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1.
Viruses ; 13(12)2021 12 10.
Article in English | MEDLINE | ID: covidwho-1572659

ABSTRACT

Large variability in COVID-19 clinical progression urges the need to find the most relevant biomarkers to predict patients' outcomes. We evaluated iron metabolism and immune response in 303 patients admitted to the main hospital of the northern region of Portugal with variable clinical pictures, from September to November 2020. One hundred and twenty-seven tested positive for SARS-CoV-2 and 176 tested negative. Iron-related laboratory parameters and cytokines were determined in blood samples collected soon after admission. Demographic data, comorbidities and clinical outcomes were recorded. Patients were assigned into five groups according to severity. Serum iron and transferrin levels at admission were lower in COVID-19-positive than in COVID-19-negative patients. The levels of interleukin (IL)-6 and monocyte chemoattractant protein 1 (MCP-1) were increased in COVID-19-positive patients. The lowest serum iron and transferrin levels at diagnosis were associated with the worst outcomes. Iron levels negatively correlated with IL-6 and higher levels of this cytokine were associated with a worse prognosis. Serum ferritin levels at diagnosis were higher in COVID-19-positive than in COVID-19-negative patients. Serum iron is the simplest laboratory test to be implemented as a predictor of disease progression in COVID-19-positive patients.


Subject(s)
Biomarkers/blood , COVID-19 , Iron/blood , Severity of Illness Index , Adult , Aged , Aged, 80 and over , Chemokine CCL2/blood , Cohort Studies , Cytokines/blood , Female , Ferritins , Hepcidins , Humans , Inflammation , Interleukin-6/blood , Male , Middle Aged , Portugal , SARS-CoV-2
2.
J Cell Mol Med ; 26(2): 274-286, 2022 01.
Article in English | MEDLINE | ID: covidwho-1566302

ABSTRACT

Based on the recent reports, cardiovascular events encompass a large portion of the mortality caused by the COVID-19 pandemic, which drawn cardiologists into the management of the admitted ill patients. Given that common laboratory values may provide key insights into the illness caused by the life-threatening SARS-CoV-2 virus, it would be more helpful for screening, clinical management and on-time therapeutic strategies. Commensurate with these issues, this review article aimed to discuss the dynamic changes of the common laboratory parameters during COVID-19 and their association with cardiovascular diseases. Besides, the values that changed in the early stage of the disease were considered and monitored during the recovery process. The time required for returning biomarkers to basal levels was also discussed. Finally, of particular interest, we tended to abridge the latest updates regarding the cardiovascular biomarkers as prognostic and diagnostic criteria to determine the severity of COVID-19.


Subject(s)
COVID-19/blood , Cardiovascular Diseases/blood , Cardiovascular System/metabolism , SARS-CoV-2/pathogenicity , Biomarkers/blood , COVID-19/complications , COVID-19/diagnosis , COVID-19/immunology , Cardiovascular Diseases/complications , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/immunology , Cardiovascular System/pathology , Cardiovascular System/virology , Chemokine CCL2/blood , Creatine Kinase, MB Form/blood , Fibrin Fibrinogen Degradation Products/metabolism , Homocysteine/blood , Humans , Interferon-gamma/blood , Interleukin-6/blood , L-Lactate Dehydrogenase/blood , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , Prognosis , SARS-CoV-2/growth & development , SARS-CoV-2/immunology , Troponin I/blood , Troponin T/blood , Tumor Necrosis Factor-alpha/blood
3.
PLoS One ; 16(12): e0260623, 2021.
Article in English | MEDLINE | ID: covidwho-1546962

ABSTRACT

PURPOSE: Cytokines are major mediators of COVID-19 pathogenesis and several of them are already being regarded as predictive markers for the clinical course and outcome of COVID-19 cases. A major pitfall of many COVID-19 cytokine studies is the lack of a benchmark sampling timing. Since cytokines and their relative change during an infectious disease course is quite dynamic, we evaluated the predictive value of serially measured cytokines for COVID-19 cases. METHODS: In this single-center, prospective study, a broad spectrum of cytokines were determined by multiplex ELISA assay in samples collected at admission and at the third day of hospitalization. Appropriateness of cytokine levels in predicting mortality were assessed by receiver-operating characteristic (ROC) analyses for both sampling times in paralel to conventional biomarkers. RESULTS: At both sampling points, higher levels of IL-6, IL-7, IL-10, IL-15, IL-27 IP-10, MCP-1, and GCSF were found to be more predictive for mortality (p<0.05). Some of these cytokines, such as IL-6, IL-10, IL-7 and GCSF, had higher sensitivity and specificity in predicting mortality. AUC values of IL-6, IL-10, IL-7 and GCSF were 0.85 (0.65 to 0.92), 0.88 (0.73 to 0.96), 0.80 (0.63 to 0.91) and 0.86 (0.70 to 0.95), respectively at hospital admission. Compared to hospital admission, on the 3rd day of hospitalization serum levels of IL-6 and, IL-10 decreased significantly in the survivor group, unlike the non-survivor group (IL-6, p = 0.015, and IL-10, p = 0.016). CONCLUSION: Our study results suggest that single-sample-based cytokine analyzes can be misleading and that cytokine levels measured serially at different sampling times provide a more precise and accurate estimate for the outcome of COVID-19 patients.


Subject(s)
COVID-19/blood , Cytokines/blood , Aged , Aged, 80 and over , COVID-19/mortality , Chemokine CCL2/blood , Chemokine CXCL10/blood , Enzyme-Linked Immunosorbent Assay , Female , Granulocyte Colony-Stimulating Factor/blood , Humans , Interleukin-10/blood , Interleukin-15/blood , Interleukin-27/blood , Interleukin-6/blood , Interleukin-7/blood , Male , Middle Aged , Predictive Value of Tests , Prospective Studies , Treatment Outcome
4.
J Am Soc Nephrol ; 32(1): 115-126, 2021 01.
Article in English | MEDLINE | ID: covidwho-1496665

ABSTRACT

BACKGROUND: Although diabetic kidney disease is the leading cause of ESKD in the United States, identifying those patients who progress to ESKD is difficult. Efforts are under way to determine if plasma biomarkers can help identify these high-risk individuals. METHODS: In our case-cohort study of 894 Chronic Renal Insufficiency Cohort Study participants with diabetes and an eGFR of <60 ml/min per 1.73 m2 at baseline, participants were randomly selected for the subcohort; cases were those patients who developed progressive diabetic kidney disease (ESKD or 40% eGFR decline). Using a multiplex system, we assayed plasma biomarkers related to tubular injury, inflammation, and fibrosis (KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40). Weighted Cox regression models related biomarkers to progression of diabetic kidney disease, and mixed-effects models estimated biomarker relationships with rate of eGFR change. RESULTS: Median follow-up was 8.7 years. Higher concentrations of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were each associated with a greater risk of progression of diabetic kidney disease, even after adjustment for established clinical risk factors. After accounting for competing biomarkers, KIM-1, TNFR-2, and YKL-40 remained associated with progression of diabetic kidney disease; TNFR-2 had the highest risk (adjusted hazard ratio, 1.61; 95% CI, 1.15 to 2.26). KIM-1, TNFR-1, TNFR-2, and YKL-40 were associated with rate of eGFR decline. CONCLUSIONS: Higher plasma levels of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were associated with increased risk of progression of diabetic kidney disease; TNFR-2 had the highest risk after accounting for the other biomarkers. These findings validate previous literature on TNFR-1, TNFR-2, and KIM-1 in patients with prevalent CKD and provide new insights into the influence of suPAR and YKL-40 as plasma biomarkers that require validation.


Subject(s)
Biomarkers/blood , Diabetic Nephropathies/genetics , Kidney Failure, Chronic/genetics , Renal Insufficiency, Chronic/genetics , Adult , Aged , Chemokine CCL2/blood , Chitinase-3-Like Protein 1/blood , Cohort Studies , Diabetic Nephropathies/blood , Disease Progression , Female , Glomerular Filtration Rate , Hepatitis A Virus Cellular Receptor 1/blood , Humans , Kidney Failure, Chronic/blood , Male , Middle Aged , Phenotype , Prevalence , Receptors, Tumor Necrosis Factor, Type I/blood , Receptors, Tumor Necrosis Factor, Type II/blood , Receptors, Urokinase Plasminogen Activator/blood , Renal Insufficiency, Chronic/blood , Risk , Young Adult
5.
Int Immunopharmacol ; 97: 107685, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1188659

ABSTRACT

BACKGROUND: The 2019 Coronavirus (COVID-19) pandemic poses a huge threat internationally; however, the role of the host immune system in the pathogenesis of COVID-19 is not well understood. METHODS: Cytokine and chemokine levels and characterisation of immune cell subsets from 20 COVID-19 cases after hospital admission (17 critically ill and 3 severe patients) and 16 convalescent patients were determined using a multiplex immunoassay and flow cytometry, respectively. RESULTS: IP-10, MCP-1, MIG, IL-6, and IL-10 levels were significantly higher in acute severe/critically ill patients with COVID-19, whereas were normal in patients who had reached convalescence. CD8 T cells in severe and critically ill COVID-19 patients expressed high levels of cytotoxic granules (granzyme B and perforin)and was hyperactivated as evidenced by the high proportions of CD38. Furthermore, the cytotoxic potential of natural killer (NK) cells, and the frequencies of myeloid dendritic cells and plasmacytoid dendritic cells was reduced in patients with severe and critical COVID-19; however, these dysregulations were found to be restored in convalescent phases. CONCLUSION: Thus, elicitation of the hyperactive cytokine-mediated inflammatory response, dysregulation of CD8 T and NK cells, and deficiency of host myeloid and plasmacytoid DCs, may contribute to COVID-19 pathogenesis and provide insights into potential therapeutic targets and strategies.


Subject(s)
COVID-19/blood , COVID-19/immunology , Convalescence , Inflammation/etiology , ADP-ribosyl Cyclase 1/blood , Acute Disease , Adult , Aged , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/enzymology , CD8-Positive T-Lymphocytes/immunology , Chemokine CCL2/blood , Chemokine CXCL10/blood , Chemokine CXCL9/blood , Critical Illness , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/immunology , Dendritic Cells/immunology , Female , Granzymes/metabolism , Humans , Interleukin-10/blood , Interleukin-6/blood , Killer Cells, Natural/enzymology , Killer Cells, Natural/immunology , Male , Membrane Glycoproteins/blood , Middle Aged , Perforin/metabolism
6.
Virol J ; 18(1): 12, 2021 01 07.
Article in English | MEDLINE | ID: covidwho-1067244

ABSTRACT

BACKGROUND: Chemokine levels in severe coronavirus disease 2019 (COVID-19) patients have been shown to be markedly elevated. But the role of chemokines in mild COVID-19 has not yet been established. According to the epidemiological statistics, most of the COVID-19 cases in Shiyan City, China, have been mild. The purpose of this study was to evaluate the level of chemokines in mild COVID-19 patients and explore the correlation between chemokines and host immune response. METHODS: In this study, we used an enzyme-linked immunosorbent assay to detect serum levels of chemokines in COVID-19 patients in Shiyan City. Expression of chemokine receptors and of other signaling molecules was measured by real-time polymerase chain reaction. RESULTS: We first demonstrated that COVID-19 patients, both sever and mild cases, are characterized by higher level of chemokines. Specifically, monocyte chemotactic protein 1 (MCP-1) is expressed at higher levels both in severe and mild cases of COVID-19. The receptor of MCP-1, C-C chemokine receptor type 2, was expressed at higher levels in mild COVID-19 patients. Finally, we observed a significant negative correlation between expression levels of interferon (IFN) regulatory factor 3 (IRF3) and serum levels of MCP-1 in mild COVID-19 patients. CONCLUSION: Higher expression of MCP-1 in mild COVID-19 patients might be correlated with inhibition of IFN signaling. The finding adds to our understanding of the immunopathological mechanisms of severe acute respiratory syndrome coronavirus 2 infection and provides potential therapeutic targets and strategies.


Subject(s)
COVID-19/immunology , Chemokine CCL2/blood , Chemokines/blood , Interferon Type I/metabolism , Adult , COVID-19/metabolism , COVID-19/physiopathology , China , Disease Progression , Enzyme-Linked Immunosorbent Assay , Female , Humans , Interferon Regulatory Factor-3/blood , Leukocytes, Mononuclear/metabolism , Male , Middle Aged , Receptors, CCR2/blood , Signal Transduction/immunology
7.
Sci Rep ; 10(1): 21697, 2020 12 10.
Article in English | MEDLINE | ID: covidwho-1059940

ABSTRACT

In SARS-CoV-2 infection there is an urgent need to identify patients that will progress to severe COVID-19 and may benefit from targeted treatment. In this study we analyzed plasma cytokines in COVID-19 patients and investigated their association with respiratory failure (RF) and treatment in Intensive Care Unit (ICU). Hospitalized patients (n = 34) with confirmed COVID-19 were recruited into a prospective cohort study. Clinical data and blood samples were collected at inclusion and after 2-5 and 7-10 days. RF was defined as PaO2/FiO2 ratio (P/F) < 40 kPa. Plasma cytokines were analyzed by a Human Cytokine 27-plex assay. COVID-19 patients with RF and/or treated in ICU showed overall increased systemic cytokine levels. Plasma IL-6, IL-8, G-CSF, MCP-1, MIP-1α levels were negatively correlated with P/F, whereas combinations of IL-6, IP-10, IL-1ra and MCP-1 showed the best association with RF in ROC analysis (AUC 0.79-0.80, p < 0.05). During hospitalization the decline was most significant for IP-10 (p < 0.001). Elevated levels of pro-inflammatory cytokines were present in patients with severe COVID-19. IL-6 and MCP-1 were inversely correlated with P/F with the largest AUC in ROC analyses and should be further explored as biomarkers to identify patients at risk for severe RF and as targets for improved treatment strategies.


Subject(s)
COVID-19/blood , Chemokine CCL2/blood , Interleukin-6/blood , Respiratory Insufficiency/blood , SARS-CoV-2/metabolism , Adult , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19/complications , Female , Humans , Male , Middle Aged , Prospective Studies , Respiratory Insufficiency/etiology , Severity of Illness Index
8.
J Infect Dis ; 222(5): 746-754, 2020 08 04.
Article in English | MEDLINE | ID: covidwho-990712

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We investigated the serum cytokine and chemokine levels in asymptomatic, mild, moderate, severe, and convalescent SARS-CoV-2-infected cases. Proinflammatory cytokine and chemokine production induced by SARS-CoV-2 were observed not only in symptomatic patients but also in asymptomatic cases, and returned to normal after recovery. IL-6, IL-7, IL-10, IL-18, G-CSF, M-CSF, MCP-1, MCP-3, IP-10, MIG, and MIP-1α were found to be associated with the severity of COVID-19. Moreover, a set of cytokine and chemokine profiles were significantly higher in SARS-CoV-2-infected male than female patients. The serum levels of MCP-1, G-CSF, and VEGF were weakly and positively correlated with viral titers. We suggest that combinatorial analysis of serum cytokines and chemokines with clinical classification may contribute to evaluation of the severity of COVID-19 and optimize the therapeutic strategies.


Subject(s)
Chemokines/blood , Coronavirus Infections/blood , Cytokines/blood , Pneumonia, Viral/blood , Adult , Betacoronavirus/isolation & purification , COVID-19 , Chemokine CCL2/blood , Coronavirus Infections/diagnosis , Coronavirus Infections/immunology , Coronavirus Infections/virology , Female , Granulocyte Colony-Stimulating Factor/blood , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , SARS-CoV-2 , Severity of Illness Index , Vascular Endothelial Growth Factor A/blood , Viral Load
9.
Mol Med ; 26(1): 97, 2020 10 29.
Article in English | MEDLINE | ID: covidwho-894988

ABSTRACT

BACKGROUND: COVID-19 is a viral respiratory disease caused by the severe acute respiratory syndrome-Coronavirus type 2 (SARS-CoV-2). Patients with this disease may be more prone to venous or arterial thrombosis because of the activation of many factors involved in it, including inflammation, platelet activation and endothelial dysfunction. Interferon gamma inducible protein-10 (IP-10), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein 1-alpha (MIP1α) are cytokines related to thrombosis. Therefore, this study focused on these three indicators in COVID-19, with the hope to find biomarkers that are associated with patients' outcome. METHODS: This is a retrospective single-center study involving 74 severe and critically ill COVID-19 patients recruited from the ICU department of the Tongji Hospital in Wuhan, China. The patients were divided into two groups: severe patients and critically ill patients. The serum IP-10, MCP-1 and MIP1α level in both groups was detected using the enzyme-linked immunosorbent assay (ELISA) kit. The clinical symptoms, laboratory test results, and the outcome of COVID-19 patients were retrospectively analyzed. RESULTS: The serum IP-10 and MCP-1 level in critically ill patients was significantly higher than that in severe patients (P < 0.001). However, no statistical difference in MIP1α between the two groups was found. The analysis of dynamic changes showed that these indicators remarkably increased in patients with poor prognosis. Since the selected patients were severe or critically ill, no significant difference was observed between survival and death. CONCLUSIONS: IP-10 and MCP-1 are biomarkers associated with the severity of COVID-19 disease and can be related to the risk of death in COVID-19 patients.


Subject(s)
Chemokine CCL2/blood , Chemokine CXCL10/blood , Coronavirus Infections/complications , Cytokine Release Syndrome/complications , Disseminated Intravascular Coagulation/complications , Pneumonia, Viral/complications , Pulmonary Embolism/complications , Respiratory Insufficiency/complications , Adaptor Proteins, Signal Transducing/blood , Aged , Betacoronavirus/pathogenicity , Biomarkers/blood , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/mortality , Coronavirus Infections/virology , Critical Illness , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/virology , Disseminated Intravascular Coagulation/diagnosis , Disseminated Intravascular Coagulation/mortality , Disseminated Intravascular Coagulation/virology , Female , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Prognosis , Pulmonary Embolism/diagnosis , Pulmonary Embolism/mortality , Pulmonary Embolism/virology , Respiratory Insufficiency/diagnosis , Respiratory Insufficiency/mortality , Respiratory Insufficiency/virology , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , Survival Analysis
10.
Eur J Immunol ; 50(9): 1412-1414, 2020 09.
Article in English | MEDLINE | ID: covidwho-615368

ABSTRACT

Study of immunological features of immune response in 14 children (aged from 12 days up to 15 years) and of 10 adults who developed COVID-19 show increased number of activated CD4 and CD8 cells expressing DR and higher plasmatic levels of IL-12 and IL-1ß in adults with COVID-19, but not in children. In addition, plasmatic levels of CCL5/RANTES are higher in children and adults with COVID-19, while CXCL9/MIG was only increased in adults. Higher number of activated T cells and expression of IL-12 and CXCL9 suggest prominent Th1 polarization of immune response against SARS-CoV2 in infected adults as compared with children.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/blood , Chemokines/blood , SARS-CoV-2/immunology , Adolescent , COVID-19/immunology , COVID-19/pathology , Chemokine CCL2/blood , Chemokine CCL5/blood , Chemokine CXCL10/blood , Chemokine CXCL9/blood , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Interleukin-8/blood , Lymphocyte Activation , Lymphocyte Count , Lymphopenia/pathology , Male , T-Lymphocyte Subsets/immunology
11.
JCI Insight ; 5(12)2020 06 18.
Article in English | MEDLINE | ID: covidwho-611544

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), has become a pandemic. This study addresses the clinical and immunopathological characteristics of severe COVID-19. METHODS: Sixty-nine patients with COVID-19 were classified into severe and nonsevere groups to analyze their clinical and laboratory characteristics. A panel of blood cytokines was quantified over time. Biopsy specimens from 2 deceased cases were obtained for immunopathological, ultrastructural, and in situ hybridization examinations. RESULTS: Circulating cytokines, including IL-8, IL-6, TNF-α, IP10, MCP1, and RANTES, were significantly elevated in patients with severe COVID-19. Dynamic IL-6 and IL-8 were associated with disease progression. SARS-CoV-2 was demonstrated to infect type II and type I pneumocytes and endothelial cells, leading to severe lung damage through cell pyroptosis and apoptosis. In severe cases, lymphopenia, neutrophilia, depletion of CD4+ and CD8+ T lymphocytes, and massive macrophage and neutrophil infiltrates were observed in both blood and lung tissues. CONCLUSIONS: A panel of circulating cytokines could be used to predict disease deterioration and inform clinical interventions. Severe pulmonary damage was predominantly attributed to both cytopathy caused by SARS-CoV-2 and immunopathologic damage. Strategies that prohibit pulmonary recruitment and overactivation of inflammatory cells by suppressing cytokine storm might improve the outcomes of patients with severe COVID-19.


Subject(s)
Coronavirus Infections/diagnosis , Coronavirus Infections/pathology , Pneumonia, Viral/diagnosis , Pneumonia, Viral/pathology , Adult , Aged , Betacoronavirus/isolation & purification , Biopsy , CD8-Positive T-Lymphocytes , COVID-19 , Chemokine CCL2/blood , Chemokine CCL5/blood , China/epidemiology , Coronavirus Infections/blood , Coronavirus Infections/epidemiology , Cytokines/blood , Disease Progression , Endothelial Cells/pathology , Female , Humans , Lung/diagnostic imaging , Lung/pathology , Lymphocyte Count , Lymphopenia/pathology , Lymphopenia/virology , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/epidemiology , SARS-CoV-2
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