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1.
J Intern Med ; 291(6): 801-812, 2022 06.
Article in English | MEDLINE | ID: covidwho-1714240

ABSTRACT

BACKGROUND: Although coronavirus disease 2019 (COVID-19) is primarily a respiratory infection, mounting evidence suggests that the gastrointestinal tract is involved in the disease, with gut barrier dysfunction and gut microbiota alterations being related to disease severity. Whether these alterations persist and are related to long-term respiratory dysfunction remains unknown. METHODS: Plasma was collected during hospital admission and after 3 months from the NOR-Solidarity trial (n = 181) and analyzed for markers of gut barrier dysfunction and inflammation. At the 3-month follow-up, pulmonary function was assessed by measuring the diffusing capacity of the lungs for carbon monoxide (DLCO ). Rectal swabs for gut microbiota analyses were collected (n = 97) and analyzed by sequencing the 16S rRNA gene. RESULTS: Gut microbiota diversity was reduced in COVID-19 patients with respiratory dysfunction, defined as DLCO below the lower limit of normal 3 months after hospitalization. These patients also had an altered global gut microbiota composition, with reduced relative abundance of 20 bacterial taxa and increased abundance of five taxa, including Veillonella, potentially linked to fibrosis. During hospitalization, increased plasma levels of lipopolysaccharide-binding protein (LBP) were strongly associated with respiratory failure, defined as pO2 /fiO2 (P/F ratio) <26.6 kPa. LBP levels remained elevated during and after hospitalization and were associated with low-grade inflammation and respiratory dysfunction after 3 months. CONCLUSION: Respiratory dysfunction after COVID-19 is associated with altered gut microbiota and persistently elevated LBP levels. Our results should be regarded as hypothesis generating, pointing to a potential gut-lung axis that should be further investigated in relation to long-term pulmonary dysfunction and long COVID.


Subject(s)
COVID-19 , Gastrointestinal Microbiome , COVID-19/complications , Clinical Trials as Topic , Humans , Inflammation , RNA, Ribosomal, 16S/genetics , SARS-CoV-2
2.
Platelets ; 33(4): 640-644, 2022 May 19.
Article in English | MEDLINE | ID: covidwho-1713376

ABSTRACT

Thromboembolic events are frequent and associated with poor outcome in severe COVID-19 disease. Anti-PF4/polyanion antibodies are related to heparin-induced thrombocytopenia (HIT) and thrombus formation, but data on these antibodies in unselected COVID-19 populations are scarce. We assessed the presence of anti-PF4/polyanion antibodies in prospectively collected serum from an unselected cohort of hospitalized COVID-19 patients and evaluated if elevated levels could give prognostic information on ICU admission and respiratory failure (RF), were associated with markers of inflammation, endothelial activation, platelet activation, coagulation and fibrosis and were associated with long-term pulmonary CT changes. Five out of 65 patients had anti-PF4/polyanion reactivity with OD ≥0.200. These patients had more severe disease as reflected by ICU admission without any evidence of HIT. They also had signs of enhanced inflammation and fibrinogenesis as reflected by elevated ferritin and osteopontin, respectively, during the first 10 days of hospitalization. Increased ferritin and osteopontin persisted in these patients at 3 months follow-up, concomitant with pulmonary CT pathology. Our finding shows that the presence of anti-PF4/polyanion antibodies in unselected hospitalized COVID-19 patients was not related to HIT, but was associated with disease severity, inflammation, and pulmonary pathology after 3 months.


Subject(s)
COVID-19 , Thrombocytopenia , Anticoagulants/adverse effects , Ferritins/adverse effects , Heparin/adverse effects , Humans , Inflammation , Osteopontin/adverse effects , Platelet Factor 4 , Severity of Illness Index , Thrombocytopenia/diagnosis
3.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327209

ABSTRACT

ABSTRACT Background The Omicron variant of SARS-CoV-2 is now overtaking the Delta variant in many countries. Results showing that sera from double vaccinated individuals have minimal neutralizing activity against Omicron may indicate that the higher rate of transmission is due to evasion from vaccine-induced immunity. However, there is little information about activation of recall responses to Omicron in vaccinated individuals. Methods We measured inflammatory mediators, antibodies to the SARS-CoV-2 spike and nucleocapsid proteins, and spike peptide-induced release of interferon gamma in whole blood in 51 vaccinated individuals infected with Omicron, in 14 infected with Delta, and in 18 healthy controls. The median time points for the first and second samples were 7 and 14 days after symptom onset, respectively. Findings Infection with Omicron or Delta led to a rapid and similar increase in antibodies to the SARS-CoV-2 spike and nucleocapsid proteins and spike peptide-induced interferon gamma in whole blood. Both the Omicron and the Delta infected patients had a mild and transient increase in inflammatory parameters. Interpretation The results suggest that vaccine-induced immunological memory yields similar coverage for the Omicron and Delta variants.

4.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-313539

ABSTRACT

Background: 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. Objectives: Analyze plasma cytokines in COVID-19 patients and investigate their association with respiratory failure (RF) and treatment in Intensive Care Unit (ICU). Method: 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) <40kPa. Plasma cytokines were analyzed by a Human Cytokine 27-plex assay. Measurements and Results: 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). Conclusion: 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.

5.
Sci Rep ; 11(1): 23205, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1545647

ABSTRACT

The association between pulmonary sequelae and markers of disease severity, as well as pro-fibrotic mediators, were studied in 108 patients 3 months after hospital admission for COVID-19. The COPD assessment test (CAT-score), spirometry, diffusion capacity of the lungs (DLCO), and chest-CT were performed at 23 Norwegian hospitals included in the NOR-SOLIDARITY trial, an open-labelled, randomised clinical trial, investigating the efficacy of remdesivir and hydroxychloroquine (HCQ). Thirty-eight percent had a CAT-score ≥ 10. DLCO was below the lower limit of normal in 29.6%. Ground-glass opacities were present in 39.8% on chest-CT, parenchymal bands were found in 41.7%. At admission, low pO2/FiO2 ratio, ICU treatment, high viral load, and low antibody levels, were predictors of a poorer pulmonary outcome after 3 months. High levels of matrix metalloproteinase (MMP)-9 during hospitalisation and at 3 months were associated with persistent CT-findings. Except for a negative effect of remdesivir on CAT-score, we found no effect of remdesivir or HCQ on long-term pulmonary outcomes. Three months after hospital admission for COVID-19, a high prevalence of respiratory symptoms, reduced DLCO, and persistent CT-findings was observed. Low pO2/FiO2 ratio, ICU-admission, high viral load, low antibody levels, and high levels of MMP-9 were associated with a worse pulmonary outcome.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , COVID-19/drug therapy , Hydroxychloroquine/adverse effects , Lung Diseases/pathology , Matrix Metalloproteinase 9/metabolism , SARS-CoV-2/drug effects , Viral Load , Adenosine Monophosphate/adverse effects , Aged , Alanine/adverse effects , Antibody Formation , Antimalarials/adverse effects , Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , COVID-19/virology , Female , Hospitalization , Humans , Lung Diseases/chemically induced , Lung Diseases/enzymology , Lung Diseases/virology , Male , Middle Aged , Severity of Illness Index
7.
Eur Heart J ; 42(39): 4064-4072, 2021 10 14.
Article in English | MEDLINE | ID: covidwho-1361770

ABSTRACT

AIMS: We recently reported five cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) 7-10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against corona virus disease 2019 (COVID-19). We aimed to investigate the pathogenic immunological responses operating in these patients. METHODS AND RESULTS: We assessed circulating inflammatory markers by immune assays and immune cell phenotyping by flow cytometry analyses and performed immunoprecipitation with anti-platelet factor (PF)4 antibody in plasma samples followed by mass spectrometry from all five patients. A thrombus was retrieved from the sinus sagittal superior of one patient and analysed by immunohistochemistry and flow cytometry. Precipitated immune complexes revealed multiple innate immune pathway triggers for platelet and leucocyte activation. Plasma contained increased levels of innate immune response cytokines and markers of systemic inflammation, extensive degranulation of neutrophils, and tissue and endothelial damage. Blood analyses showed activation of neutrophils and increased levels of circulating H3Cit, dsDNA, and myeloperoxidase-DNA complex. The thrombus had extensive infiltration of neutrophils, formation of neutrophil extracellular traps (NETs), and IgG deposits. CONCLUSIONS: The results show that anti-PF4/polyanion IgG-mediated thrombus formation in VITT patients is accompanied by a massive innate immune activation and particularly the fulminant activation of neutrophils including NETosis. These results provide novel data on the immune response in this rare adenoviral vector-induced VITT.


Subject(s)
COVID-19 , Thrombocytopenia , Vaccines , Antigen-Antibody Complex , COVID-19 Vaccines , Humans , Immunity, Innate , SARS-CoV-2
8.
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
10.
J Allergy Clin Immunol ; 147(1): 92-98, 2021 01.
Article in English | MEDLINE | ID: covidwho-779084

ABSTRACT

BACKGROUND: The pathogenesis of coronavirus disease 2019 (COVID-19) is still incompletely understood, but it seems to involve immune activation and immune dysregulation. OBJECTIVE: We examined the parameters of activation of different leukocyte subsets in COVID-19-infected patients in relation to disease severity. METHODS: We analyzed plasma levels of myeloperoxidase (a marker of neutrophil activation), soluble (s) CD25 (sCD25) and soluble T-cell immunoglobulin mucin domain-3 (sTIM-3) (markers of T-cell activation and exhaustion), and sCD14 and sCD163 (markers of monocyte/macrophage activation) in 39 COVID-19-infected patients at hospital admission and 2 additional times during the first 10 days in relation to their need for intensive care unit (ICU) treatment. RESULTS: Our major findings were as follows: (1) severe clinical outcome (ICU treatment) was associated with high plasma levels of sTIM-3 and myeloperoxidase, suggesting activated and potentially exhausted T cells and activated neutrophils, respectively; (2) in contrast, sCD14 and sCD163 showed no association with need for ICU treatment; and (3) levels of sCD25, sTIM-3, and myeloperoxidase were inversely correlated with degree of respiratory failure, as assessed by the ratio of Pao2 to fraction of inspired oxygen, and were positively correlated with the cardiac marker N-terminal pro-B-type natriuretic peptide. CONCLUSION: Our findings suggest that neutrophil activation and, in particular, activated T cells may play an important role in the pathogenesis of COVID-19 infection, suggesting that T-cell-targeted treatment options and downregulation of neutrophil activation could be of importance in this disorder.


Subject(s)
COVID-19/blood , Hepatitis A Virus Cellular Receptor 2/blood , SARS-CoV-2/metabolism , Aged , Antigens, CD/blood , Antigens, Differentiation, Myelomonocytic/blood , Female , Humans , Interleukin-2 Receptor alpha Subunit/blood , Lipopolysaccharide Receptors/blood , Lymphocyte Activation , Male , Middle Aged , Receptors, Cell Surface/blood , Severity of Illness Index , T-Lymphocytes/metabolism , Time Factors
11.
Proc Natl Acad Sci U S A ; 117(40): 25018-25025, 2020 10 06.
Article in English | MEDLINE | ID: covidwho-780138

ABSTRACT

Respiratory failure in the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is hypothesized to be driven by an overreacting innate immune response, where the complement system is a key player. In this prospective cohort study of 39 hospitalized coronavirus disease COVID-19 patients, we describe systemic complement activation and its association with development of respiratory failure. Clinical data and biological samples were obtained at admission, days 3 to 5, and days 7 to 10. Respiratory failure was defined as PO2/FiO2 ratio of ≤40 kPa. Complement activation products covering the classical/lectin (C4d), alternative (C3bBbP) and common pathway (C3bc, C5a, and sC5b-9), the lectin pathway recognition molecule MBL, and antibody serology were analyzed by enzyme-immunoassays; viral load by PCR. Controls comprised healthy blood donors. Consistently increased systemic complement activation was observed in the majority of COVID-19 patients during hospital stay. At admission, sC5b-9 and C4d were significantly higher in patients with than without respiratory failure (P = 0.008 and P = 0.034). Logistic regression showed increasing odds of respiratory failure with sC5b-9 (odds ratio 31.9, 95% CI 1.4 to 746, P = 0.03) and need for oxygen therapy with C4d (11.7, 1.1 to 130, P = 0.045). Admission sC5b-9 and C4d correlated significantly to ferritin (r = 0.64, P < 0.001; r = 0.69, P < 0.001). C4d, sC5b-9, and C5a correlated with antiviral antibodies, but not with viral load. Systemic complement activation is associated with respiratory failure in COVID-19 patients and provides a rationale for investigating complement inhibitors in future clinical trials.


Subject(s)
Betacoronavirus/immunology , Complement Activation , Coronavirus Infections/immunology , Pneumonia, Viral/immunology , Respiratory Insufficiency/immunology , Aged , Biomarkers/blood , COVID-19 , Case-Control Studies , Coronavirus Infections/blood , Coronavirus Infections/complications , Female , Host-Pathogen Interactions/immunology , Humans , Male , Mannose-Binding Lectin/blood , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/complications , Respiratory Insufficiency/virology , SARS-CoV-2 , Viral Load
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