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1.
Int J Clin Pract ; 75(9): e14462, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1494712

ABSTRACT

BACKGROUND AND PURPOSE: Studies have shown that some cytokines in COVID-19 patients were elevated. This study aims to assess whether IL-10, IL-1ß, IL-6, MCP-1, TNF-α, IP-10 and IL-4 serve as potential diagnostic biomarkers of COVID-19. METHODS: The above serum cytokines in COVID-19 patients and non-COVID-19 patients were detected by ELISA and SARS-CoV-2 IgM and IgG were detected by the chemiluminescence method. The independent-sample Mann-Whitney U test was utilised to compare cytokine levels in different groups and courses, the Levene T-test and T'-test were utilised to compare they in different genders and the Spearman correlation test was utilised to analyse the correlation between the cytokine levels with ages and SARS-CoV-2 IgG and IgM. RESULTS: Serum levels of IL-10, IL-1ß, MCP-1, TNF-α and IL-4 in COVID-19 patients were significantly higher than those in non-COVID-19 patients, while IL-6 were only significantly higher than in healthy people, IP-10 were significantly lower than in other diseases patients. AUCs of COVID-19 diagnosed by IL-10, IL-1ß, IL-6, MCP-1, TNF-α, IP-10 and IL-4 were 0.735, 0.775, 0.595, 0.821, 0.848, 0.38 and 0.682, respectively. In the COVID-19 patients' serum, the levels of IL-10 and MCP-1 of male were noticeably higher than those of female, and all cytokines were significantly positively correlated with age, IL-1ß and IL-4 were significantly negatively correlated with SARS-CoV-2 IgM, while IL-10, IL-1ß, IL-6, TNF- and IP-10 were significantly negatively correlated with SARS-CoV-2 IgG. IL-10 on 43-56 days was significantly lower than at 29-42 days, TNF-α at 15-42 days was significantly higher than at 0-14 days, IP-10 at 0-14 days was the highest and IL-4 at 29-42 days was significantly higher than at 0-14 days. CONCLUSIONS: The detection of IL-10, IL-1 ß, IL-6, MCP-1, TNF-α and IL-4 would assist the clinical study of COVID-19, and IP-10 may be the cytokine of early elevation in COVID-19 patients.


Subject(s)
COVID-19 , Tumor Necrosis Factor-alpha , Chemokine CXCL10 , Cytokines , Female , Humans , Interleukin-10 , Interleukin-1beta , Interleukin-4 , Interleukin-6 , Male , SARS-CoV-2
2.
Engineering (Beijing) ; 7(7): 958-965, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1482579

ABSTRACT

The longitudinal immunologic status of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients and its association with the clinical outcome are barely known. Thus, we sought to analyze the temporal profiles of specific antibodies, as well as the associations between the antibodies, proinflammatory cytokines, and survival of patients with coronavirus disease 2019 (COVID-19). A total of 1830 laboratory-confirmed COVID-19 cases were recruited. The temporal profiles of the virus, antibodies, and cytokines of the patients until 12 weeks since illness onset were fitted by the locally weighted scatter plot smoothing method. The mediation effect of cytokines on the associations between antibody responses and survival were explored by mediation analysis. Of the 1830 patients, 1435 were detectable for SARS-CoV-2, while 395 were positive in specific antibodies only. Of the 1435 patients, 2.4% presented seroconversion for neither immunoglobulin G (IgG) nor immunoglobulin M (IgM) during hospitalization. The seropositive rates of IgG and IgM were 29.6% and 48.1%, respectively, in the first week, and plateaued within five weeks. For the patients discharged from the hospital, the IgM decreased slowly, while high levels of IgG were maintained at around 188 AU·mL-1 for the 12 weeks since illness onset. In contrast, in the patients who subsequently died, IgM declined rapidly and IgG dropped to 87 AU·mL-1 at the twelfth week. Elevated interleukin-6, interleukin-8, interleukin-10, interleukin-1ß, interleukin-2R, and tumor necrosis factor-α levels were observed in the deceased patients in comparison with the discharged patients, and 12.5% of the association between IgG level and mortality risk was mediated by these cytokines. Our study deciphers the temporal profiles of SARS-CoV-2-specific antibodies within the 12 weeks since illness onset and indicates the protective effect of antibody response on survival, which may help to guide prognosis estimation.

3.
Cells ; 10(4)2021 04 14.
Article in English | MEDLINE | ID: covidwho-1456314

ABSTRACT

Introduction: Intra-articular fractures are a major cause of post-traumatic osteoarthritis (PTOA). Despite adequate surgical treatment, the long-term risk for PTOA is high. Previous studies reported that joint injuries initiate an inflammatory cascade characterized by an elevation of synovial pro-inflammatory cytokines, which can lead to cartilage degradation and PTOA development. This review summarizes the literature on the post-injury regulation of pro-inflammatory cytokines and the markers of cartilage destruction in patients suffering from intra-articular fractures. Methods: We searched Medline, Embase, and Cochrane databases (1960-February 2020) and included studies that were performed on human participants, and we included control groups. Two investigators assessed the quality of the included studies using Covidence and the Newcastle-Ottawa Scale. Results: Based on the surveyed literature, several synovial pro-inflammatory cytokines, including interleukins (IL)-1ß, IL-2, IL-6, IL-8, IL-12p70, interferon-y, and tumor necrosis factor-α, were significantly elevated in patients suffering from intra-articular fractures compared to the control groups. A simultaneous elevation of anti-inflammatory cytokines such as IL-10 and IL-1RA was also observed. In contrast, IL-13, CTX-II, and aggrecan concentrations did not differ significantly between the compared cohorts. Conclusions: Overall, intra-articular fractures are associated with an increase in inflammation-related synovial cytokines. However, more standardized studies which focus on the ratio of pro- and anti-inflammatory cytokines at different time points are needed.


Subject(s)
Cytokines/metabolism , Inflammation Mediators/metabolism , Intra-Articular Fractures/metabolism , Case-Control Studies , Humans , Joints/pathology , Synovial Fluid/metabolism
5.
Iran J Immunol ; 18(1): 54-64, 2021 03.
Article in English | MEDLINE | ID: covidwho-1160833

ABSTRACT

BACKGROUND: SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is recognized for the first time in Wuhan, China. The cytokine storm is a known factor causing major clinical symptoms leading to death in COVID-19 patients. OBJECTIVE: To investigate and compare the serum levels of different cytokines in COVID-19 patients with different clinical severity. METHODS: Concentrations of serum cytokines, including IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, IFN-γ, and GM-CSF, were measured in 61 COVID-19 patients and 31 normal controls with ELISA. We investigated the correlation between the levels of these cytokines and clinical severity, CRP level, neutrophil and lymphocyte count in patients with COVID-19. RESULTS: Our data indicated that the levels of IL-1ß, IL-2, IL-4, IL-6, IL-8, TNF-α, IFN-γ, and GM-CSF, but not IL-10 were significantly increased in COVID-19 patients compared to normal controls. Statistical analysis showed that the level of IL-1ß, IL-2, IL-4, IL-6, IL-8, TNF-α, IFN-γ, and GM-CSF were higher in severe COVID-19 than those of mild cases. The concentrations of all mentioned cytokines were negatively associated with the absolute count of lymphocytes, and positively correlated with the CRP level and the absolute count of neutrophils. CONCLUSION: The current study suggests that high levels of various cytokines correlate with the disease severity and immunopathogenesis of COVID-19.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Cytokines/blood , SARS-CoV-2/immunology , Aged , Biomarkers/blood , C-Reactive Protein/analysis , COVID-19/blood , COVID-19/diagnosis , COVID-19/virology , Case-Control Studies , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/virology , Female , Host-Pathogen Interactions , Humans , Iran , Lymphocytes/immunology , Lymphocytes/metabolism , Lymphocytes/virology , Male , Middle Aged , Neutrophils/immunology , Neutrophils/metabolism , Neutrophils/virology , SARS-CoV-2/pathogenicity , Severity of Illness Index
6.
Life Sci ; 276: 119376, 2021 Jul 01.
Article in English | MEDLINE | ID: covidwho-1157590

ABSTRACT

The severe forms and worsened outcomes of COVID-19 (coronavirus disease 19) are closely associated with hypertension and cardiovascular disease. Endothelial cells express Angiotensin-Converting Enzyme 2 (ACE2), which is the entrance door for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The hallmarks of severe illness caused by SARS-CoV-2 infection are increased levels of IL-6, C-reactive protein, D-dimer, ferritin, neutrophilia and lymphopenia, pulmonary intravascular coagulopathy and microthrombi of alveolar capillaries. The endothelial glycocalyx, a proteoglycan- and glycoprotein-rich layer covering the luminal side of endothelial cells, contributes to vascular homeostasis. It regulates vascular tonus and permeability, prevents thrombosis, and modulates leukocyte adhesion and inflammatory response. We hypothesized that cytokine production and reactive oxygen species (ROS) generation associated with COVID-19 leads to glycocalyx degradation. A cohort of 20 hospitalized patients with a confirmed COVID-19 diagnosis and healthy subjects were enrolled in this study. Mechanisms associated with glycocalyx degradation in COVID-19 were investigated. Increased plasma concentrations of IL-6 and IL1-ß, as well as increased lipid peroxidation and glycocalyx components were detected in plasma from COVID-19 patients compared to plasma from healthy subjects. Plasma from COVID-19 patients induced glycocalyx shedding in cultured human umbilical vein endothelial cells (HUVECs) and disrupted redox balance. Treatment of HUVECs with low molecular weight heparin inhibited the glycocalyx perturbation. In conclusion, plasma from COVID-19 patients promotes glycocalyx shedding and redox imbalance in endothelial cells, and heparin treatment potentially inhibits glycocalyx disruption.


Subject(s)
COVID-19/blood , COVID-19/pathology , Glycocalyx/pathology , Heparin/pharmacology , Aged , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/virology , COVID-19/metabolism , COVID-19 Testing , Case-Control Studies , Cell Adhesion/physiology , Endothelium, Vascular/metabolism , Female , Glycocalyx/metabolism , Glycocalyx/virology , Human Umbilical Vein Endothelial Cells , Humans , Interleukin-1beta/blood , Interleukin-6/blood , Male , Middle Aged , Oxidation-Reduction , SARS-CoV-2 , Thrombosis/metabolism
7.
J Immunol ; 206(7): 1597-1608, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1082059

ABSTRACT

Coronavirus disease 2019 (COVID-19) is associated with immune dysregulation and cytokine storm. Exploring the immune-inflammatory characteristics of COVID-19 patients is essential to reveal pathogenesis and predict progression. In this study, COVID-19 patients showed decreased CD3+, CD4+, and CD8+ T cells but increased neutrophils in circulation, exhibiting upregulated neutrophil-to-lymphocyte and neutrophil-to-CD8+ T cell ratio. IL-6, TNF-α, IL-1ß, IL-18, IL-12/IL-23p40, IL-10, Tim-3, IL-8, neutrophil extracellular trap-related proteinase 3, and S100A8/A9 were elevated, whereas IFN-γ and C-type lectin domain family 9 member A (clec9A) were decreased in COVID-19 patients compared with healthy controls. When compared with influenza patients, the expressions of TNF-α, IL-18, IL-12/IL-23p40, IL-8, S100A8/A9 and Tim-3 were significantly increased in critical COVID-19 patients, and carcinoembryonic Ag, IL-8, and S100A8/A9 could serve as clinically available hematologic indexes for identifying COVID-19 from influenza. Moreover, IL-6, IL-8, IL-1ß, TNF-α, proteinase 3, and S100A8/A9 were increased in bronchoalveolar lavage fluid of severe/critical patients compared with moderate patients, despite decreased CD4+ T cells, CD8+ T cells, B cells, and NK cells. Interestingly, bronchoalveolar IL-6, carcinoembryonic Ag, IL-8, S100A8/A9, and proteinase 3 were found to be predictive of COVID-19 severity and may serve as potential biomarkers for predicting COVID-19 progression and potential targets in therapeutic intervention of COVID-19.


Subject(s)
COVID-19 , Inflammation Mediators , SARS-CoV-2 , Severity of Illness Index , Aged , COVID-19/blood , COVID-19/immunology , Calgranulin A/blood , Calgranulin A/immunology , Calgranulin B/blood , Calgranulin B/immunology , Cytokines/blood , Cytokines/immunology , Disease Progression , Female , Hepatitis A Virus Cellular Receptor 2/blood , Hepatitis A Virus Cellular Receptor 2/immunology , Humans , Inflammation Mediators/blood , Inflammation Mediators/immunology , Leukocyte Count , Male , Middle Aged , Myeloblastin/blood , Myeloblastin/immunology , Retrospective Studies , SARS-CoV-2/immunology , SARS-CoV-2/metabolism
8.
Front Immunol ; 11: 603389, 2020.
Article in English | MEDLINE | ID: covidwho-1069720

ABSTRACT

The catastrophic outbreak of coronavirus disease 2019 (COVID-19) is currently a public emergency. Adult-onset Still's disease (AOSD) is an autoinflammatory disease characterized by life-threatening complications. Systemic hyperinflammation and cytokine storm play a critical role in the pathogenesis of both COVID-19 and AOSD. We aimed to compare the similarities and differences focusing on ferritin and cytokine levels between severe COVID-19 and active AOSD. A literature search was performed using the databases PubMed, EMBASE, and Web of Science to collect the levels of cytokine including IL-1ß, IL-6, IL-18, TNF-α, IL-10, and ferritin in severe COVID-19 patients. After extracting available data of indicators of interest, we acquired these statistics with a single-arm meta-analysis. Furthermore, a comparison was conducted between 52 patients with active AOSD in our center and severe COVID-19 patients from databases. The levels of IL-6 and IL-10 were higher in severe COVID-19 compared with those in active AOSD. There were no significant differences on the cytokine of IL-1ß and TNF-α. Fold changes of IL-18 were defined as the mean expression level ratio of severe COVID-19 to healthy controls in the COVID-19 study and active AOSD to healthy controls in our study, individually. Although the fold change of IL-18 in patients with AOSD was significantly higher than patients with severe COVID-19 (fold change: 594.00 vs 2.17), there was no statistical comparability. In addition, the level of ferritin was higher in active AOSD in comparison with severe COVID-19. Our findings suggest that severe COVID-19 and active AOSD have differences in cytokine panel and ferritin level, indicating the pathogenic role of ferritin in overwhelming inflammation. And it paves the way to make efficacy therapeutic strategy targeting the hyperinflammatory process in COVID-19 according to AOSD management, especially in severe COVID-19.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Inflammation/immunology , Still's Disease, Adult-Onset/immunology , Adult , Aged , COVID-19/epidemiology , Cytokine Release Syndrome/epidemiology , Cytokines/blood , Female , Ferritins/blood , Humans , Male , Middle Aged , Still's Disease, Adult-Onset/epidemiology
9.
J Cyst Fibros ; 20(1): 31-35, 2021 01.
Article in English | MEDLINE | ID: covidwho-1065291

ABSTRACT

BACKGROUND: The clinical course of severe COVID-19 in cystic fibrosis (CF) is incompletely understood. We describe the use of alpha-1 antitrypsin (AAT) as a salvage therapy in a critically unwell patient with CF (PWCF) who developed COVID-19 while awaiting lung transplantation. METHODS: IV AAT was administered at 120 mg/kg/week for 4 consecutive weeks. Levels of interleukin (IL)-1ß, IL-6, IL-8, and soluble TNF receptor 1 (sTNFR1) were assessed at regular intervals in plasma, with IL-1ß, IL-6, IL-8 and neutrophil elastase (NE) activity measured in airway secretions. Levels were compared to baseline and historic severe exacerbation measurements. RESULTS: Systemic and airway inflammatory markers were increased compared to both prior exacerbation and baseline levels, in particular IL-6, IL-1ß and NE activity. Following each AAT dose, rapid decreases in each inflammatory parameter were observed. These were matched by marked clinical and radiographic improvement. CONCLUSIONS: The results support further investigation of AAT as a COVID-19 therapeutic, and re-exploration of its use in CF.


Subject(s)
COVID-19/complications , Cystic Fibrosis/complications , Cystic Fibrosis/drug therapy , alpha 1-Antitrypsin/therapeutic use , Adult , Biomarkers/blood , COVID-19/diagnostic imaging , Cystic Fibrosis/diagnostic imaging , Female , Humans , Ireland , Respiratory Function Tests , SARS-CoV-2
10.
J Biomol Struct Dyn ; 40(13): 5769-5784, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1045962

ABSTRACT

The unavailability of vaccine and medicines raised serious issues during COVID-19 pandemic and peoples from different parts of world relied on traditional medicine for their immediate recovery from COVID-19 and it found effective also. The current research aims to target COVID-19 immunological human host receptors i.e. angiotensin-converting enzyme (ACE)-2, interleukin (IL)-1ß, IL-6, tumor necrosis factor-alpha (TNF-α) and protease-activated receptor (PAR)-1 using curcumin derivatives to prevent viral infection and control overproduction of early clinical responses of COVID-19. Targeting these host proteins will mitigate the infection and will filter out many complications caused by these proteins in COVID-19 patients. It is proven through computer-aided computational modeling approaches, total 30 compounds of curcumin and its derivatives were chosen. Drug-likeness parameters were calculated for curcumin and its derivatives and 20 curcumin analogs were selected for docking analysis. From docking analysis of 20 curcumin analogs against five chosen human host receptor targets reveals 11 curcumin analogs possess least binding affinity and best interaction at active sites subjected to absorption, distribution, metabolism, excretion (ADME) analysis. Density functional theory (DFT) analysis of five final shortlisted curcumin derivatives was done to show least binding affinity toward chosen host target protein. Molecular dynamics simulation (MDS) was performed to observe behavior and interaction of potential drug hydrazinocurcumin against target proteins ACE-2 and PAR-1. It was performed at 100 nanoseconds and showed satisfactory results. Finally, our investigation reveals that hydrazinocurcumin possesses immunomodulatory and anti-cytokine therapeutic potential against COVID-19 and it can act as COVID-19 warrior drug molecule and promising choice of drug for COVID-19 treatment, however, it needs further in vivo clinical evaluation to commercialize as COVID-19 drug.Communicated by Ramaswamy H. Sarma.


Subject(s)
COVID-19 , Curcumin , COVID-19/drug therapy , Curcumin/chemistry , Curcumin/pharmacology , Curcumin/therapeutic use , Cytokines , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics
11.
Cytokine ; 140: 155439, 2021 04.
Article in English | MEDLINE | ID: covidwho-1032441

ABSTRACT

BACKGROUND: Immunodeficiency has pivotal role in the pathogenesis of coronavirus disease 2019 (COVID-19). Several studies have indicated defects in the immune system of COVID-19 patients at different disease stages. Therefore, this study investigated whether alters in immune responses of COVID-19 patients may be considered as predicting factors for disease outcome. METHODS: The percentages of innate and adoptive immune cells in the recovered and dead patients with COVID-19, and healthy subjects were determined by flow cytometry. The levels of pro- and anti-inflammatory cytokines and other immune factors were also measured by enzyme-linked immunosorbent assay. RESULTS: At the first day of hospitalization, the frequencies of CD56dim CD16+ NK cells and CD56bright CD16dim/- NK cells in patients who died during treatment were significantly increased compared to recovered and healthy individuals (P < 0.0001). The recovered and dead patients had a significant increase in monocyte number in comparison with healthy subjects (P < 0.05). No significant change was observed in Th1 cell numbers between the recovered and dead patients while Th2, Th17 cell, and Treg percentages in death cases were significantly lower than healthy control and those recovered, unlike exhausted CD4 + and CD8 + T cells and activated CD4 + T cells (P < 0.0001-0.05). The activated CD8 + T cell was significantly higher in the recovered patients than healthy individuals (P < 0.0001-0.05). IL-1α, IL-1ß, IL-6, and TNF-α levels in patients were significantly increased (P < 0.0001-0.01). However, there were no differences in TNF-α and IL-1ß levels between dead and recovered patients. Unlike TGF-ß1 level, IL-10 was significantly increased in recovered patients (P < 0.05). Lymphocyte numbers in recovered patients were significantly increased compared to dead patients, unlike ESR value (P < 0.001-0.01). CRP value in recovered patients significantly differed from dead patients (P < 0.001). CONCLUSION: Changes in frequencies of some immune cells and levels of some immune factors may be considered as predictors of mortality in COVID-19 patients.


Subject(s)
COVID-19/immunology , Cytokines/immunology , Immune System/immunology , Immunity/immunology , SARS-CoV-2/immunology , Survivors/statistics & numerical data , Adult , Aged , Aged, 80 and over , COVID-19/mortality , COVID-19/virology , Cytokines/blood , Female , Humans , Immune System/cytology , Male , Middle Aged , Monocytes/immunology , SARS-CoV-2/physiology , Survival Rate , T-Lymphocytes/immunology , T-Lymphocytes, Helper-Inducer/classification , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Regulatory/immunology
12.
Front Pharmacol ; 11: 569849, 2020.
Article in English | MEDLINE | ID: covidwho-972744

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the novel coronavirus, causing coronavirus disease 2019 (COVID-19). During virus infection, several pro-inflammatory cytokines are produced, leading to the "cytokine storm." Among these, interleukin (IL)-6, tumor necrosis factor-α (TNF-α), and IL-1ß seem to have a central role in the progression and exacerbation of the disease, leading to the recruitment of immune cells to infection sites. Autophagy is an evolutionarily conserved lysosomal degradation pathway involved in different aspects of lymphocytes functionality. The involvement of IL-6, TNF-α, and IL-1ß in autophagy modulation has recently been demonstrated. Moreover, preliminary studies showed that SARS-CoV-2 could infect lymphocytes, playing a role in the modulation of autophagy. Several anti-rheumatic drugs, now proposed for the treatment of COVID-19, could modulate autophagy in lymphocytes, highlighting the therapeutic potential of targeting autophagy in SARS-CoV-2 infection.

13.
J Med Virol ; 92(11): 2600-2606, 2020 11.
Article in English | MEDLINE | ID: covidwho-935122

ABSTRACT

To investigate the inflammatory factors and lymphocyte subsets which play an important role in the course of severe coronavirus disease 2019 (COVID-19). A total of 27 patients with severe COVID-19 who were admitted to Tongji Hospital in Wuhan from 1 to 21 February 2020 were recruited to the study. The characteristics of interleukin-1ß (IL-1ß), IL-2 receptor (IL-2R), IL-6, IL-8, IL-10, tumor necrosis factor-α (TNF)-α, C-reactive protein (CRP), serum ferritin and procalcitonin (PCT), and lymphocyte subsets of these patients were retrospectively compared before and after treatment. Before treatment, there was no significant difference in most inflammatory factors (IL-1ß, IL-2R, IL-6, IL-8, IL-10, CRP, and serum ferritin) between male and female patients. Levels of IL-2R, IL-6, TNF-α, and CRP decreased significantly after treatment, followed by IL-8, IL-10, and PCT. Serum ferritin was increased in all patients before treatment but did not decrease significantly after treatment. IL-1ß was normal in most patients before treatment. Lymphopenia was common among these patients with severe COVID-19. Analysis of lymphocyte subsets showed that CD4+ and particularly CD8+ T lymphocytes increased significantly after treatment. However, B lymphocytes and natural killer cells showed no significant changes after treatment. A pro-inflammatory response and decreased level of T lymphocytes were associated with severe COVID-19.


Subject(s)
COVID-19/immunology , Inflammation/immunology , Lymphocyte Subsets/immunology , Adult , Aged , Aged, 80 and over , Antiviral Agents/therapeutic use , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/therapy , China , Cytokines/blood , Cytokines/immunology , Female , Humans , Interleukins/blood , Lymphocyte Count , Male , Middle Aged , Prognosis , Retrospective Studies , Severity of Illness Index
14.
Front Immunol ; 11: 583373, 2020.
Article in English | MEDLINE | ID: covidwho-902402

ABSTRACT

Coronaviruses (CoVs) are members of the genus Betacoronavirus and the Coronaviridiae family responsible for infections such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and more recently, coronavirus disease-2019 (COVID-19). CoV infections present mainly as respiratory infections that lead to acute respiratory distress syndrome (ARDS). However, CoVs, such as COVID-19, also present as a hyperactivation of the inflammatory response that results in increased production of inflammatory cytokines such as interleukin (IL)-1ß and its downstream molecule IL-6. The inflammasome is a multiprotein complex involved in the activation of caspase-1 that leads to the activation of IL-1ß in a variety of diseases and infections such as CoV infection and in different tissues such as lungs, brain, intestines and kidneys, all of which have been shown to be affected in COVID-19 patients. Here we review the literature regarding the mechanism of inflammasome activation by CoV infection, the role of the inflammasome in ARDS, ventilator-induced lung injury (VILI), and Disseminated Intravascular Coagulation (DIC) as well as the potential mechanism by which the inflammasome may contribute to the damaging effects of inflammation in the cardiac, renal, digestive, and nervous systems in COVID-19 patients.


Subject(s)
Caspase 1/metabolism , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Cytokine Release Syndrome/pathology , Inflammasomes/immunology , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Betacoronavirus/immunology , COVID-19 , Disseminated Intravascular Coagulation/pathology , Humans , Inflammation/pathology , Interleukin-1beta/metabolism , Pandemics , SARS-CoV-2 , Severe Acute Respiratory Syndrome/pathology , Ventilator-Induced Lung Injury/pathology
15.
Aging (Albany NY) ; 12(20): 19867-19879, 2020 10 16.
Article in English | MEDLINE | ID: covidwho-875021

ABSTRACT

The ongoing outbreak of COVID-19 has been announced by the World Health Organization as a worldwide public health emergency. The aim of this study was to distinguish between severe and non-severe patients in early diagnosis. The results showed that the mortality of COVID-19 patients increased accompanied by age. Host factors CRP, IL-1ß, hs-CRP, IL-8, and IL-6 levels in severe pneumonia patients were higher than in non-severe patients. CD3, CD8, and CD45 counts were decreased in COVID-19 patients. The results of this study suggest that the K-values of CD45 might be useful in distinguishing between severe and non-severe cases. The cut-off value for CD45 was -94.33. The K-values for CD45 in non-severe case were above the cut-off values, indicating a 100% prediction success rate for severe and non-severe cases following SARS-CoV-2 infection. The results confirmed that immune system dysfunction is a potential cause of mortality following COVID-19 infection, particularly for the elderly. CD45 deficiency dysfunction the naïve and memory T lymphocytes which may affects the long-term effectiveness of COVID-19 vaccines. K-values of CD45 might be useful in distinguishing between severe and non-severe cases in the early infection. May be CD45 could increase the diagnostic sensitivity.


Subject(s)
Betacoronavirus/immunology , CD3 Complex/deficiency , Coronavirus Infections/immunology , Host-Pathogen Interactions/immunology , Leukocyte Common Antigens/deficiency , Pneumonia, Viral/immunology , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Early Diagnosis , Female , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , Retrospective Studies , SARS-CoV-2 , Young Adult
16.
Respir Res ; 21(1): 245, 2020 Sep 22.
Article in English | MEDLINE | ID: covidwho-781468

ABSTRACT

BACKGROUND: The COVID-19 pandemic has led to more than 760,000 deaths worldwide (correct as of 16th August 2020). Studies suggest a hyperinflammatory response is a major cause of disease severity and death. Identitfying COVID-19 patients with hyperinflammation may identify subgroups who could benefit from targeted immunomodulatory treatments. Analysis of cytokine levels at the point of diagnosis of SARS-CoV-2 infection can identify patients at risk of deterioration. METHODS: We used a multiplex cytokine assay to measure serum IL-6, IL-8, TNF, IL-1ß, GM-CSF, IL-10, IL-33 and IFN-γ in 100 hospitalised patients with confirmed COVID-19 at admission to University Hospital Southampton (UK). Demographic, clinical and outcome data were collected for analysis. RESULTS: Age > 70 years was the strongest predictor of death (OR 28, 95% CI 5.94, 139.45). IL-6, IL-8, TNF, IL-1ß and IL-33 were significantly associated with adverse outcome. Clinical parameters were predictive of poor outcome (AUROC 0.71), addition of a combined cytokine panel significantly improved the predictability (AUROC 0.85). In those ≤70 years, IL-33 and TNF were predictive of poor outcome (AUROC 0.83 and 0.84), addition of a combined cytokine panel demonstrated greater predictability of poor outcome than clinical parameters alone (AUROC 0.92 vs 0.77). CONCLUSIONS: A combined cytokine panel improves the accuracy of the predictive value for adverse outcome beyond standard clinical data alone. Identification of specific cytokines may help to stratify patients towards trials of specific immunomodulatory treatments to improve outcomes in COVID-19.


Subject(s)
Coronavirus Infections/blood , Coronavirus Infections/epidemiology , Cytokines/analysis , Hospital Mortality , Inflammation Mediators/blood , Pandemics/statistics & numerical data , Pneumonia, Viral/blood , Pneumonia, Viral/epidemiology , Age Factors , Analysis of Variance , Area Under Curve , COVID-19 , COVID-19 Testing , Clinical Laboratory Techniques/methods , Cohort Studies , Coronavirus Infections/diagnosis , Coronavirus Infections/physiopathology , Female , Hospitalization/statistics & numerical data , Hospitals, University , Humans , Incidence , Male , Pandemics/prevention & control , Phenotype , Pneumonia, Viral/physiopathology , Predictive Value of Tests , ROC Curve , Retrospective Studies , Severity of Illness Index , Sex Factors , United Kingdom
17.
Pharmaceuticals (Basel) ; 13(9)2020 Sep 09.
Article in English | MEDLINE | ID: covidwho-760948

ABSTRACT

Herein, we discuss the potential role of folic acid-based radiopharmaceuticals for macrophage imaging to support clinical decision-making in patients with COVID-19. Activated macrophages play an important role during coronavirus infections. Exuberant host responses, i.e., a cytokine storm with increase of macrophage-related cytokines, such as TNFα, IL-1ß, and IL-6 can lead to life-threatening complications, such as acute respiratory distress syndrome (ARDS), which develops in approximately 20% of the patients. Diverse immune modulating therapies are currently being tested in clinical trials. In a preclinical proof-of-concept study in experimental interstitial lung disease, we showed the potential of 18F-AzaFol, an 18F-labeled folic acid-based radiotracer, as a specific novel imaging tool for the visualization and monitoring of macrophage-driven lung diseases. 18F-AzaFol binds to the folate receptor-beta (FRß) that is expressed on activated macrophages involved in inflammatory conditions. In a recent multicenter cancer trial, 18F-AzaFol was successfully and safely applied (NCT03242993). It is supposed that the visualization of activated macrophage-related disease processes by folate radiotracer-based nuclear imaging can support clinical decision-making by identifying COVID-19 patients at risk of a severe disease progression with a potentially lethal outcome.

18.
Nat Med ; 26(10): 1636-1643, 2020 10.
Article in English | MEDLINE | ID: covidwho-728994

ABSTRACT

Several studies have revealed that the hyper-inflammatory response induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major cause of disease severity and death. However, predictive biomarkers of pathogenic inflammation to help guide targetable immune pathways are critically lacking. We implemented a rapid multiplex cytokine assay to measure serum interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α and IL-1ß in hospitalized patients with coronavirus disease 2019 (COVID-19) upon admission to the Mount Sinai Health System in New York. Patients (n = 1,484) were followed up to 41 d after admission (median, 8 d), and clinical information, laboratory test results and patient outcomes were collected. We found that high serum IL-6, IL-8 and TNF-α levels at the time of hospitalization were strong and independent predictors of patient survival (P < 0.0001, P = 0.0205 and P = 0.0140, respectively). Notably, when adjusting for disease severity, common laboratory inflammation markers, hypoxia and other vitals, demographics, and a range of comorbidities, IL-6 and TNF-α serum levels remained independent and significant predictors of disease severity and death. These findings were validated in a second cohort of patients (n = 231). We propose that serum IL-6 and TNF-α levels should be considered in the management and treatment of patients with COVID-19 to stratify prospective clinical trials, guide resource allocation and inform therapeutic options.


Subject(s)
Coronavirus Infections/immunology , Interleukin-1beta/immunology , Interleukin-6/immunology , Interleukin-8/immunology , Pneumonia, Viral/immunology , Tumor Necrosis Factor-alpha/immunology , Aged , Betacoronavirus , COVID-19 , Coronavirus Infections/mortality , Coronavirus Infections/physiopathology , Coronavirus Infections/therapy , Cytokines/immunology , Female , Hospitalization , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/mortality , Pneumonia, Viral/physiopathology , Pneumonia, Viral/therapy , SARS-CoV-2 , Severity of Illness Index , Survival Rate
19.
Aging Dis ; 11(4): 756-762, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-696061

ABSTRACT

Age is one of the most important prognostic factors associated to lethality in SARS-CoV-2 infection. In multivariate analysis, advanced age was an independent risk factor for death. Recent studies suggest a role for the nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome activation in lung inflammation and fibrosis in SARS-CoV and SARS-CoV-2 infections. Increased NLRP3/ apoptosis-associated speck-like protein (ASC) mRNA expression and increased caspase-1 activity, have been observed in aged lung, provoking increased and heightened expression levels of mature Interleukin (IL)-1ß and IL-18 in aged individuals. Aged individuals have a basal predisposition to over-react to infection, displaying an increased hyper-inflammatory cascade, that seems not to be fully physiologically controlled. NLRP3 inflammasome is over-activated in aged individuals, through deficient mitochondrial functioning, increased mitochondrial Reactive Oxigen Species (mtROS) and/or mitochondrial (mt)DNA, leading to a hyper-response of classically activated macrophages and subsequent increases in IL-1 ß. This NLRP3 over-activated status in elderly individuals, is also observed in telomere dysfunctional mice models. In our opinion, the NLRP3 inflammasome plays a central role in the increased lethality observed in elderly patients infected by COVID-19. Strategies blocking inflammasome would deserve to be studied.

20.
Am J Respir Crit Care Med ; 202(6): 812-821, 2020 09 15.
Article in English | MEDLINE | ID: covidwho-614625

ABSTRACT

Rationale: Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood.Objectives: To define the cytokine profile of COVID-19 and to identify evidence of immunometabolic alterations in those with severe illness.Methods: Levels of IL-1ß, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVIDstable patients), patients with COVID-19 requiring ICU admission (COVIDICU patients), and patients with severe community-acquired pneumonia requiring ICU support (CAPICU patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated.Measurements and Main Results: IL-1ß, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVIDICU patients could be clearly differentiated from COVIDstable patients, and demonstrated higher levels of IL-1ß, IL-6, and sTNFR1 but lower IL-10 than CAPICU patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission (P < 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution (P < 0.0001).Conclusions: The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population.


Subject(s)
Acute-Phase Reaction/immunology , Carrier Proteins/metabolism , Coronavirus Infections/immunology , Coronavirus Infections/metabolism , Cytokines/immunology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Lactic Acid/metabolism , Membrane Proteins/metabolism , Pneumonia, Viral/immunology , Pneumonia, Viral/metabolism , Thyroid Hormones/metabolism , alpha 1-Antitrypsin/immunology , Acute-Phase Reaction/metabolism , Adult , Aged , Betacoronavirus , Blotting, Western , COVID-19 , Case-Control Studies , Community-Acquired Infections/immunology , Community-Acquired Infections/metabolism , Coronavirus Infections/mortality , Coronavirus Infections/physiopathology , Critical Illness , Electrophoresis, Polyacrylamide Gel , Enzyme-Linked Immunosorbent Assay , Female , Hospitalization , Humans , Intensive Care Units , Interleukin-10/immunology , Interleukin-1beta/immunology , Interleukin-6/immunology , Interleukin-8/immunology , Length of Stay , Male , Middle Aged , Neutrophils/immunology , Neutrophils/metabolism , Pandemics , Phosphorylation , Pneumonia/immunology , Pneumonia/metabolism , Pneumonia, Viral/mortality , Pneumonia, Viral/physiopathology , Receptors, Tumor Necrosis Factor, Type I/immunology , SARS-CoV-2 , Severity of Illness Index , alpha 1-Antitrypsin/metabolism
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