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1.
Crit Care Clin ; 37(4): 777-793, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1433018

ABSTRACT

Reports examining lung histopathology in coronavirus disease 2019 (COVID-19) infection provide an essential body of information for clinicians and investigators. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced lung injury is complex, involving the airways, alveoli, and pulmonary vessels. Although no anatomic marker is specific, the signature histologic lesion is diffuse alveolar damage (DAD). The biological and molecular mechanisms that drive this pattern of injury are unknown, and the relationship of SARS-CoV-2-induced DAD to physiologic alterations and clinical outcomes in COVID-19-associated acute respiratory distress syndrome is undefined. Additional histologic patterns that may be variant phenotypes have been reported.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Humans , Lung , Respiratory Distress Syndrome/etiology , SARS-CoV-2
2.
medRxiv ; 2020 Nov 04.
Article in English | MEDLINE | ID: covidwho-1388081

ABSTRACT

To examine innate immune responses in early SARS-CoV-2 infection that may change clinical outcomes, we compared nasopharyngeal swab data from 20 virus-positive and 20 virus-negative individuals. Multiple innate immune-related and ACE-2 transcripts increased with infection and were strongly associated with increasing viral load. We found widespread discrepancies between transcription and translation. Interferon proteins were unchanged or decreased in infected samples suggesting virally-induced shut-off of host anti-viral protein responses. However, IP-10 and several interferon-stimulated gene proteins increased with viral load. Older age was associated with modifications of some effects. Our findings may characterize the disrupted immune landscape of early disease.

3.
JCI Insight ; 6(17)2021 09 08.
Article in English | MEDLINE | ID: covidwho-1327774

ABSTRACT

Vascular injury has emerged as a complication contributing to morbidity in coronavirus disease 2019 (COVID-19). The glycosaminoglycan hyaluronan (HA) is a major component of the glycocalyx, a protective layer of glycoconjugates that lines the vascular lumen and regulates key endothelial cell functions. During critical illness, as in the case of sepsis, enzymes degrade the glycocalyx, releasing fragments with pathologic activities into circulation and thereby exacerbating disease. Here, we analyzed levels of circulating glycosaminoglycans in 46 patients with COVID-19 ranging from moderate to severe clinical severity and measured activities of corresponding degradative enzymes. This report provides evidence that the glycocalyx becomes significantly damaged in patients with COVID-19 and corresponds with severity of disease. Circulating HA fragments and hyaluronidase, 2 signatures of glycocalyx injury, strongly associate with sequential organ failure assessment scores and with increased inflammatory cytokine levels in patients with COVID-19. Pulmonary microvascular endothelial cells exposed to COVID-19 milieu show dysregulated HA biosynthesis and degradation, leading to production of pathological HA fragments that are released into circulation. Finally, we show that HA fragments present at high levels in COVID-19 patient plasma can directly induce endothelial barrier dysfunction in a ROCK- and CD44-dependent manner, indicating a role for HA in the vascular pathology of COVID-19.


Subject(s)
COVID-19/metabolism , Endothelium, Vascular/metabolism , Hyaluronic Acid/metabolism , Aged , COVID-19/blood , COVID-19/pathology , Cytokines/blood , Endothelium, Vascular/pathology , Female , Glycocalyx/metabolism , Glycocalyx/pathology , Humans , Hyaluronan Receptors/metabolism , Hyaluronic Acid/blood , Hyaluronoglucosaminidase/blood , Hyaluronoglucosaminidase/metabolism , Male , Middle Aged , rho-Associated Kinases/metabolism
4.
Res Pract Thromb Haemost ; 5(4): e12525, 2021 May.
Article in English | MEDLINE | ID: covidwho-1233232

ABSTRACT

Background: Coronavirus disease 2019 (COVID-19) is associated with activation of coagulation that mainly presents as thrombosis. Sepsis is also associated with activation of coagulation that mainly presents as disseminated intravascular coagulation. Many studies have reported increased levels of plasma d-dimer in patients with COVID-19 that is associated with severity, thrombosis, and mortality. Objectives: The aim of this study was to compare levels of circulating extracellular vesicle tissue factor (EVTF) activity and active plasminogen activator inhibitor 1 (PAI-1) in plasma from patients with COVID-19 or sepsis. Methods: We measured levels of d-dimer, EVTF activity, and active PAI-1 in plasma samples from patients with COVID-19 (intensive care unit [ICU], N = 15; and non-ICU, N = 20) and patients with sepsis (N = 35). Results: Patients with COVID-19 had significantly higher levels of d-dimer, EVTF activity, and active PAI-1 compared with healthy controls. Patients with sepsis had significantly higher levels of d-dimer and EVTF activity compared with healthy controls. Levels of d-dimer were significantly lower in patients with COVID-19 compared with patients with sepsis. Levels of EVTF activity were significantly higher in ICU patients with COVID-19 compared with patients with sepsis. Levels of active PAI-1 were significantly higher in patients with COVID-19 compared with patients with sepsis. Conclusions: High levels of both EVTF activity and active PAI-1 may promote thrombosis in patients with COVID-19 due to simultaneous activation of coagulation and inhibition of fibrinolysis. The high levels of active PAI-1 in patients with COVID-19 may limit plasmin degradation of crosslinked fibrin and the release of d-dimer. This may explain the lower levels of D-dimer in patients with COVID-19 compared with patients with sepsis.

5.
J Leukoc Biol ; 109(1): 55-66, 2021 01.
Article in English | MEDLINE | ID: covidwho-1188009

ABSTRACT

COVID-19 rapidly emerged as a crippling public health crisis in the last few months, which has presented a series health risk. Understanding of the immune response and biomarker analysis is needed to progress toward understanding disease pathology and developing improved treatment options. The goal of this study is to identify pathogenic factors that are linked to disease severity and patient characteristics. Patients with COVID-19 who were hospitalized from March 17 to June 5, 2020 were analyzed for clinical features of disease and soluble plasma cytokines in association with disease severity and sex. Data from COVID-19 patients with acute illness were examined along with an age- and gender-matched control cohort. We identified a group of 16 soluble factors that were found to be increased in COVID-19 patients compared to controls, whereas 2 factors were decreased. In addition to inflammatory cytokines, we found significant increases in factors known to mediate vasculitis and vascular remodeling (PDGF-AA, PDGF-AB-BB, soluble CD40L (sCD40L), FGF, and IP10). Four factors such as platelet-derived growth factors, fibroblast growth factor-2, and IFN-γ-inducible protein 10 were strongly associated with severe disease and ICU admission. Th2-related factors (IL-4 and IL-13) were increased with IL-4 and sCD40L present at increased levels in males compared with females. Our analysis revealed networking clusters of cytokines and growth factors, including previously unknown roles of vascular and stromal remodeling, activation of the innate immunity, as well activation of type 2 immune responses in the immunopathogenesis of COVID-19. These data highlight biomarker associations with disease severity and sex in COVID-19 patients.


Subject(s)
Blood Platelets , COVID-19 , Cytokine Release Syndrome , Cytokines , Immunity, Innate , SARS-CoV-2 , Sex Characteristics , Adult , Aged , Biomarkers/blood , Blood Platelets/immunology , Blood Platelets/metabolism , COVID-19/blood , COVID-19/complications , COVID-19/immunology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Cytokines/blood , Cytokines/immunology , Female , Humans , Male , Middle Aged , Prospective Studies , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Severity of Illness Index , Th2 Cells/immunology
6.
Trials ; 22(1): 221, 2021 Mar 20.
Article in English | MEDLINE | ID: covidwho-1143248

ABSTRACT

BACKGROUND: Convalescent plasma is being used widely as a treatment for coronavirus disease 2019 (COVID-19). However, the clinical efficacy of COVID-19 convalescent plasma is unclear. METHODS: The Passive Immunity Trial for Our Nation (PassITON) is a multicenter, placebo-controlled, blinded, randomized clinical trial being conducted in the USA to provide high-quality evidence on the efficacy of COVID-19 convalescent plasma as a treatment for adults hospitalized with symptomatic disease. Adults hospitalized with COVID-19 with respiratory symptoms for less than 14 days are eligible. Enrolled patients are randomized in a 1:1 ratio to 1 unit (200-399 mL) of COVID-19 convalescent plasma that has demonstrated neutralizing function using a SARS-CoV-2 chimeric virus neutralization assay. Study treatments are administered in a blinded fashion and patients are followed for 28 days. The primary outcome is clinical status 14 days after study treatment as measured on a 7-category ordinal scale assessing mortality, respiratory support, and return to normal activities of daily living. Key secondary outcomes include mortality and oxygen-free days. The trial is projected to enroll 1000 patients and is designed to detect an odds ratio ≤ 0.73 for the primary outcome. DISCUSSION: This trial will provide the most robust data available to date on the efficacy of COVID-19 convalescent plasma for the treatment of adults hospitalized with acute moderate to severe COVID-19. These data will be useful to guide the treatment of COVID-19 patients in the current pandemic and for informing decisions about whether developing a standardized infrastructure for collecting and disseminating convalescent plasma to prepare for future viral pandemics is indicated. TRIAL REGISTRATION: ClinicalTrials.gov NCT04362176 . Registered on 24 April 2020.


Subject(s)
COVID-19/therapy , Hospitalization , SARS-CoV-2/pathogenicity , COVID-19/diagnosis , COVID-19/immunology , COVID-19/virology , Host-Pathogen Interactions , Humans , Immunization, Passive , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , SARS-CoV-2/immunology , Time Factors , Treatment Outcome , United States
7.
Physiol Rep ; 9(4): e14761, 2021 02.
Article in English | MEDLINE | ID: covidwho-1100463

ABSTRACT

COVID-19 causes severe disease with poor outcomes. We tested the hypothesis that early SARS-CoV-2 viral infection disrupts innate immune responses. These changes may be important for understanding subsequent clinical outcomes. We obtained residual nasopharyngeal swab samples from individuals who requested COVID-19 testing for symptoms at drive-through COVID-19 clinical testing sites operated by the University of Utah. We applied multiplex immunoassays, real-time polymerase chain reaction assays and quantitative proteomics to 20 virus-positive and 20 virus-negative samples. ACE-2 transcripts increased with infection (OR =17.4, 95% CI [CI] =4.78-63.8) and increasing viral N1 protein transcript load (OR =1.16, CI =1.10-1.23). Transcripts for two interferons (IFN) were elevated, IFN-λ1 (OR =71, CI =7.07-713) and IFN-λ2 (OR =40.2, CI =3.86-419), and closely associated with viral N1 transcripts (OR =1.35, CI =1.23-1.49 and OR =1.33 CI =1.20-1.47, respectively). Only transcripts for IP-10 were increased among systemic inflammatory cytokines that we examined (OR =131, CI =1.01-2620). We found widespread discrepancies between transcription and translation. IFN proteins were unchanged or decreased in infected samples (IFN-γ OR =0.90 CI =0.33-0.79, IFN-λ2,3 OR =0.60 CI =0.48-0.74) suggesting viral-induced shut-off of host antiviral protein responses. However, proteins for IP-10 (OR =3.74 CI =2.07-6.77) and several interferon-stimulated genes (ISG) increased with viral load (BST-1 OR =25.1, CI =3.33-188; IFIT1 OR =19.5, CI =4.25-89.2; IFIT3 OR =245, CI =15-4020; MX-1 OR =3.33, CI =1.44-7.70). Older age was associated with substantial modifications of some effects. Ambulatory symptomatic patients had an innate immune response with SARS-CoV-2 infection characterized by elevated IFN, proinflammatory cytokine and ISG transcripts, but there is evidence of a viral-induced host shut-off of antiviral responses. Our findings may characterize the disrupted immune landscape common in patients with early disease.


Subject(s)
COVID-19/immunology , Immunity, Innate/immunology , Nasopharyngeal Diseases/virology , SARS-CoV-2/immunology , Viral Load/immunology , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , COVID-19/virology , Child , Cytokines/blood , Enzyme-Linked Immunosorbent Assay , Female , Humans , Male , Middle Aged , Nasopharyngeal Diseases/immunology , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , SARS-CoV-2/genetics , Sex Factors , Young Adult
8.
J Thromb Haemost ; 18(11): 3067-3073, 2020 11.
Article in English | MEDLINE | ID: covidwho-780981

ABSTRACT

BACKGROUND: Emerging evidence implicates dysfunctional platelet responses in thrombotic complications in COVID-19 patients. Platelets are important players in inflammation-induced thrombosis. In particular, procoagulant platelets support thrombin generation and mediate thromboinflammation. OBJECTIVES: To examine if procoagulant platelet formation is altered in COVID-19 patients and if procoagulant platelets contribute to pulmonary thrombosis. PATIENTS/METHODS: Healthy donors and COVID-19 patients were recruited from the University of Utah Hospital System. Platelets were isolated and procoagulant platelet formation measured by annexin V binding as well as mitochondrial function were examined. We utilized mice lacking the ability to form procoagulant platelets (CypDplt-/- ) to examine the role of procoagulant platelets in pulmonary thrombosis. RESULTS AND CONCLUSIONS: We observed that platelets isolated from COVID-19 patients had a reduced ability to become procoagulant compared to those from matched healthy donors, as evidenced by reduced mitochondrial depolarization and phosphatidylserine exposure following dual stimulation with thrombin and convulxin. To understand what impact reduced procoagulant platelet responses might have in vivo, we subjected mice with a platelet-specific deletion of cyclophilin D, which are deficient in procoagulant platelet formation, to a model of pulmonary microvascular thrombosis. Mice with platelets lacking cyclophilin D died significantly faster from pulmonary microvascular thrombosis compared to littermate wild-type controls. These results suggest dysregulated procoagulant platelet responses may contribute to thrombotic complications during SARS-CoV-2 infection.


Subject(s)
Blood Coagulation , Blood Platelets/metabolism , COVID-19/complications , Platelet Activation , Thrombosis/etiology , Adult , Aged , Animals , COVID-19/blood , COVID-19/diagnosis , Case-Control Studies , Cyclophilin D/blood , Cyclophilin D/genetics , Disease Models, Animal , Female , Humans , Male , Mice, Knockout , Middle Aged , Thrombosis/blood , Thrombosis/diagnosis
9.
Blood ; 136(10): 1169-1179, 2020 09 03.
Article in English | MEDLINE | ID: covidwho-748867

ABSTRACT

COVID-19 affects millions of patients worldwide, with clinical presentation ranging from isolated thrombosis to acute respiratory distress syndrome (ARDS) requiring ventilator support. Neutrophil extracellular traps (NETs) originate from decondensed chromatin released to immobilize pathogens, and they can trigger immunothrombosis. We studied the connection between NETs and COVID-19 severity and progression. We conducted a prospective cohort study of COVID-19 patients (n = 33) and age- and sex-matched controls (n = 17). We measured plasma myeloperoxidase (MPO)-DNA complexes (NETs), platelet factor 4, RANTES, and selected cytokines. Three COVID-19 lung autopsies were examined for NETs and platelet involvement. We assessed NET formation ex vivo in COVID-19 neutrophils and in healthy neutrophils incubated with COVID-19 plasma. We also tested the ability of neonatal NET-inhibitory factor (nNIF) to block NET formation induced by COVID-19 plasma. Plasma MPO-DNA complexes increased in COVID-19, with intubation (P < .0001) and death (P < .0005) as outcome. Illness severity correlated directly with plasma MPO-DNA complexes (P = .0360), whereas Pao2/fraction of inspired oxygen correlated inversely (P = .0340). Soluble and cellular factors triggering NETs were significantly increased in COVID-19, and pulmonary autopsies confirmed NET-containing microthrombi with neutrophil-platelet infiltration. Finally, COVID-19 neutrophils ex vivo displayed excessive NETs at baseline, and COVID-19 plasma triggered NET formation, which was blocked by nNIF. Thus, NETs triggering immunothrombosis may, in part, explain the prothrombotic clinical presentations in COVID-19, and NETs may represent targets for therapeutic intervention.


Subject(s)
Coronavirus Infections/complications , Extracellular Traps/immunology , Neutrophils/immunology , Pneumonia, Viral/complications , Thrombosis/complications , Adult , Aged , Betacoronavirus/immunology , Blood Platelets/immunology , Blood Platelets/pathology , Blood Proteins/immunology , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Female , Humans , Male , Middle Aged , Neutrophil Infiltration , Neutrophils/pathology , Pandemics , Peroxidase/immunology , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Prospective Studies , SARS-CoV-2 , Thrombosis/immunology , Thrombosis/pathology
10.
Blood ; 136(11): 1317-1329, 2020 09 10.
Article in English | MEDLINE | ID: covidwho-612131

ABSTRACT

There is an urgent need to understand the pathogenesis of coronavirus disease 2019 (COVID-19). In particular, thrombotic complications in patients with COVID-19 are common and contribute to organ failure and mortality. Patients with severe COVID-19 present with hemostatic abnormalities that mimic disseminated intravascular coagulopathy associated with sepsis, with the major difference being increased risk of thrombosis rather than bleeding. However, whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection alters platelet function to contribute to the pathophysiology of COVID-19 remains unknown. In this study, we report altered platelet gene expression and functional responses in patients infected with SARS-CoV-2. RNA sequencing demonstrated distinct changes in the gene-expression profile of circulating platelets of COVID-19 patients. Pathway analysis revealed differential gene-expression changes in pathways associated with protein ubiquitination, antigen presentation, and mitochondrial dysfunction. The receptor for SARS-CoV-2 binding, angiotensin-converting enzyme 2 (ACE2), was not detected by messenger RNA (mRNA) or protein in platelets. Surprisingly, mRNA from the SARS-CoV-2 N1 gene was detected in platelets from 2 of 25 COVID-19 patients, suggesting that platelets may take-up SARS-COV-2 mRNA independent of ACE2. Resting platelets from COVID-19 patients had increased P-selectin expression basally and upon activation. Circulating platelet-neutrophil, -monocyte, and -T-cell aggregates were all significantly elevated in COVID-19 patients compared with healthy donors. Furthermore, platelets from COVID-19 patients aggregated faster and showed increased spreading on both fibrinogen and collagen. The increase in platelet activation and aggregation could partially be attributed to increased MAPK pathway activation and thromboxane generation. These findings demonstrate that SARS-CoV-2 infection is associated with platelet hyperreactivity, which may contribute to COVID-19 pathophysiology.


Subject(s)
Betacoronavirus/isolation & purification , Blood Coagulation Disorders/pathology , Blood Platelets/pathology , Coronavirus Infections/complications , Pneumonia, Viral/complications , Transcriptome , Biomarkers , Blood Coagulation Disorders/genetics , Blood Coagulation Disorders/metabolism , Blood Coagulation Disorders/virology , Blood Platelets/metabolism , Blood Platelets/virology , COVID-19 , Case-Control Studies , Coronavirus Infections/genetics , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Female , Follow-Up Studies , Gene Expression Profiling , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/genetics , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Prognosis , Prospective Studies , SARS-CoV-2
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