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1.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-323557

ABSTRACT

Background: The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has gradually become a global public health crisis. Some patients who have recovered from COVID-19 subsequently tested positive again for SARS-CoV-2 after discharge (retesting-positive, RTP). However, the underlying mechanism is unknown.Methods: Here, 30 RTP patients, 20 convalescent patients, and 20 healthy controls were enrolled for analysis of the immunological characteristics of their peripheral blood mononuclear cells (PBMCs). Furthermore, we sought to comprehensively characterize the transcriptional changes in the three groups by transcriptome sequencing.Findings: It was found that the absolute numbers of CD4+ T cells, CD8+ T cells, and NK cells were not decreased remarkably, while the expression of activation markers on these cells was significantly decreased in RTP patients. Furthermore, the percentage of granzyme B-producing T cells was also decreased in RTP patients compared with that in convalescent patients. Moreover, the high expression of inhibitor of differentiation-1 (ID1) and the low expression of IFITM10 may be associated with the insufficient activation of immune cells and RTP occurrence.Interpretation: Our findings provide insights into the impaired immune function and pathogenesis of RTP occurrence in COVID-19, which may contribute to the development of immunotherapy for RTP patients.Funding Statement: This work was supported by China National Center for Biotechnology Development (2020YFC0843800 and 2020YFC0846800), Ministry of Science and Technology of China (2020TFC0844100), and China Postdoctoral Science Foundation (2020T130112ZX).Declaration of Interests: The authors declare no potential conflict of interest.Ethics Approval Statement: The studies were approved by the Ethics Committee of the First Affiliated Hospital of the University of Science & Technology of China (2020-XG(H)-005) and Peking University First Hospital (2020-Research-112) for Emerging Infectious Diseases. Experiments were conducted in accordance with the ethical guidelines of the 1975 Declaration of Helsinki, the Principles of Good Clinical Practice, and the guidelines of China’s regulatory requirements.

2.
Front Immunol ; 12: 716940, 2021.
Article in English | MEDLINE | ID: covidwho-1507125

ABSTRACT

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.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , SARS-CoV-2/physiology , Animals , COVID-19/therapy , Clinical Protocols , Cytokine Release Syndrome , Humans , Immunity , Immunomodulation , Inflammation , Signal Transduction
3.
J Mol Cell Biol ; 13(10): 748-759, 2021 12 30.
Article in English | MEDLINE | ID: covidwho-1483467

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has become a global public health crisis. Some patients who have recovered from COVID-19 subsequently test positive again for SARS-CoV-2 RNA after discharge from hospital. How such retest-positive (RTP) patients become infected again is not known. In this study, 30 RTP patients, 20 convalescent patients, and 20 healthy controls were enrolled for the analysis of immunological characteristics of their peripheral blood mononuclear cells. We found that absolute numbers of CD4+ T cells, CD8+ T cells, and natural killer cells were not substantially decreased in RTP patients, but the expression of activation markers on these cells was significantly reduced. The percentage of granzyme B-producing T cells was also lower in RTP patients than in convalescent patients. Through transcriptome sequencing, we demonstrated that high expression of inhibitor of differentiation 1 (ID1) and low expression of interferon-induced transmembrane protein 10 (IFITM10) were associated with insufficient activation of immune cells and the occurrence of RTP. These findings provide insight into the impaired immune function associated with COVID-19 and the pathogenesis of RTP, which may contribute to a better understanding of the mechanisms underlying RTP.


Subject(s)
COVID-19/immunology , Convalescence , Reinfection/immunology , SARS-CoV-2/immunology , Transcriptome/immunology , Adult , Aged , Aged, 80 and over , Antigens, CD/genetics , Antigens, CD/immunology , COVID-19/genetics , COVID-19/virology , COVID-19 Nucleic Acid Testing , Case-Control Studies , Female , Healthy Volunteers , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Inhibitor of Differentiation Protein 1/genetics , Inhibitor of Differentiation Protein 1/immunology , Male , Middle Aged , Patient Readmission , RNA, Viral/isolation & purification , Reinfection/genetics , Reinfection/virology , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Young Adult
6.
Front Med ; 15(3): 486-494, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1122810

ABSTRACT

Tocilizumab has been reported to attenuate the "cytokine storm" in COVID-19 patients. We attempted to verify the effectiveness and safety of tocilizumab therapy in COVID-19 and identify patients most likely to benefit from this treatment. We conducted a randomized, controlled, open-label multicenter trial among COVID-19 patients. The patients were randomly assigned in a 1:1 ratio to receive either tocilizumab in addition to standard care or standard care alone. The cure rate, changes of oxygen saturation and interference, and inflammation biomarkers were observed. Thirty-three patients were randomized to the tocilizumab group, and 32 patients to the control group. The cure rate in the tocilizumab group was higher than that in the control group, but the difference was not statistically significant (94.12% vs. 87.10%, rate difference 95% CI-7.19%-21.23%, P = 0.4133). The improvement in hypoxia for the tocilizumab group was higher from day 4 onward and statistically significant from day 12 (P = 0.0359). In moderate disease patients with bilateral pulmonary lesions, the hypoxia ameliorated earlier after tocilizumab treatment, and less patients (1/12, 8.33%) needed an increase of inhaled oxygen concentration compared with the controls (4/6, 66.67%; rate difference 95% CI-99.17% to-17.50%, P = 0.0217). No severe adverse events occurred. More mild temporary adverse events were recorded in tocilizumab recipients (20/34, 58.82%) than the controls (4/31, 12.90%). Tocilizumab can improve hypoxia without unacceptable side effect profile and significant influences on the time virus load becomes negative. For patients with bilateral pulmonary lesions and elevated IL-6 levels, tocilizumab could be recommended to improve outcome.


Subject(s)
COVID-19 , Antibodies, Monoclonal, Humanized , COVID-19/drug therapy , Humans , SARS-CoV-2 , Treatment Outcome
7.
J Autoimmun ; 118: 102596, 2021 03.
Article in English | MEDLINE | ID: covidwho-1062442

ABSTRACT

Forty-seven samples of peripheral blood mononuclear cells from four groups of coronavirus disease (COVID)-19 patients (mild, severe, convalescent, retesting-positive) and healthy controls were applied to profile the immune repertoire of COVID-19 patients in acute infection or convalescence by transcriptome sequencing and immune-receptor repertoire (IRR) sequencing. Transcriptome analyses showed that genes within principal component group 1 (PC1) were associated with infection and disease severity whereas genes within PC2 were associated with recovery from COVID-19. A "dual-injury mechanism" of COVID-19 severity was related to an increased number of proinflammatory pathways and activated hypercoagulable pathways. A machine-learning model based on the genes associated with inflammatory and hypercoagulable pathways had the potential to be employed to monitor COVID-19 severity. Signature analyses of B-cell receptors (BCRs) and T-cell receptors (TCRs) revealed the dominant selection of longer V-J pairs (e.g., IGHV3-9-IGHJ6 and IGHV3-23-IGHJ6) and continuous tyrosine motifs in BCRs and lower diversity of TCRs. These findings provide potential predictors for COVID-19 outcomes, and new potential targets for COVID-19 treatment.


Subject(s)
COVID-19/genetics , Receptors, Antigen, B-Cell/genetics , Receptors, Antigen, T-Cell/genetics , Adult , COVID-19/drug therapy , COVID-19/immunology , Female , Humans , Male , Middle Aged , Receptors, Antigen, B-Cell/immunology , Receptors, Antigen, T-Cell/immunology
8.
SSRN; 2020.
Preprint | SSRN | ID: ppcovidwho-5138

ABSTRACT

Background: Tocilizumab is reported to be able to attenuate the "cytokine storm" in COVID-19 patients. We tried to ascertain the effectiveness and safety of tocilizumab in COVID-19 and identify patients most likely to be benefit from the treatment. Methods: This was a randomized, controlled, open-label, multicenter trial at 6 hospitals in Anhui and Hubei. Patients were randomly assigned in a 1:1 ratio to receive either tocilizumab in addition to standard care, or standard care alone. The first dose of tocilizumab was 400 mg, diluted in 100 ml 0.9% saline, and intravenous dripped in more than 1 h. A second dose was given if a patient remained febrile for 24 hours after the first dose. The primary endpoint was the cure rate. Primary analysis was done in the intention -to -treat (ITT) population and safety analysis was done in all patients who started their assigned treatment. Findings: Between Feb 13, 2020, and March 13, 2020, 65 patients were enrolled and randomly assigned to a treatment group (33 to tocilizumab and 32 to the controls). One patient in the control group, who aggravated severely 3 days after randomization, was transferred to the tocilizumab group. The cure rate in tocilizumab group was higher than that in the controls but not significant (94.12% vs 87.10%, P=0.4133). Adverse events were recorded in 20 (58.82%) of 34 tocilizumab recipients versus 4 (12.90%) of 31 in the controls. No serious adverse events were reported in tocilizumab group. Interpretation: Tocilizumab treatment did not increase the cure rate of COVID-19. A large scale of study enrolling more patients is needed. However,tocilizumab can improve oxygenation without significant influence on the time virus load tunes negative. For patients with bilateral pulmonary lesions and elevated IL-6 levels, tocilizumab should be recommended for better disease management. Trial Registration: This trial was registered in Chinese Clinical Trial Registry (Number: ChiCTR2000029765). Funding: This work was supported by Department of Science and Technology of Anhui Province and Health Commission of Anhui Province (grant number: 202004a07020001) and the China National Center for Biotechnology Development (grant number: 2020YFC0843800).

12.
Proc Natl Acad Sci U S A ; 117(20): 10970-10975, 2020 05 19.
Article in English | MEDLINE | ID: covidwho-155000

ABSTRACT

After analyzing the immune characteristics of patients with severe coronavirus disease 2019 (COVID-19), we have identified that pathogenic T cells and inflammatory monocytes with large amount of interleukin 6 secreting may incite the inflammatory storm, which may potentially be curbed through monoclonal antibody that targets the IL-6 pathways. Here, we aimed to assess the efficacy of tocilizumab in severe patients with COVID-19 and seek a therapeutic strategy. The patients diagnosed as severe or critical COVID-19 in The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital) and Anhui Fuyang Second People's Hospital were given tocilizumab in addition to routine therapy between 5 and 14 February 2020. The changes of clinical manifestations, computerized tomography (CT) scan image, and laboratory examinations were retrospectively analyzed. Fever returned to normal on the first day, and other symptoms improved remarkably within a few days. Within 5 d after tocilizumab, 15 of the 20 patients (75.0%) had lowered their oxygen intake, and 1 patient needed no oxygen therapy. CT scans manifested that the lung lesion opacity absorbed in 19 patients (90.5%). The percentage of lymphocytes in peripheral blood, which decreased in 85.0% of patients (17/20) before treatment (mean, 15.52 ± 8.89%), returned to normal in 52.6% of patients (10/19) on the fifth day after treatment. Abnormally elevated C-reactive protein decreased significantly in 84.2% of patients (16/19). No obvious adverse reactions were observed. All patients have been discharged on average 15.1 d after giving tocilizumab. Preliminary data show that tocilizumab, which improved the clinical outcome immediately in severe and critical COVID-19 patients, is an effective treatment to reduce mortality.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Betacoronavirus , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Adult , Aged , Aged, 80 and over , COVID-19 , China , Coronavirus Infections/blood , Coronavirus Infections/physiopathology , Disease Progression , Female , Humans , Interleukin-6/antagonists & inhibitors , Interleukin-6/blood , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/physiopathology , SARS-CoV-2 , Treatment Outcome
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