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1.
Viruses ; 13(11)2021 11 08.
Article in English | MEDLINE | ID: covidwho-1512696

ABSTRACT

Survivors of severe SARS-CoV-2 infections frequently suffer from a range of post-infection sequelae. Whether survivors of mild or asymptomatic infections can expect any long-term health consequences is not yet known. Herein we investigated lasting changes to soluble inflammatory factors and cellular immune phenotype and function in individuals who had recovered from mild SARS-CoV-2 infections (n = 22), compared to those that had recovered from other mild respiratory infections (n = 11). Individuals who had experienced mild SARS-CoV-2 infections had elevated levels of C-reactive protein 1-3 months after symptom onset, and changes in phenotype and function of circulating T-cells that were not apparent in individuals 6-9 months post-symptom onset. Markers of monocyte activation, and expression of adherence and chemokine receptors indicative of altered migratory capacity, were also higher at 1-3 months post-infection in individuals who had mild SARS-CoV-2, but these were no longer elevated by 6-9 months post-infection. Perhaps most surprisingly, significantly more T-cells could be activated by polyclonal stimulation in individuals who had recently experienced a mild SARS-CoV-2, infection compared to individuals with other recent respiratory infections. These data are indicative of prolonged immune activation and systemic inflammation that persists for at least three months after mild or asymptomatic SARS-CoV-2 infections.


Subject(s)
Asymptomatic Infections , COVID-19/immunology , Cytokines/metabolism , Leukocytes/immunology , Leukocytes/metabolism , Respiratory Tract Infections/immunology , SARS-CoV-2/immunology , Adult , Aged , Antibodies, Viral , Biomarkers , C-Reactive Protein/immunology , C-Reactive Protein/metabolism , COVID-19/virology , Cytokines/immunology , Female , Humans , Immunophenotyping/methods , Inflammation/metabolism , Inflammation/virology , Lymphocyte Activation , Male , Middle Aged , Respiratory Tract Infections/virology , Spike Glycoprotein, Coronavirus/immunology , Survivors , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
3.
N Engl J Med ; 385(8): 720-728, 2021 08 19.
Article in English | MEDLINE | ID: covidwho-1262030

ABSTRACT

The use of high-dose intravenous immune globulin (IVIG) plus anticoagulation is recommended for the treatment of vaccine-induced immune thrombotic thrombocytopenia (VITT), a rare side effect of adenoviral vector vaccines against coronavirus disease 2019 (Covid-19). We describe the response to IVIG therapy in three of the first patients in whom VITT was identified in Canada after the receipt of the ChAdOx1 nCoV-19 vaccine. The patients were between the ages of 63 and 72 years; one was female. At the time of this report, Canada had restricted the use of the ChAdOx1 nCoV-19 vaccine to persons who were 55 years of age or older on the basis of reports that VITT had occurred primarily in younger persons. Two of the patients in our study presented with limb-artery thrombosis; the third had cerebral venous and arterial thrombosis. Variable patterns of serum-induced platelet activation were observed in response to heparin and platelet factor 4 (PF4), indicating the heterogeneity of the manifestations of VITT in serum. After the initiation of IVIG, reduced antibody-induced platelet activation in serum was seen in all three patients. (Funded by the Canadian Institutes of Health Research.).


Subject(s)
COVID-19 Vaccines/adverse effects , Immunoglobulins, Intravenous , Thrombocytopenia/therapy , Thrombosis/therapy , Aged , Female , Fibrin Fibrinogen Degradation Products/analysis , Fibrinogen/analysis , Heparin/pharmacology , Humans , Male , Middle Aged , Platelet Count , Platelet Factor 4/pharmacology , Serotonin/blood , Thrombocytopenia/blood , Thrombocytopenia/etiology , Thrombosis/etiology , Thrombosis/immunology
4.
Viruses ; 13(4)2021 04 16.
Article in English | MEDLINE | ID: covidwho-1194709

ABSTRACT

Coronavirus Disease 2019 (COVID-19) is a global pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While detection of SARS-CoV-2 by polymerase chain reaction with reverse transcription (RT-PCR) is currently used to diagnose acute COVID-19 infection, serological assays are needed to study the humoral immune response to SARS-CoV-2. Anti-SARS-CoV-2 immunoglobulin (Ig)G/A/M antibodies against spike (S) protein and its receptor-binding domain (RBD) were characterized in recovered subjects who were RT-PCR-positive (n = 153) and RT-PCR-negative (n = 55) using an enzyme-linked immunosorbent assay (ELISA). These antibodies were also further assessed for their ability to neutralize live SARS-CoV-2 virus. Anti-SARS-CoV-2 antibodies were detected in 90.9% of resolved subjects up to 180 days post-symptom onset. Anti-S protein and anti-RBD IgG titers correlated (r = 0.5157 and r = 0.6010, respectively) with viral neutralization. Of the RT-PCR-positive subjects, 22 (14.3%) did not have anti-SARS-CoV-2 antibodies; and of those, 17 had RT-PCR cycle threshold (Ct) values > 27. These high Ct values raise the possibility that these indeterminate results are from individuals who were not infected or had mild infection that failed to elicit an antibody response. This study highlights the importance of serological surveys to determine population-level immunity based on infection numbers as determined by RT-PCR.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , COVID-19/blood , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19 Nucleic Acid Testing , COVID-19 Serological Testing , Female , Humans , Immunoglobulin Isotypes/blood , Immunoglobulin Isotypes/immunology , Male , Middle Aged , Spike Glycoprotein, Coronavirus/immunology , Young Adult
5.
J Thromb Haemost ; 19(5): 1342-1347, 2021 05.
Article in English | MEDLINE | ID: covidwho-1105342

ABSTRACT

BACKGROUND: Thrombocytopenia and thrombosis are prominent in coronavirus disease 2019 (COVID-19), particularly among critically ill patients; however, the mechanism is unclear. Such critically ill COVID-19 patients may be suspected of heparin-induced thrombocytopenia (HIT), given similar clinical features. OBJECTIVES: We investigated the presence of platelet-activating anti-platelet-factor 4 (PF4)/heparin antibodies in critically ill COVID-19 patients suspected of HIT. PATIENTS/METHODS: We tested 10 critically ill COVID-19 patients suspected of HIT for anti-PF4/heparin antibodies and functional platelet activation in the serotonin release assay (SRA). Anti-human CD32 antibody (IV.3) was added to the SRA to confirm FcγRIIA involvement. Additionally, SARS-CoV-2 antibodies were measured using an in-house ELISA. Finally, von Willebrand factor (VWF) antigen and activity were measured along with A Disintegrin And Metalloprotease with ThromboSpondin-13 Domain (ADAMTS13) activity and the presence of anti-ADAMTS13 antibodies. RESULTS: Heparin-induced thrombocytopenia was excluded in all samples based on anti-PF4/heparin antibody and SRA results. Notably, six COVID-19 patients demonstrated platelet activation by the SRA that was inhibited by FcγRIIA receptor blockade, confirming an immune complex (IC)-mediated reaction. Platelet activation was independent of heparin but inhibited by both therapeutic and high dose heparin. All six samples were positive for antibodies targeting the receptor binding domain (RBD) or the spike protein of the SARS-CoV-2 virus. These samples also featured significantly increased VWF antigen and activity, which was not statistically different from the four COVID-19 samples without platelet activation. ADAMTS13 activity was not severely reduced, and ADAMTS13 inhibitors were not present, thus ruling out a primary thrombotic microangiopathy. CONCLUSIONS: Our study identifies platelet-activating ICs as a novel mechanism that contributes to critically ill COVID-19.


Subject(s)
COVID-19 , Thrombocytopenia , Anticoagulants , Antigen-Antibody Complex , Critical Illness , Heparin/adverse effects , Humans , Platelet Factor 4 , SARS-CoV-2 , Thrombocytopenia/chemically induced , Thrombocytopenia/diagnosis
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