reaction was performed to quantify the mRNA expressions of the pro-inflammatory cytokines/chemokines. Results Among the most highly increased inflammatory mediators in severe/critically ill patients, S100A9, an alarmin and TLR4 ligand, was found as a noteworthy biomarker, because it inversely correlated with the serum albumin levels. We also observed that recombinant S2 and nucleocapsid proteins of SARS-CoV-2 significantly increased pro-inflammatory cytokines/chemokines and S100A9 in human primary PBMCs. Conclusion These data support a link between TLR4 signaling and pathological inflammation during COVID-19 and contribute to develop therapeutic approaches through targeting TLR4-mediated inflammation., Graphical Abstract

Background: A pooling test is a useful tool for mass screening of coronavirus disease 2019 (COVID-19) in the pandemic era We aimed to optimize a simple two-step pooling test by estimating the optimal pool size using experimental and mathematical validation Materials and Methods: Experimental pools were created by mixing one positive respiratory sample with various numbers of negative samples We selected positive samples with cycle threshold (Ct) values greater than 32 to validate the efficiency of the pooling test assuming a high likelihood of false-negative results due to low viral loads The positivities of the experimental pools were investigated with a single reverse-transcription polymerase chain reaction (RT-PCR) using the U-TOP™ COVID-19 Detection Kit Plus (Seasun Biomaterials, Daejeon, Korea) We used the Dorfman equation to calculate the optimal size of a pooling test mathematically Results: Viral RNA could be detected in a pool with a size up to 11, even if the Ct value of a positive sample was about 35 The Dorfman equation showed that the optimal number of samples in a pool was 11 when the prevalence was assumed to be 0 66% based on the test positivity in Daejeon, Korea from April 1, 2020 to November 10, 2020 The efficiency of the pooling test was 6 2, which can save 83 9 of 100 individual tests Conclusion: Eleven samples in a pool were validated optimal experimentally assuming a prevalence of 0 66% The pool size needs modification as the pandemic progresses;thus, the prevalence should be carefully estimated before pooling tests are conducted Copyright © 2021 by The Korean Society of Infectious Diseases

As the outbreak of coronavirus disease 2019 continues and the number of confirmed cases requiring isolation increases, there is a need for a safe and efficient system to assess patients' condition. We developed and evaluated a self-assessment questionnaire consisting of 23 symptoms with linear-scale scores from 0 to 10. Patients were asked to indicate their worst score for each symptom daily, and medical personnel assessed clinical improvement or deterioration based on the changes in scores. Focused communication on severity of specific symptoms was the primary advantage for the clinicians, and a thorough check for their symptoms was helpful for patients.