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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 Pharmacol ; 12: 718089, 2021.
Article in English | MEDLINE | ID: covidwho-1340189

ABSTRACT

Sepsis is a host immune disorder induced by infection. It can lead to multiple organ dysfunction syndrome (MODS), which has high morbidity and mortality. There has been great progress in the clinical diagnosis and treatment of sepsis, such as improvements in pathogen detection technology, innovations regarding anti-infection drugs, and the development of organ function support. Abnormal immune responses triggered by pathogens, ranging from excessive inflammation to immunosuppression, are recognized to be an important cause of the high mortality rate. However, no drugs have been approved specifically for treating sepsis. Here, we review the recent research progress on immune responses in sepsis to provide a theoretical basis for the treatment of sepsis. Constructing and optimizing a dynamic immune system treatment regimen based on anti-infection treatment, fluid replacement, organ function support, and timely use of immunomodulatory interventions may improve the prognosis of sepsis patients.

7.
Pathogens ; 10(7)2021 Jul 12.
Article in English | MEDLINE | ID: covidwho-1308389

ABSTRACT

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global concern. Immunoglobin A (IgA) contributes to virus neutralization at the early stage of infection. Longitudinal studies are needed to assess whether SARS-CoV-2-specific IgA production persists for a longer time in patients recovered from severe COVID-19 and its lasting symptoms that can have disabling consequences should also be alerted to susceptible hosts. Here, we tracked the anti-SARS-CoV-2 spike protein receptor-binding domain (RBD) antibody levels in a cohort of 88 COVID-19 patients. We found that 52.3% of the patients produced more anti-SARS-CoV-2 RBD IgA than IgG or IgM, and the levels of IgA remained stable during 4-41 days of infection. One of these IgA-dominant COVID-19 patients, concurrently with IgA nephropathy (IgAN), presented with elevated serum creatinine and worse proteinuria during the infection, which continued until seven months post-infection. The serum levels of anti-SARS-CoV-2 RBD and total IgA were higher in this patient than in healthy controls. Changes in the composition of the intestinal microbiota, increased IgA highly coated bacteria, and elevated concentration of the proinflammatory cytokine IL-18 were indicative of potential involvement of intestinal dysbiosis and inflammation to the systemic IgA level and, consequently, the disease progression. Collectively, our work highlighted the potential adverse effect of the mucosal immune response to SARS-CoV-2 infection, and that additional care should be taken with COVID-19 patients presenting with chronic diseases such as IgAN.

8.
J Immunother Cancer ; 9(4)2021 04.
Article in English | MEDLINE | ID: covidwho-1175186

ABSTRACT

The ongoing pandemic caused by the novel coronavirus SARS-CoV-2 has disrupted the global economy and strained healthcare systems to their limits. After the virus first emerged in late 2019, the first intervention that demonstrated significant reductions in mortality for severe COVID-19 in large-scale trials was corticosteroids. Additional options that may reduce the burden on the healthcare system by reducing the number of patients requiring intensive care unit support are desperately needed, yet no therapy has conclusively established benefit in randomized studies for the management of moderate or mild cases of disease. Severe COVID-19 disease is characterized by a respiratory distress syndrome accompanied by elevated levels of several systemic cytokines, in a profile that shares several features with known inflammatory pathologies such as hemophagocytic lymphohistiocytosis and cytokine release syndrome secondary to chimeric antigen receptor (CAR) T cell therapy. Based on these observations, modulation of inflammatory cytokines, particularly interleukin (IL)-6, was proposed as a strategy to mitigate severe disease. Despite encouraging recoveries with anti-IL-6 agents, especially tocilizumab from single-arm studies, early randomized trials returned mixed results in terms of clinical benefit with these interventions. Later, larger trials such as RECOVERY and REMAP-CAP, however, are establishing anti-IL-6 in combination with steroids as a potential option for hypoxic patients with evidence of hyperinflammation. We propose that a positive feedback loop primarily mediated by macrophages and monocytes initiates the inflammatory cascade in severe COVID-19, and thus optimal benefit with anti-IL-6 therapies may require intervention during a finite window of opportunity at the outset of hyperinflammation but before fulminant disease causes irreversible tissue damage-as defined clinically by C reactive protein levels higher than 75 mg/L.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/prevention & control , Interleukin-6/antagonists & inhibitors , SARS-CoV-2/isolation & purification , COVID-19/epidemiology , COVID-19/virology , Cytokines/immunology , Cytokines/metabolism , Humans , Inflammation/immunology , Inflammation/metabolism , Interleukin-6/immunology , Interleukin-6/metabolism , Macrophages/drug effects , Macrophages/immunology , Macrophages/metabolism , Monocytes/drug effects , Monocytes/immunology , Monocytes/metabolism , Pandemics , SARS-CoV-2/physiology
9.
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
10.
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
11.
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).

14.
Nat Commun ; 11(1): 3924, 2020 08 06.
Article in English | MEDLINE | ID: covidwho-695765

ABSTRACT

Several studies show that the immunosuppressive drugs targeting the interleukin-6 (IL-6) receptor, including tocilizumab, ameliorate lethal inflammatory responses in COVID-19 patients infected with SARS-CoV-2. Here, by employing single-cell analysis of the immune cell composition of two severe-stage COVID-19 patients prior to and following tocilizumab-induced remission, we identify a monocyte subpopulation that contributes to the inflammatory cytokine storms. Furthermore, although tocilizumab treatment attenuates the inflammation, immune cells, including plasma B cells and CD8+ T cells, still exhibit robust humoral and cellular antiviral immune responses. Thus, in addition to providing a high-dimensional dataset on the immune cell distribution at multiple stages of the COVID-19, our work also provides insights into the therapeutic effects of tocilizumab, and identifies potential target cell populations for treating COVID-19-related cytokine storms.


Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Betacoronavirus/immunology , Coronavirus Infections/immunology , Cytokines/immunology , Monocytes/immunology , Pneumonia, Viral/immunology , Antibodies, Monoclonal, Humanized/administration & dosage , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , COVID-19 , Computational Biology , Coronavirus Infections/blood , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Cytokines/blood , Humans , Inflammation/drug therapy , Macrophages/drug effects , Macrophages/immunology , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Receptors, Interleukin-6/immunology , SARS-CoV-2 , Single-Cell Analysis/methods
16.
J Immunother Cancer ; 8(1)2020 05.
Article in English | MEDLINE | ID: covidwho-220167

ABSTRACT

The pandemic caused by the novel coronavirus SARS-CoV-2 has placed an unprecedented burden on healthcare systems around the world. In patients who experience severe disease, acute respiratory distress is often accompanied by a pathological immune reaction, sometimes referred to as 'cytokine storm'. One hallmark feature of the profound inflammatory state seen in patients with COVID-19 who succumb to pneumonia and hypoxia is marked elevation of serum cytokines, especially interferon gamma, tumor necrosis factor alpha, interleukin 17 (IL-17), interleukin 8 (IL-8) and interleukin 6 (IL-6). Initial experience from the outbreaks in Italy, China and the USA has anecdotally demonstrated improved outcomes for critically ill patients with COVID-19 with the administration of cytokine-modulatory therapies, especially anti-IL-6 agents. Although ongoing trials are investigating anti-IL-6 therapies, access to these therapies is a concern, especially as the numbers of cases worldwide continue to climb. An immunology-informed approach may help identify alternative agents to modulate the pathological inflammation seen in patients with COVID-19. Drawing on extensive experience administering these and other immune-modulating therapies, the Society for Immunotherapy of Cancer offers this perspective on potential alternatives to anti-IL-6 that may also warrant consideration for management of the systemic inflammatory response and pulmonary compromise that can be seen in patients with severe COVID-19.


Subject(s)
Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Immunotherapy , Interleukin-6/antagonists & inhibitors , Interleukin-6/immunology , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/drug therapy , Societies, Medical , Adoptive Transfer , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Humans , Inflammation/complications , Inflammation/drug therapy , Inflammation/immunology , Inflammation/pathology , Interferon-gamma/antagonists & inhibitors , Interleukin-1/antagonists & inhibitors , Interleukin-17/antagonists & inhibitors , Interleukin-23/antagonists & inhibitors , Interleukin-6/genetics , Interleukin-6/metabolism , Janus Kinases/antagonists & inhibitors , Neoplasms/immunology , Neoplasms/therapy , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/pathology , STAT Transcription Factors/antagonists & inhibitors , Severe Acute Respiratory Syndrome/pathology , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors
17.
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
18.
J Transl Med ; 18(1): 164, 2020 04 14.
Article in English | MEDLINE | ID: covidwho-52547

ABSTRACT

A severe pneumonia-associated respiratory syndrome caused by a new coronavirus was identified in December 2019 (COVID-19), spread rapidly and has become a world-wide public health challenge. About 25% of COVID-19 patients experienced severe complications including acute respiratory distress syndrome (ARDS), and even progressed into an intensive care unit (ICU) admission and died. The exploration for the mortality causes and advancing novel therapeutic development of severe COVID-19 is crucial at the moment. The biopsy samples analysis at autopsy suggested that increased alveolar exudate caused by aberrant host immune response and inflammatory cytokine storm probably impedes alveolar gas exchange and contributes to the high mortality of severe COVID-19 patients. Our research has identified that pathogenic T cells and inflammatory monocytes incite inflammatory storm with large amount of interleukin 6, therefore monoclonal antibody that targets the IL-6 pathways may potentially curb inflammatory storm. Moreover, Tocilizumab treatment that blocking IL-6 receptors showed inspiring clinical results including temperature returned to normal quickly and respiratory function improved. Therefore, we suggest that Tocilizumab is an effective treatment in severe patients of COVID-19 to calm the inflammatory storm and reduce mortality.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , COVID-19 , Coronavirus Infections/immunology , Humans , Interleukin-6/antagonists & inhibitors , Pandemics , Pneumonia, Viral/immunology , SARS-CoV-2 , Severity of Illness Index
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