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2.
Cell ; 184(19): 4953-4968.e16, 2021 09 16.
Article in English | MEDLINE | ID: covidwho-1363913

ABSTRACT

Severe coronavirus disease 2019 (COVID-19) is characterized by overproduction of immune mediators, but the role of interferons (IFNs) of the type I (IFN-I) or type III (IFN-III) families remains debated. We scrutinized the production of IFNs along the respiratory tract of COVID-19 patients and found that high levels of IFN-III, and to a lesser extent IFN-I, characterize the upper airways of patients with high viral burden but reduced disease risk or severity. Production of specific IFN-III, but not IFN-I, members denotes patients with a mild pathology and efficiently drives the transcription of genes that protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In contrast, compared to subjects with other infectious or noninfectious lung pathologies, IFNs are overrepresented in the lower airways of patients with severe COVID-19 that exhibit gene pathways associated with increased apoptosis and decreased proliferation. Our data demonstrate a dynamic production of IFNs in SARS-CoV-2-infected patients and show IFNs play opposing roles at distinct anatomical sites.


Subject(s)
COVID-19/pathology , Interferons/metabolism , Respiratory System/virology , Severity of Illness Index , Age Factors , Aging/pathology , COVID-19/genetics , COVID-19/immunology , Epithelial Cells/pathology , Epithelial Cells/virology , Gene Expression Regulation , Humans , Interferons/genetics , Leukocytes/pathology , Leukocytes/virology , Lung/pathology , Lung/virology , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , Viral Load
3.
J Virol ; 95(17): e0079421, 2021 08 10.
Article in English | MEDLINE | ID: covidwho-1350003

ABSTRACT

Increased mortality in COVID-19 cases is often associated with microvascular complications. We have recently shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein promotes an inflammatory cytokine interleukin 6 (IL-6)/IL-6R-induced trans signaling response and alarmin secretion. Virus-infected or spike-transfected human epithelial cells exhibited an increase in senescence, with a release of senescence-associated secretory phenotype (SASP)-related inflammatory molecules. Introduction of the bromodomain-containing protein 4 (BRD4) inhibitor AZD5153 to senescent epithelial cells reversed this effect and reduced SASP-related inflammatory molecule release in TMNK-1 or EAhy926 (representative human endothelial cell lines), when cells were exposed to cell culture medium (CM) derived from A549 cells expressing SARS-CoV-2 spike protein. Cells also exhibited a senescence phenotype with enhanced p16, p21, and senescence-associated ß-galactosidase (SA-ß-Gal) expression and triggered SASP pathways. Inhibition of IL-6 trans signaling by tocilizumab and inhibition of inflammatory receptor signaling by the Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib, prior to exposure of CM to endothelial cells, inhibited p21 and p16 induction. We also observed an increase in reactive oxygen species (ROS) in A549 spike-transfected and endothelial cells exposed to spike-transfected CM. ROS generation in endothelial cell lines was reduced after treatment with tocilizumab and zanubrutinib. Cellular senescence was associated with an increased level of the endothelial adhesion molecules vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), which have in vitro leukocyte attachment potential. Inhibition of senescence or SASP function prevented VCAM-1/ICAM-1 expression and leukocyte attachment. Taken together, we identified that human endothelial cells exposed to cell culture supernatant derived from SARS-CoV-2 spike protein expression displayed cellular senescence markers, leading to enhanced leukocyte adhesion. IMPORTANCE The present study was aimed at examining the underlying mechanism of extrapulmonary manifestations of SARS-CoV-2 spike protein-associated pathogenesis, with the notion that infection of the pulmonary epithelium can lead to mediators that drive endothelial dysfunction. We utilized SARS-CoV-2 spike protein expression in cultured human hepatocytes (Huh7.5) and pneumocytes (A549) to generate conditioned culture medium (CM). Endothelial cell lines (TMNK-1 or EAhy926) treated with CM exhibited an increase in cellular senescence markers by a paracrine mode and led to leukocyte adhesion. Overall, the link between these responses in endothelial cell senescence and a potential contribution to microvascular complication in productively SARS-CoV-2-infected humans is implicated. Furthermore, the use of inhibitors (BTK, IL-6, and BRD4) showed a reverse effect in the senescent cells. These results may support the selection of potential adjunct therapeutic modalities to impede SARS-CoV-2-associated pathogenesis.


Subject(s)
Cellular Senescence , Endothelial Cells/metabolism , Leukocytes/metabolism , Paracrine Communication , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , A549 Cells , Cell Adhesion , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/metabolism , Endothelial Cells/pathology , Endothelial Cells/virology , Heterocyclic Compounds, 2-Ring/pharmacology , Humans , Intercellular Adhesion Molecule-1/metabolism , Interleukin-6/metabolism , Leukocytes/pathology , Leukocytes/virology , Piperazines/pharmacology , Pyrazoles , Pyridazines , Reactive Oxygen Species/metabolism , Receptors, Interleukin-6/metabolism , Signal Transduction , Transcription Factors/antagonists & inhibitors , Transcription Factors/metabolism , Vascular Cell Adhesion Molecule-1/metabolism
4.
EBioMedicine ; 70: 103485, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1322072

ABSTRACT

Background Older age is the most powerful risk factor for adverse coronavirus disease-19 (COVID-19) outcomes. It is uncertain whether leucocyte telomere length (LTL), previously proposed as a marker of biological age, is also associated with COVID-19 outcomes. Methods We associated LTL values obtained from participants recruited into UK Biobank (UKB) during 2006-2010 with adverse COVID-19 outcomes recorded by 30 November 2020, defined as a composite of any of the following: hospital admission, need for critical care, respiratory support, or mortality. Using information on 130 LTL-associated genetic variants, we conducted exploratory Mendelian randomisation (MR) analyses in UKB to evaluate whether observational associations might reflect cause-and-effect relationships. Findings Of 6775 participants in UKB who tested positive for infection with SARS-CoV-2 in the community, there were 914 (13.5%) with adverse COVID-19 outcomes. The odds ratio (OR) for adverse COVID-19 outcomes was 1·17 (95% CI 1·05-1·30; P = 0·004) per 1-SD shorter usual LTL, after adjustment for age, sex and ethnicity. Similar ORs were observed in analyses that: adjusted for additional risk factors; disaggregated the composite outcome and reduced the scope for selection or collider bias. In MR analyses, the OR for adverse COVID-19 outcomes was directionally concordant but non-significant. Interpretation Shorter LTL is associated with higher risk of adverse COVID-19 outcomes, independent of several major risk factors for COVID-19 including age. Further data are needed to determine whether this association reflects causality. Funding UK Medical Research Council, Biotechnology and Biological Sciences Research Council and British Heart Foundation.


Subject(s)
COVID-19/virology , Leukocytes/pathology , SARS-CoV-2/genetics , Telomere/genetics , Aged , Biological Specimen Banks , COVID-19/pathology , Cohort Studies , Female , Humans , Male , Mendelian Randomization Analysis , Middle Aged , Risk Factors , United Kingdom
5.
Arch Iran Med ; 24(5): 419-426, 2021 05 01.
Article in English | MEDLINE | ID: covidwho-1308612

ABSTRACT

BACKGROUND: The pathogenesis of the COVID19 pandemic, that has killed one million nine hundred people and infected more the 90 million until end of 2020, has been studied by many researchers. Here, we try to explain its biological behavior based on our recent autopsy information and review of literature. METHODS: In this study, patients with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) result were considered eligible for enrollment. Histopathological examinations were done on 13 people who were hospitalized in Afzalipour hospital, Kerman, Iran. Clinical and laboratory data were reviewed. Tissue examination was done by light microscopy, immunohistochemistry and electron microscopy. RESULTS: The most frequent co-morbidity in the patients was cardiovascular disease. The common initial symptoms of COVID-19 infection were dyspnea and cough. In all cases, the number of white blood cells was higher than the normal range. Common histopathological findings were variable degrees of vasculitis as degenerative to necrotic changes of endothelium and trafficking of inflammatory cells in the vessel wall with fibrinoid necrosis. Tissue damage included interstitial acute inflammatory cells reaction with degenerative to necrotic changes of the parenchymal cells. CD34 and Factor VIII immunohistochemistry staining showed endothelial cell degeneration to necrosis at the vessel wall and infiltration by inflammatory cells. Electron microscopic features confirmed the degenerative damages in the endothelial cells. CONCLUSION: Our histopathological studies suggest that the main focus of the viral damage is the endothelial cells (endotheliopathica) in involved organs. Also, our findings suggest that degeneration of leukocytes occurs at the site of inflammation and release of cytokines (leukocytoclastica) resulting in a cytokine storm.


Subject(s)
COVID-19/complications , COVID-19/pathology , Endothelial Cells/pathology , Leukocytes/pathology , Adult , Aged , COVID-19/metabolism , Cohort Studies , Cytokines/metabolism , Female , Humans , Iran , Male , Middle Aged , Pericarditis/pathology , Pericarditis/virology , Skin Diseases/pathology , Skin Diseases/virology
6.
J Microbiol Immunol Infect ; 54(1): 61-68, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1272575

ABSTRACT

OBJECTIVES: To analyse the diagnostic performance of eosinopenia, alone or combined with polymorphonuclear neutrophils (PMN) and/or lymphocytes, as a marker of active COVID-19 in patients hospitalized for suspicion of SARS-CoV-2 infection. METHODS: A prospective observational study including patients hospitalized for suspicion of COVID-19 in a COVID unit was performed from 20th March to 5th April 2020, in Perpignan, France. Patients for which there was a doubt upon diagnosis, who were recently under oral corticosteroids, had myeloid malignancy or human immunodeficient virus infection were excluded. SARS-CoV-2 detection was performed using an RT-PCR assay, from nasopharyngeal swab specimens. Complete blood count were performed for all patients. RESULTS: One-hundred and twenty-one patient were included: 57 patients were diagnosed with COVID-19, 64 patients were not. Eosinophil count was lower in the COVID-19 group (median: 0/µL versus 70/µL, p < 0.0001). To diagnose COVID-19, eosinopenia had a sensitivity of 89.5% and a specificity of 78.1% while lymphopenia's were 73.7% and 62.5% respectively. Using area under curve (AUC) of receiving operating characteristics (ROC) curves, eosinophil's optimal cut-off level was 10/µL, sensitivity and specificity were 86%, and 79.7% respectively. Regarding the eosinophil/PMN ratio, the optimal cut-off level was 3.344, sensitivity and specificity were 87.7% and 73.4% respectively. The AUC of lymphocyte/PMN ratio was significantly lower than eosinophil/PMN ratio's (0.621 versus 0.846, p = 0.0003). CONCLUSION: Eosinopenia - <10/µL - and eosinophil/PMN ratio are useful, low-cost, reproducible tools to help diagnose COVID-19, during an epidemic period, in a population of hospitalized patients admitted for suspicion of COVID-19.


Subject(s)
COVID-19/blood , COVID-19/diagnosis , Eosinophils/pathology , Aged , Aged, 80 and over , Biomarkers/blood , Blood Cell Count , COVID-19 Testing/methods , Female , Humans , Leukocyte Count , Leukocytes/pathology , Male , Middle Aged , Prospective Studies , ROC Curve , SARS-CoV-2 , Sensitivity and Specificity
7.
JAMA Neurol ; 78(8): 948-960, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1265359

ABSTRACT

Importance: Myalgia, increased levels of creatine kinase, and persistent muscle weakness have been reported in patients with COVID-19. Objective: To study skeletal muscle and myocardial inflammation in patients with COVID-19 who had died. Design, Setting, and Participants: This case-control autopsy series was conducted in a university hospital as a multidisciplinary postmortem investigation. Patients with COVID-19 or other critical illnesses who had died between March 2020 and February 2021 and on whom an autopsy was performed were included. Individuals for whom informed consent to autopsy was available and the postmortem interval was less than 6 days were randomly selected. Individuals who were infected with SARS-CoV-2 per polymerase chain reaction test results and had clinical features suggestive of COVID-19 were compared with individuals with negative SARS-CoV-2 polymerase chain reaction test results and an absence of clinical features suggestive of COVID-19. Main Outcomes and Measures: Inflammation of skeletal muscle tissue was assessed by quantification of immune cell infiltrates, expression of major histocompatibility complex (MHC) class I and class II antigens on the sarcolemma, and a blinded evaluation on a visual analog scale ranging from absence of pathology to the most pronounced pathology. Inflammation of cardiac muscles was assessed by quantification of immune cell infiltrates. Results: Forty-three patients with COVID-19 (median [interquartile range] age, 72 [16] years; 31 men [72%]) and 11 patients with diseases other than COVID-19 (median [interquartile range] age, 71 [5] years; 7 men [64%]) were included. Skeletal muscle samples from the patients who died with COVID-19 showed a higher overall pathology score (mean [SD], 3.4 [1.8] vs 1.5 [1.0]; 95% CI, 0-3; P < .001) and a higher inflammation score (mean [SD], 3.5 [2.1] vs 1.0 [0.6]; 95% CI, 0-4; P < .001). Relevant expression of MHC class I antigens on the sarcolemma was present in 23 of 42 specimens from patients with COVID-19 (55%) and upregulation of MHC class II antigens in 7 of 42 specimens from patients with COVID-19 (17%), but neither were found in any of the controls. Increased numbers of natural killer cells (median [interquartile range], 8 [8] vs 3 [4] cells per 10 high-power fields; 95% CI, 1-10 cells per 10 high-power fields; P < .001) were found. Skeletal muscles showed more inflammatory features than cardiac muscles, and inflammation was most pronounced in patients with COVID-19 with chronic courses. In some muscle specimens, SARS-CoV-2 RNA was detected by reverse transcription-polymerase chain reaction, but no evidence for a direct viral infection of myofibers was found by immunohistochemistry and electron microscopy. Conclusions and Relevance: In this case-control study of patients who had died with and without COVID-19, most individuals with severe COVID-19 showed signs of myositis ranging from mild to severe. Inflammation of skeletal muscles was associated with the duration of illness and was more pronounced than cardiac inflammation. Detection of viral load was low or negative in most skeletal and cardiac muscles and probably attributable to circulating viral RNA rather than genuine infection of myocytes. This suggests that SARS-CoV-2 may be associated with a postinfectious, immune-mediated myopathy.


Subject(s)
COVID-19/pathology , Muscle, Skeletal/pathology , Myocarditis/pathology , Myocardium/pathology , Myositis/pathology , Aged , Aged, 80 and over , Autopsy , CD8-Positive T-Lymphocytes/pathology , COVID-19/metabolism , COVID-19 Nucleic Acid Testing , COVID-19 Serological Testing , Case-Control Studies , Female , Histocompatibility Antigens Class I/metabolism , Histocompatibility Antigens Class II/metabolism , Humans , Killer Cells, Natural/pathology , Leukocytes/pathology , Macrophages/pathology , Male , Middle Aged , Muscle, Skeletal/metabolism , Myocarditis/metabolism , Myocardium/metabolism , Myositis/metabolism , RNA, Viral/metabolism , SARS-CoV-2 , Sarcolemma/metabolism , Time Factors
8.
Nature ; 594(7862): 265-270, 2021 06.
Article in English | MEDLINE | ID: covidwho-1246377

ABSTRACT

Fast and reliable detection of patients with severe and heterogeneous illnesses is a major goal of precision medicine1,2. Patients with leukaemia can be identified using machine learning on the basis of their blood transcriptomes3. However, there is an increasing divide between what is technically possible and what is allowed, because of privacy legislation4,5. Here, to facilitate the integration of any medical data from any data owner worldwide without violating privacy laws, we introduce Swarm Learning-a decentralized machine-learning approach that unites edge computing, blockchain-based peer-to-peer networking and coordination while maintaining confidentiality without the need for a central coordinator, thereby going beyond federated learning. To illustrate the feasibility of using Swarm Learning to develop disease classifiers using distributed data, we chose four use cases of heterogeneous diseases (COVID-19, tuberculosis, leukaemia and lung pathologies). With more than 16,400 blood transcriptomes derived from 127 clinical studies with non-uniform distributions of cases and controls and substantial study biases, as well as more than 95,000 chest X-ray images, we show that Swarm Learning classifiers outperform those developed at individual sites. In addition, Swarm Learning completely fulfils local confidentiality regulations by design. We believe that this approach will notably accelerate the introduction of precision medicine.


Subject(s)
Blockchain , Clinical Decision-Making/methods , Confidentiality , Datasets as Topic , Machine Learning , Precision Medicine/methods , COVID-19/diagnosis , COVID-19/epidemiology , Disease Outbreaks , Female , Humans , Leukemia/diagnosis , Leukemia/pathology , Leukocytes/pathology , Lung Diseases/diagnosis , Machine Learning/trends , Male , Software , Tuberculosis/diagnosis
9.
Int Immunopharmacol ; 96: 107794, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1233464

ABSTRACT

To explore the characteristics of COVID-19 infection related kidney injury, we retrospectively collected cases of COVID-19 patients with definite clinical outcomes (discharge or death) and relevant laboratory results from Jan 3 to Mar 30, 2020 in Tongji hospital, Wuhan, China. 1509 patients were included, 1393 cases with normal baseline serum creatinine, and 116 cases with elevated baseline serum creatinine (EBSC). On admission, the prevalence of elevated serum creatinine, elevated blood urea nitrogen (BUN) and estimated glomerular filtration (eGFR) under 60 ml/min/1.73 m2 were 7.7%, 6.6% and 7.2%, respectively. The incidence of in-hospital death in the patients with EBSC was 7.8%, which was significantly higher than those with normal serum creatinine (1.2%). Inflammatory, immunological, and organ damage indices were relatively higher in the EBSC group, in which lymphocytes, albumin, and hemoglobin were significantly lower. Kaplan-Meier analysis revealed age above 65 years, males, comorbidities (especially for cardiovascular disease and tumor patients), lymphocyte count < 1.5 × 109/L, leukocyte count > 10 × 109/L, EBSC, eGFR < 60 ml/min/1.73 m2 were associated with in-hospital death. Multivariate Cox proportional hazard regression confirmed that EBSC (HR: 2.643, 95% CI: 1.111-6.285, P = 0.028), eGFR < 60 ml/min/1.73 m2 (HR: 3.889, 95% CI: 1.634-9.257, P = 0.002), were independent risk factors after adjusting for age, sex, any comorbidity, leukocyte and lymphocyte count. Therefore, the prevalence of kidney injury in patients with COVID-19 was high and associated with in-hospital mortality. Early detection and effective intervention of kidney injury may reduce COVID-19 deaths.


Subject(s)
Acute Kidney Injury/mortality , COVID-19/complications , SARS-CoV-2/physiology , Aged , Cardiovascular Diseases/complications , China , Comorbidity , Creatinine/blood , Creatinine/metabolism , Female , Hospital Mortality , Humans , Inflammation/pathology , Leukocytes/pathology , Lymphocytes/pathology , Male , Middle Aged , Neoplasms/complications , Prognosis , Retrospective Studies , Risk Factors
10.
Life Sci ; 277: 119503, 2021 Jul 15.
Article in English | MEDLINE | ID: covidwho-1185151

ABSTRACT

Severe coronavirus disease 2019 (COVID-19) caused by the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) is characterized by an unpredictable disease course, with variable presentations of different organ systems. The clinical manifestations of COVID-19 are highly variable ranging from mild presentations to severe, life-threatening symptoms and the wide individual variability may be due to the broad heterogeneity in the underlying pathologies. There is no doubt that early management may have a major influence on the outcome. This led the scientists to search for ways to monitor disease progression or to predict outcomes in COVID-19. Although it is not yet possible to predict who will progress to the severe forms or in what time, numerous prospective and longitudinal studies represent the evidence for determining the potential immunological risk factors of COVID-19 critical disease and death. The kinetics and breadth of immune responses during COVID-19 appear to follow a trend which is consistent to the predominant pathological alterations. Recent publications have used these biomarkers to help identify patients who will develop the severe acute COVID-19. Of particular interest is the relationship between the kinetics of peripheral leukocytes and clinical progress of the disease in COVID-19. Although research is ongoing in this area, we present details about the current status of the evaluation. Understanding of the COVID-19 related alterations of the innate and adaptive immune responses may help to promote the vaccine development and immunological interventions.


Subject(s)
COVID-19/immunology , Leukocytes/immunology , SARS-CoV-2/immunology , COVID-19/etiology , COVID-19/pathology , COVID-19/therapy , Disease Progression , Humans , Immunity, Cellular , Immunity, Innate , Immunotherapy , Leukocyte Count , Leukocytes/pathology , Macrophages/immunology , Macrophages/pathology , Risk Factors , SARS-CoV-2/isolation & purification , T-Lymphocytes/immunology , T-Lymphocytes/pathology
11.
Scand J Clin Lab Invest ; 81(3): 213-217, 2021 05.
Article in English | MEDLINE | ID: covidwho-1123177

ABSTRACT

In this nested case-control study, we evaluated haematological and morphological parameters of hospitalised patients with real-time polymerase chain reaction verified COVID-19 infection compared to patients with similar symptomatology but without COVID-19 infection. Seventy-four COVID-19 positive and 228 COVID-19 negative patients were evaluated with routine haematological parameters. Severe disease was defined as death and/or need of intensive care treatment. Twenty-seven COVID-19 positive and 18 COVID-19 negative patients were furthermore included for morphological evaluation using smear examination. Significant differences were found for platelet indices and white blood cell parameters. Thus, platelet count and plateletcrit was lower in COVID-19 patients, whilst mean platelet volume, platelet distribution width, and platelet large cell ratio was significantly higher than in non-COVID-19 patients. Leukocyte, neutrophil, immature granulocyte, lymphocyte, monocyte, eosinophil, and basophil count was lower in COVID-19 patients. No significant differences were found for red blood cell count, haemoglobin, haematocrit or mean corpuscular haemoglobin for COVID-19 versus non-COVID-19 patients. COVID-19 patients with a severe disease course had higher levels of immature granulocytes, but lower lymphocyte and platelet counts compared to patients with non-severe COVID-19. In terms of morphology, 14.8% of COVID-19 patients had a normal smear examination, compared to 83.3% of non-COVID-19 patients. Hypogranulated neutrophils were more frequent in COVID-19 patients (p < .001), but non-COVID-19 patients had higher levels of reactive lymphocytes, compared to COVID-19 patients. In conclusion, several haematological morphological abnormalities are more frequent in patients with COVID-19 disease, and several findings indicate that platelets play a fundamental role in the pathophysiology of the disease.


Subject(s)
Blood Platelets/pathology , COVID-19/blood , Leukocytes/pathology , SARS-CoV-2 , Adult , Aged , Case-Control Studies , Female , Humans , Leukocyte Count , Male , Middle Aged , Platelet Count
12.
Int Immunopharmacol ; 90: 107157, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1065211

ABSTRACT

Coronavirus disease 2019 (COVID-19) pandemic has brought challenges to health and social care systems. However, the empirical use of antibiotics is still confusing. Presently, a total of 1123 patients with COVID-19 admitted to Renmin Hospital of Wuhan University was included in this retrospective cohort study. The clinical features, complications and outcomes were compared between the suspected bacterial infection and the no evidence of bacterial infection. The risk factors of mortality and the incidence of acute organ injury were analyzed. As a result, 473 patients were selected to suspected bacterial infection (SI) group based on higher white blood cell count and procalcitonin or bacterial pneumonia on chest radiography. 650 patients were selected to the no evidence of bacterial infection (NI) group. The SI group had more severely ill patients (70.2% vs. 39.8%), more death (20.5% vs. 2.2%), and more acute organ injury (40.2% vs. 11.2%). Antibiotics were found associated with improved mortality and an increased risk for acute organ injury in hospitalized patients with COVID-19. Intravenous moxifloxacin and meropenem increased the death rate in patients with suspected bacterial infection, while oral antibiotics reduced mortality in this group. Moreover, penicillin and meropenem treatments were associated with increased mortality of the patients with no evidence of bacterial infection. In conclusion, patients with suspected bacterial infection were more likely to have negative clinical outcomes than those without bacterial infection. Empirical use of antibiotics may not have the expected benefits.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Bacterial Infections/drug therapy , COVID-19/drug therapy , Leukocytes/pathology , Lung/diagnostic imaging , SARS-CoV-2/physiology , Aged , Bacterial Infections/complications , Bacterial Infections/mortality , COVID-19/complications , COVID-19/mortality , China , Cohort Studies , Female , Humans , Lung/pathology , Male , Middle Aged , Pneumonia, Bacterial , Procalcitonin/metabolism , Retrospective Studies , Risk Factors , Survival Analysis
13.
Int Immunopharmacol ; 93: 107390, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1059618

ABSTRACT

BACKGROUND: Exposure to viral or bacterial pathogens increases the number of neutrophils with a relative decrease in lymphocytes, leading to elevated neutrophil to lymphocyte ratio (NLR). This study aimed to investigate whether differences in NLR among real-time polymerase chain reaction (PCR)-positive and -negative patients presenting with a prediagnosis of COVID-19 pneumonia could be useful in the differential diagnosis. METHODS: The study included 174 patients admitted because of suspected COVID-19 infection between March and April 2020. Patients were divided into two groups: PCR-negative and PCR-positive. Hemogram, NLR, urea, creatinine, aspartate aminotransferase, alanine aminotransferase, bilirubin, ferritin, D-dimer, C-reactive protein, procalcitonin, troponin, and coagulation parameters were analyzed. RESULTS: On comparison of laboratory parameters between both groups at presentation, PCR-positive patients were significantly more likely to have leukopenia (p < 0.001), thrombocytopenia (p = 0.006), neutropenia (p < 0.001), lymphopenia (p = 0.001), and increased NLR (p = 0.003). Furthermore, PCR-positive patients showed significant elevations of ferritin (p = 0.012) and procalcitonin (p = 0.038) and significant lower potassium levels (p = 0.05). CONCLUSION: COVID-19 pneumonia has become a major global health problem. Early diagnosis and treatment of these patients are crucial, as COVID-19 pneumonia shows a rapid progression in most cases. Thus, leukopenia, thrombocytopenia, elevated NLR, and elevated ferritin may be useful as supplementary diagnostic tests in these patients, which may allow early initiation of treatment and may contribute to preventing progression in patients with abnormal results.


Subject(s)
COVID-19/blood , COVID-19/diagnosis , Coronavirus Infections/diagnosis , Adult , Aged , Aged, 80 and over , Coronavirus Infections/blood , Female , Ferritins/metabolism , Humans , Leukocyte Count , Leukocytes/pathology , Leukopenia/blood , Leukopenia/virology , Lymphocyte Count , Male , Middle Aged , Neutrophils/pathology , Platelet Count , Polymerase Chain Reaction , Retrospective Studies , SARS-CoV-2/isolation & purification , Thrombocytopenia/blood , Thrombocytopenia/virology
14.
J Microbiol Immunol Infect ; 54(1): 61-68, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1039451

ABSTRACT

OBJECTIVES: To analyse the diagnostic performance of eosinopenia, alone or combined with polymorphonuclear neutrophils (PMN) and/or lymphocytes, as a marker of active COVID-19 in patients hospitalized for suspicion of SARS-CoV-2 infection. METHODS: A prospective observational study including patients hospitalized for suspicion of COVID-19 in a COVID unit was performed from 20th March to 5th April 2020, in Perpignan, France. Patients for which there was a doubt upon diagnosis, who were recently under oral corticosteroids, had myeloid malignancy or human immunodeficient virus infection were excluded. SARS-CoV-2 detection was performed using an RT-PCR assay, from nasopharyngeal swab specimens. Complete blood count were performed for all patients. RESULTS: One-hundred and twenty-one patient were included: 57 patients were diagnosed with COVID-19, 64 patients were not. Eosinophil count was lower in the COVID-19 group (median: 0/µL versus 70/µL, p < 0.0001). To diagnose COVID-19, eosinopenia had a sensitivity of 89.5% and a specificity of 78.1% while lymphopenia's were 73.7% and 62.5% respectively. Using area under curve (AUC) of receiving operating characteristics (ROC) curves, eosinophil's optimal cut-off level was 10/µL, sensitivity and specificity were 86%, and 79.7% respectively. Regarding the eosinophil/PMN ratio, the optimal cut-off level was 3.344, sensitivity and specificity were 87.7% and 73.4% respectively. The AUC of lymphocyte/PMN ratio was significantly lower than eosinophil/PMN ratio's (0.621 versus 0.846, p = 0.0003). CONCLUSION: Eosinopenia - <10/µL - and eosinophil/PMN ratio are useful, low-cost, reproducible tools to help diagnose COVID-19, during an epidemic period, in a population of hospitalized patients admitted for suspicion of COVID-19.


Subject(s)
COVID-19/blood , COVID-19/diagnosis , Eosinophils/pathology , Aged , Aged, 80 and over , Biomarkers/blood , Blood Cell Count , COVID-19 Testing/methods , Female , Humans , Leukocyte Count , Leukocytes/pathology , Male , Middle Aged , Prospective Studies , ROC Curve , SARS-CoV-2 , Sensitivity and Specificity
15.
Cell Death Dis ; 12(1): 50, 2021 01 05.
Article in English | MEDLINE | ID: covidwho-1015003

ABSTRACT

Novel coronavirus disease 2019 (COVID-19) is associated with a hypercoagulable state, characterized by abnormal coagulation parameters and by increased incidence of cardiovascular complications. With this study, we aimed to investigate the activation state and the expression of transmembrane proteins in platelets of hospitalized COVID-19 patients. We investigated transmembrane proteins expression with a customized mass cytometry panel of 21 antibodies. Platelets of 8 hospitalized COVID-19 patients not requiring intensive care support and without pre-existing conditions were compared to platelets of healthy controls (11 donors) with and without in vitro stimulation with thrombin receptor-activating peptide (TRAP). Mass cytometry of non-stimulated platelets detected an increased surface expression of activation markers P-Selectin (0.67 vs. 1.87 median signal intensity for controls vs. patients, p = 0.0015) and LAMP-3 (CD63, 0.37 vs. 0.81, p = 0.0004), the GPIIb/IIIa complex (4.58 vs. 5.03, p < 0.0001) and other adhesion molecules involved in platelet activation and platelet-leukocyte interactions. Upon TRAP stimulation, mass cytometry detected a higher expression of P-selectin in COVID-19 samples compared to controls (p < 0.0001). However, we observed a significantly reduced capacity of COVID-19 platelets to increase the expression of activation markers LAMP-3 and P-Selectin upon stimulation with TRAP. We detected a hyperactivated phenotype in platelets during SARS-CoV-2 infection, consisting of highly expressed platelet activation markers, which might contribute to the hypercoagulopathy observed in COVID-19. In addition, several transmembrane proteins were more highly expressed compared to healthy controls. These findings support research projects investigating antithrombotic and antiplatelet treatment regimes in COVID-19 patients, and provide new insights on the phenotypical platelet expression during SARS-CoV-2 infection.


Subject(s)
Blood Platelets/pathology , COVID-19/complications , Leukocytes/pathology , SARS-CoV-2/isolation & purification , Thrombosis/epidemiology , Adult , Blood Platelets/metabolism , Blood Platelets/virology , COVID-19/transmission , COVID-19/virology , Case-Control Studies , Female , Germany/epidemiology , Humans , Leukocytes/metabolism , Leukocytes/virology , Male , Middle Aged , P-Selectin/metabolism , Peptide Fragments/metabolism , Phenotype , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Thrombosis/virology
16.
Am J Clin Pathol ; 155(3): 364-375, 2021 Feb 11.
Article in English | MEDLINE | ID: covidwho-955795

ABSTRACT

OBJECTIVES: To investigate the clinical significance of numeric and morphologic peripheral blood (PB) changes in coronavirus disease 2019 (COVID-19)-positive patients in predicting the outcome, as well as to compare these changes between critically ill COVID-19-positive and COVID-19-negative patients. METHODS: The study included 90 COVID-19-positive (51 intensive care unit [ICU] and 39 non-ICU) patients and 30 COVID-19-negative ICU patients. We collected CBC parameters (both standard and research) and PB morphologic findings, which were independently scored by two hematopathologists. RESULTS: All patients with COVID-19 demonstrated striking numeric and morphologic WBC changes, which were different between mild and severe disease states. More severe disease was associated with significant neutrophilia and lymphopenia, which was intensified in critically ill patients. Abnormal WBC morphology, most pronounced in monocytes and lymphocytes, was associated with more mild disease; the changes were lost with disease progression. Between COVID-19-positive and COVID-19-negative ICU patients, significant differences in morphology-associated research parameters were indicative of changes due to the severe acute respiratory syndrome coronavirus 2 virus, including higher RNA content in monocytes, lower RNA content in lymphocytes, and smaller hypogranular neutrophils. CONCLUSIONS: Hospitalized patients with COVID-19 should undergo a comprehensive daily CBC with manual WBC differential to monitor for numerical and morphologic changes predictive of poor outcome and signs of disease progression.


Subject(s)
COVID-19/blood , COVID-19/complications , Leukocytes/pathology , Lymphopenia/virology , Neutrophils/pathology , Aged , Blood Cell Count , COVID-19/pathology , Critical Illness , Disease Progression , Female , Humans , Leukocyte Count , Male , Middle Aged , SARS-CoV-2
17.
Int J Lab Hematol ; 43(2): 160-168, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-954105

ABSTRACT

In December 2019, a new type of coronavirus was detected for the first time in Wuhan, Hubei Province, China. According to the reported data, the emerging coronavirus has spread worldwide, infecting more than fifty-seven million individuals, leading to more than one million deaths. The current study aimed to review and discuss the hematological findings of COVID-19. Laboratory changes and hematologic abnormalities have been reported repeatedly in COVID-19 patients. WBC count and peripheral blood lymphocytes are normal or slightly reduced while these indicators may change with the progression of the disease. In addition, several studies demonstrated that decreased hemoglobin levels in COVID-19 patients were associated with the severity of the disease. Moreover, thrombocytopenia, which is reported in 5%-40% of patients, is known to be associated with poor prognosis of the disease. COVID-19 can present with various hematologic manifestations. In this regard, accurate evaluation of laboratory indicators at the beginning and during COVID-19 can help physicians to adjust appropriate treatment and provide special and prompt care for those in need.


Subject(s)
COVID-19/blood , COVID-19/epidemiology , Hematology/methods , Pandemics , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Biomarkers/blood , Blood Platelets/immunology , Blood Platelets/pathology , Blood Platelets/virology , COVID-19/pathology , COVID-19/virology , China/epidemiology , Erythrocytes/immunology , Erythrocytes/pathology , Erythrocytes/virology , Hematology/instrumentation , Humans , Laboratories , Leukocytes/immunology , Leukocytes/pathology , Leukocytes/virology , Receptors, Virus/genetics , Receptors, Virus/immunology , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Serine Endopeptidases/immunology , Severity of Illness Index , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Virus Internalization
18.
Inflamm Res ; 70(1): 7-10, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-880306

ABSTRACT

OBJECTIVE: The orf8b protein of the coronavirus SARS-CoV, analogous to SARS-CoV-2, triggers the NLRP3 inflammasome in macrophages in vitro. Deregulated inflammasome-mediated release of interleukin-1 family cytokines is important in hyper-inflammatory syndromes, like happens in SARS-CoV-2-mediated cytokine release syndrome. We propose that an intense inflammasome formation characterizes the lungs of patients with fatal COVID-19 disease due to pneumonia and acute respiratory distress syndrome (ARDS). METHODS: Samples from four patients with confirmed COVID-19 pneumonia who had been hospitalized at the Hospital of the University of Trieste (Italy) and died of ARDS and four lung samples from a historical repository from subjects who had died of cardiopulmonary arrest and had not been placed on mechanical ventilation and without evidence of pulmonary infection at postmortem examination were collected. Pathology samples had been fixed in formalin 10% at time of collection and subsequently embedded in paraffin. We conducted staining for ASC (Apoptosis-associated Speck-like protein containing a Caspase recruitment domain), NLRP3 (NACHT, LRR, and PYD domains-containing protein 3), and cleaved caspase-1. RESULTS: Intense expression of the inflammasome was detected, mainly in leukocytes, within the lungs of all patients with fatal COVID-19 in the areas of lung injury. The number of ASC inflammasome specks per high power fields was significantly higher in the lungs of patients with fatal COVID-19 as compared with the lungs of control subjects (52 ± 22 vs 6 ± 3, P = 0.0064). CONCLUSIONS: These findings identify the presence of NLRP3 inflammasome aggregates in the lungs of fatal COVID-19 pneumonia thus providing the potential molecular link between viral infection and cytokine release syndrome.


Subject(s)
COVID-19/pathology , Inflammasomes , Lung/pathology , Adult , Aged , Autopsy , CARD Signaling Adaptor Proteins/analysis , CARD Signaling Adaptor Proteins/metabolism , Caspase 1/analysis , Caspase 1/metabolism , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/pathology , Female , Heart Arrest/etiology , Humans , Leukocytes/pathology , Male , Middle Aged , NLR Family, Pyrin Domain-Containing 3 Protein/analysis , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pneumonia, Viral/etiology , Pneumonia, Viral/pathology , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/pathology
19.
Nat Med ; 26(11): 1701-1707, 2020 11.
Article in English | MEDLINE | ID: covidwho-722216

ABSTRACT

Recent reports highlight a new clinical syndrome in children related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1-multisystem inflammatory syndrome in children (MIS-C)-which comprises multiorgan dysfunction and systemic inflammation2-13. We performed peripheral leukocyte phenotyping in 25 children with MIS-C, in the acute (n = 23; worst illness within 72 h of admission), resolution (n = 14; clinical improvement) and convalescent (n = 10; first outpatient visit) phases of the illness and used samples from seven age-matched healthy controls for comparisons. Among the MIS-C cohort, 17 (68%) children were SARS-CoV-2 seropositive, suggesting previous SARS-CoV-2 infections14,15, and these children had more severe disease. In the acute phase of MIS-C, we observed high levels of interleukin-1ß (IL-1ß), IL-6, IL-8, IL-10, IL-17, interferon-γ and differential T and B cell subset lymphopenia. High CD64 expression on neutrophils and monocytes, and high HLA-DR expression on γδ and CD4+CCR7+ T cells in the acute phase, suggested that these immune cell populations were activated. Antigen-presenting cells had low HLA-DR and CD86 expression, potentially indicative of impaired antigen presentation. These features normalized over the resolution and convalescence phases. Overall, MIS-C presents as an immunopathogenic illness1 and appears distinct from Kawasaki disease.


Subject(s)
COVID-19/blood , COVID-19/immunology , Leukocytes/classification , Leukocytes/pathology , SARS-CoV-2/immunology , Systemic Inflammatory Response Syndrome/blood , Systemic Inflammatory Response Syndrome/immunology , Adolescent , Age of Onset , Blood Coagulation/physiology , COVID-19/complications , COVID-19/epidemiology , Cardiomyopathies/blood , Cardiomyopathies/etiology , Cardiomyopathies/immunology , Case-Control Studies , Child , Child, Preschool , Cohort Studies , Female , Humans , Immunophenotyping , Inflammation/blood , Inflammation/etiology , Inflammation/immunology , Leukocytes/immunology , Male , Systemic Inflammatory Response Syndrome/complications , Systemic Inflammatory Response Syndrome/epidemiology
20.
Clin Appl Thromb Hemost ; 26: 1076029620943293, 2020.
Article in English | MEDLINE | ID: covidwho-690632

ABSTRACT

Since the onset of the global pandemic in early 2020, coronavirus disease 2019 (COVID-19) has posed a multitude of challenges to health care systems worldwide. In order to combat these challenges and devise appropriate therapeutic strategies, it becomes of paramount importance to elucidate the pathophysiology of this illness. Coronavirus disease 2019, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), is characterized by a dysregulated immune system and hypercoagulability. COVID-associated coagulopathy (CAC) was recognized based on profound d-dimer elevations and evidence of microthrombi and macrothrombi, both in venous and arterial systems. The underlying mechanisms associated with CAC have been suggested, but not clearly defined. The model of immunothrombosis illustrates the elaborate crosstalk between the innate immune system and coagulation. The rendering of a procoagulant state in COVID-19 involves the interplay of many innate immune pathways. The SARS-CoV2 virus can directly infect immune and endothelial cells, leading to endothelial injury and dysregulation of the immune system. Activated leukocytes potentiate a procoagulant state via release of intravascular tissue factor, platelet activation, NETosis, and inhibition of anticoagulant mechanisms. Additional pathways of specific relevance in CAC include cytokine release and complement activation. All these mechanisms have recently been reported in COVID-19. Immunothrombosis provides a comprehensive perspective of the several synergistic pathways pertinent to the pathogenesis of CAC.


Subject(s)
Betacoronavirus , Blood Coagulation Disorders/virology , Coronavirus Infections/complications , Pneumonia, Viral/complications , Blood Coagulation Disorders/etiology , Blood Coagulation Disorders/pathology , COVID-19 , Coronavirus Infections/physiopathology , Coronavirus Infections/virology , Endothelial Cells/pathology , Endothelial Cells/virology , Humans , Immunity, Innate , Leukocytes/metabolism , Leukocytes/pathology , Pandemics , Pneumonia, Viral/physiopathology , Pneumonia, Viral/virology , SARS-CoV-2 , Thrombophilia/immunology , Thrombophilia/virology , Thrombosis/etiology , Thrombosis/immunology , Thrombosis/virology
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