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1.
JAMA Cardiol ; 2021 Dec 15.
Article in English | MEDLINE | ID: covidwho-1575887

ABSTRACT

Importance: Myocardial injury is a common feature of patients with SARS-CoV-2 infection. However, the cardiac inflammatory processes associated with SARS-CoV-2 infection are not completely understood. Objective: To investigate the inflammatory cardiac phenotype associated with SARS-CoV-2 infection compared with viral myocarditis, immune-mediated myocarditis, and noninflammatory cardiomyopathy by integrating histologic, transcriptomic, and proteomic profiling. Design, Setting, and Participants: This case series was a cooperative study between the Ludwig Maximilian University Hospital Munich and the Cardiopathology Referral Center at the University of Tübingen in Germany. A cohort of 19 patients with suspected myocarditis was examined; of those, 5 patients were hospitalized with SARS-CoV-2 infection between March and May 2020. Cardiac tissue specimens from those 5 patients were compared with specimens from 5 patients with immune-mediated myocarditis, 4 patients with non-SARS-CoV-2 viral myocarditis, and 5 patients with noninflammatory cardiomyopathy, collected from January to August 2019. Exposures: Endomyocardial biopsy. Main Outcomes and Measures: The inflammatory cardiac phenotypes were measured by immunohistologic analysis, RNA exome capture sequencing, and mass spectrometry-based proteomic analysis of endomyocardial biopsy specimens. Results: Among 19 participants, the median age was 58 years (range, 37-76 years), and 15 individuals (79%) were male. Data on race and ethnicity were not collected. The abundance of CD163+ macrophages was generally higher in the cardiac tissue of patients with myocarditis, whereas lymphocyte counts were lower in the tissue of patients with SARS-CoV-2 infection vs patients with non-SARS-CoV-2 virus-associated and immune-mediated myocarditis. Among those with SARS-CoV-2 infection, components of the complement cascade, including C1q subunits (transcriptomic analysis: 2.5-fold to 3.6-fold increase; proteomic analysis: 2.0-fold to 3.4-fold increase) and serine/cysteine proteinase inhibitor clade G member 1 (transcriptomic analysis: 1.7-fold increase; proteomic analysis: 2.6-fold increase), belonged to the most commonly upregulated transcripts and differentially abundant proteins. In cardiac macrophages, the abundance of C1q was highest in SARS-CoV-2 infection. Assessment of important signaling cascades identified an upregulation of the serine/threonine mitogen-activated protein kinase pathways. Conclusions and Relevance: This case series found that the cardiac immune signature varied in inflammatory conditions with different etiologic characteristics. Future studies are needed to examine the role of these immune pathways in myocardial inflammation.

2.
JCI Insight ; 6(18)2021 09 22.
Article in English | MEDLINE | ID: covidwho-1435144

ABSTRACT

Neutrophils provide a critical line of defense in immune responses to various pathogens, inflicting self-damage upon transition to a hyperactivated, procoagulant state. Recent work has highlighted proinflammatory neutrophil phenotypes contributing to lung injury and acute respiratory distress syndrome (ARDS) in patients with coronavirus disease 2019 (COVID-19). Here, we use state-of-the art mass spectrometry-based proteomics and transcriptomic and correlative analyses as well as functional in vitro and in vivo studies to dissect how neutrophils contribute to the progression to severe COVID-19. We identify a reinforcing loop of both systemic and neutrophil intrinsic IL-8 (CXCL8/IL-8) dysregulation, which initiates and perpetuates neutrophil-driven immunopathology. This positive feedback loop of systemic and neutrophil autocrine IL-8 production leads to an activated, prothrombotic neutrophil phenotype characterized by degranulation and neutrophil extracellular trap (NET) formation. In severe COVID-19, neutrophils directly initiate the coagulation and complement cascade, highlighting a link to the immunothrombotic state observed in these patients. Targeting the IL-8-CXCR-1/-2 axis interferes with this vicious cycle and attenuates neutrophil activation, degranulation, NETosis, and IL-8 release. Finally, we show that blocking IL-8-like signaling reduces severe acute respiratory distress syndrome of coronavirus 2 (SARS-CoV-2) spike protein-induced, human ACE2-dependent pulmonary microthrombosis in mice. In summary, our data provide comprehensive insights into the activation mechanisms of neutrophils in COVID-19 and uncover a self-sustaining neutrophil-IL-8 axis as a promising therapeutic target in severe SARS-CoV-2 infection.


Subject(s)
COVID-19/metabolism , Interleukin-8/metabolism , Lung/immunology , Neutrophils/immunology , SARS-CoV-2 , Thrombosis/etiology , Animals , COVID-19/complications , COVID-19/pathology , Humans , Lung/pathology , Mice , Neutrophil Activation , Neutrophils/pathology , Phenotype , Thrombosis/pathology
3.
Lancet Respir Med ; 9(8): 863-872, 2021 08.
Article in English | MEDLINE | ID: covidwho-1340915

ABSTRACT

BACKGROUND: SARS-CoV-2 entry in human cells depends on angiotensin-converting enzyme 2, which can be upregulated by inhibitors of the renin-angiotensin system (RAS). We aimed to test our hypothesis that discontinuation of chronic treatment with ACE-inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) mitigates the course o\f recent-onset COVID-19. METHODS: ACEI-COVID was a parallel group, randomised, controlled, open-label trial done at 35 centres in Austria and Germany. Patients aged 18 years and older were enrolled if they presented with recent symptomatic SARS-CoV-2 infection and were chronically treated with ACEIs or ARBs. Patients were randomly assigned 1:1 to discontinuation or continuation of RAS inhibition for 30 days. Primary outcome was the maximum sequential organ failure assessment (SOFA) score within 30 days, where death was scored with the maximum achievable SOFA score. Secondary endpoints were area under the death-adjusted SOFA score (AUCSOFA), mean SOFA score, admission to the intensive care unit, mechanical ventilation, and death. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT04353596. FINDINGS: Between April 20, 2020, and Jan 20, 2021, 204 patients (median age 75 years [IQR 66-80], 37% females) were randomly assigned to discontinue (n=104) or continue (n=100) RAS inhibition. Within 30 days, eight (8%) of 104 died in the discontinuation group and 12 (12%) of 100 patients died in the continuation group (p=0·42). There was no significant difference in the primary endpoint between the discontinuation and continuation group (median [IQR] maximum SOFA score 0·00 (0·00-2·00) vs 1·00 (0·00-3·00); p=0·12). Discontinuation was associated with a significantly lower AUCSOFA (0·00 [0·00-9·25] vs 3·50 [0·00-23·50]; p=0·040), mean SOFA score (0·00 [0·00-0·31] vs 0·12 [0·00-0·78]; p=0·040), and 30-day SOFA score (0·00 [10-90th percentile, 0·00-1·20] vs 0·00 [0·00-24·00]; p=0·023). At 30 days, 11 (11%) in the discontinuation group and 23 (23%) in the continuation group had signs of organ dysfunction (SOFA score ≥1) or were dead (p=0·017). There were no significant differences for mechanical ventilation (10 (10%) vs 8 (8%), p=0·87) and admission to intensive care unit (20 [19%] vs 18 [18%], p=0·96) between the discontinuation and continuation group. INTERPRETATION: Discontinuation of RAS-inhibition in COVID-19 had no significant effect on the maximum severity of COVID-19 but may lead to a faster and better recovery. The decision to continue or discontinue should be made on an individual basis, considering the risk profile, the indication for RAS inhibition, and the availability of alternative therapies and outpatient monitoring options. FUNDING: Austrian Science Fund and German Center for Cardiovascular Research.


Subject(s)
Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors , COVID-19 , Hypertension , Renin-Angiotensin System , SARS-CoV-2 , Angiotensin Receptor Antagonists/administration & dosage , Angiotensin Receptor Antagonists/adverse effects , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Area Under Curve , COVID-19/epidemiology , COVID-19/metabolism , COVID-19/therapy , Female , Humans , Hypertension/drug therapy , Hypertension/epidemiology , Male , Middle Aged , Organ Dysfunction Scores , Outcome and Process Assessment, Health Care , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Risk Adjustment/methods , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Severity of Illness Index , Withholding Treatment/statistics & numerical data
4.
Infection ; 2021 Jul 19.
Article in English | MEDLINE | ID: covidwho-1316346

ABSTRACT

PURPOSE: While more advanced COVID-19 necessitates medical interventions and hospitalization, patients with mild COVID-19 do not require this. Identifying patients at risk of progressing to advanced COVID-19 might guide treatment decisions, particularly for better prioritizing patients in need for hospitalization. METHODS: We developed a machine learning-based predictor for deriving a clinical score identifying patients with asymptomatic/mild COVID-19 at risk of progressing to advanced COVID-19. Clinical data from SARS-CoV-2 positive patients from the multicenter Lean European Open Survey on SARS-CoV-2 Infected Patients (LEOSS) were used for discovery (2020-03-16 to 2020-07-14) and validation (data from 2020-07-15 to 2021-02-16). RESULTS: The LEOSS dataset contains 473 baseline patient parameters measured at the first patient contact. After training the predictor model on a training dataset comprising 1233 patients, 20 of the 473 parameters were selected for the predictor model. From the predictor model, we delineated a composite predictive score (SACOV-19, Score for the prediction of an Advanced stage of COVID-19) with eleven variables. In the validation cohort (n = 2264 patients), we observed good prediction performance with an area under the curve (AUC) of 0.73 ± 0.01. Besides temperature, age, body mass index and smoking habit, variables indicating pulmonary involvement (respiration rate, oxygen saturation, dyspnea), inflammation (CRP, LDH, lymphocyte counts), and acute kidney injury at diagnosis were identified. For better interpretability, the predictor was translated into a web interface. CONCLUSION: We present a machine learning-based predictor model and a clinical score for identifying patients at risk of developing advanced COVID-19.

5.
J Thorac Imaging ; 36(5): 279-285, 2021 Sep 01.
Article in English | MEDLINE | ID: covidwho-1263732

ABSTRACT

PURPOSE: Coronavirus 2019 disease (COVID-19) has been shown to affect the myocardium, resulting in a worse clinical outcome. In this registry study, we aimed to identify differences in cardiac magnetic resonance imaging (CMRI) between COVID-19 and all-cause myocarditis. MATERIALS AND METHODS: We examined CMRI of patients with COVID-19 and elevated high-sensitivity serum troponin levels performed between March 31st and May 5th and compared them to CMRI of patients without SARS-CoV-2 infection with suspected myocarditis in the same time period. For this purpose, we evaluated Lake-Louise Criteria for myocarditis by determining nonischemic myocardial injury via T1-mapping, extracellular volume, late gadolinium enhancement, and myocardial edema (ME) by T2-mapping and fat-saturated T2w imaging (T2Q). RESULTS: A total of 15 of 18 (89%) patients with COVID-19 had abnormal findings. The control group consisted of 18 individuals. There were significantly fewer individuals with COVID-19 who had increased T2 (5 vs. 10; P=0.038) and all-cause ME (7 vs. 15; P=0.015); thus, significantly fewer patients with COVID-19 fulfilled Lake-Louise Criteria (6 vs. 17; P<0.001). In contrast, nonischemic myocardial injury was not significantly different. In the COVID-19 group, indexed end-diastolic volume of the left ventricle showed a significant correlation to the extent of abnormal T1 (R2=0.571; P=0.017) and extracellular volume (R2=0.605; P=0.013) and absolute T1, T2, and T2Q (R2=0.644; P=0.005, R2=0.513; P=0.035 and R2=0.629; P=0.038, respectively); in the control group, only extracellular volume showed a weak correlation (R2=0.490; P=0.046). CONCLUSIONS: Cardiac involvement in COVID-19 seems to show less ME than all-cause myocarditis. Abnormal CMRI markers correlated to left ventricle dilation only in the COVID-19 group. Larger comparative studies are needed to verify our findings.


Subject(s)
COVID-19 , Magnetic Resonance Imaging, Cine , Myocarditis , COVID-19/diagnostic imaging , Contrast Media , Diagnosis, Differential , Gadolinium , Humans , Myocarditis/diagnostic imaging , Myocardium , Predictive Value of Tests
6.
Nat Rev Cardiol ; 18(9): 666-682, 2021 09.
Article in English | MEDLINE | ID: covidwho-1220034

ABSTRACT

Thrombosis is the most feared complication of cardiovascular diseases and a main cause of death worldwide, making it a major health-care challenge. Platelets and the coagulation cascade are effectively targeted by antithrombotic approaches, which carry an inherent risk of bleeding. Moreover, antithrombotics cannot completely prevent thrombotic events, implicating a therapeutic gap due to a third, not yet adequately addressed mechanism, namely inflammation. In this Review, we discuss how the synergy between inflammation and thrombosis drives thrombotic diseases. We focus on the huge potential of anti-inflammatory strategies to target cardiovascular pathologies. Findings in the past decade have uncovered a sophisticated connection between innate immunity, platelet activation and coagulation, termed immunothrombosis. Immunothrombosis is an important host defence mechanism to limit systemic spreading of pathogens through the bloodstream. However, the aberrant activation of immunothrombosis in cardiovascular diseases causes myocardial infarction, stroke and venous thromboembolism. The clinical relevance of aberrant immunothrombosis, referred to as thromboinflammation, is supported by the increased risk of cardiovascular events in patients with inflammatory diseases but also during infections, including in COVID-19. Clinical trials in the past 4 years have confirmed the anti-ischaemic effects of anti-inflammatory strategies, backing the concept of a prothrombotic function of inflammation. Targeting inflammation to prevent thrombosis leaves haemostasis mainly unaffected, circumventing the risk of bleeding associated with current approaches. Considering the growing number of anti-inflammatory therapies, it is crucial to appreciate their potential in covering therapeutic gaps in cardiovascular diseases.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Blood Coagulation/drug effects , Fibrinolytic Agents/therapeutic use , Immune System/drug effects , Inflammation Mediators/antagonists & inhibitors , Inflammation/drug therapy , Thrombosis/prevention & control , Anti-Inflammatory Agents/adverse effects , COVID-19/blood , COVID-19/immunology , Fibrinolytic Agents/adverse effects , Humans , Immune System/immunology , Immune System/metabolism , Inflammation/blood , Inflammation/immunology , Inflammation Mediators/metabolism , Risk Assessment , Risk Factors , Signal Transduction , Thrombosis/blood , Thrombosis/immunology
7.
Nat Rev Immunol ; 21(5): 319-329, 2021 05.
Article in English | MEDLINE | ID: covidwho-1171402

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a clinical syndrome caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with severe disease show hyperactivation of the immune system, which can affect multiple organs besides the lungs. Here, we propose that SARS-CoV-2 infection induces a process known as immunothrombosis, in which activated neutrophils and monocytes interact with platelets and the coagulation cascade, leading to intravascular clot formation in small and larger vessels. Microthrombotic complications may contribute to acute respiratory distress syndrome (ARDS) and other organ dysfunctions. Therapeutic strategies aimed at reducing immunothrombosis may therefore be useful. Several antithrombotic and immunomodulating drugs have been proposed as candidates to treat patients with SARS-CoV-2 infection. The growing understanding of SARS-CoV-2 infection pathogenesis and how it contributes to critical illness and its complications may help to improve risk stratification and develop targeted therapies to reduce the acute and long-term consequences of this disease.


Subject(s)
COVID-19/immunology , COVID-19/pathology , Cytokine Release Syndrome/pathology , Venous Thrombosis/immunology , Venous Thrombosis/pathology , Blood Coagulation/immunology , Blood Platelets/immunology , Critical Illness/therapy , Cytokine Release Syndrome/immunology , Endothelium, Vascular/pathology , Fibrinolytic Agents/therapeutic use , Humans , Immunity, Innate/immunology , Lung/blood supply , Lung/pathology , Lung/virology , Monocytes/immunology , Neutrophils/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Venous Thrombosis/prevention & control
8.
Infection ; 49(3): 491-500, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1053123

ABSTRACT

PURPOSE: SARS-COV-2 infection can develop into a multi-organ disease. Although pathophysiological mechanisms of COVID-19-associated myocardial injury have been studied throughout the pandemic course in 2019, its morphological characterisation is still unclear. With this study, we aimed to characterise echocardiographic patterns of ventricular function in patients with COVID-19-associated myocardial injury. METHODS: We prospectively assessed 32 patients hospitalised with COVID-19 and presence or absence of elevated high sensitive troponin T (hsTNT+ vs. hsTNT-) by comprehensive three-dimensional (3D) and strain echocardiography. RESULTS: A minority (34.3%) of patients had normal ventricular function, whereas 65.7% had left and/or right ventricular dysfunction defined by impaired left and/or right ventricular ejection fraction and strain measurements. Concomitant biventricular dysfunction was common in hsTNT+ patients. We observed impaired left ventricular (LV) global longitudinal strain (GLS) in patients with myocardial injury (-13.9% vs. -17.7% for hsTNT+ vs. hsTNT-, p = 0.005) but preserved LV ejection fraction (52% vs. 59%, p = 0.074). Further, in these patients, right ventricular (RV) systolic function was impaired with lower RV ejection fraction (40% vs. 49%, p = 0.001) and reduced RV free wall strain (-18.5% vs. -28.3%, p = 0.003). Myocardial dysfunction partially recovered in hsTNT + patients after 52 days of follow-up. In particular, LV-GLS and RV-FWS significantly improved from baseline to follow-up (LV-GLS: -13.9% to -16.5%, p = 0.013; RV-FWS: -18.5% to -22.3%, p = 0.037). CONCLUSION: In patients with COVID-19-associated myocardial injury, comprehensive 3D and strain echocardiography revealed LV dysfunction by GLS and RV dysfunction, which partially resolved at 2-month follow-up. TRIAL REGISTRATION: COVID-19 Registry of the LMU University Hospital Munich (CORKUM), WHO trial ID DRKS00021225.


Subject(s)
COVID-19/physiopathology , Ventricular Dysfunction/physiopathology , Aged , COVID-19/complications , COVID-19/diagnostic imaging , COVID-19/pathology , Echocardiography, Three-Dimensional , Female , Follow-Up Studies , Heart Ventricles/diagnostic imaging , Heart Ventricles/pathology , Heart Ventricles/physiopathology , Hospitalization , Humans , Male , Middle Aged , Prospective Studies , SARS-CoV-2 , Stroke Volume , Troponin T/blood , Ventricular Dysfunction/diagnostic imaging , Ventricular Dysfunction/etiology , Ventricular Dysfunction/pathology
9.
Circ Cardiovasc Imaging ; 14(1): e012220, 2021 01.
Article in English | MEDLINE | ID: covidwho-1035201

ABSTRACT

BACKGROUND: Myocardial injury, defined by elevated troponin levels, is associated with adverse outcome in patients with coronavirus disease 2019 (COVID-19). The frequency of cardiac injury remains highly uncertain and confounded in current publications; myocarditis is one of several mechanisms that have been proposed. METHODS: We prospectively assessed patients with myocardial injury hospitalized for COVID-19 using transthoracic echocardiography, cardiac magnetic resonance imaging, and endomyocardial biopsy. RESULTS: Eighteen patients with COVID-19 and myocardial injury were included in this study. Echocardiography revealed normal to mildly reduced left ventricular ejection fraction of 52.5% (46.5%-60.5%) but moderately to severely reduced left ventricular global longitudinal strain of -11.2% (-7.6% to -15.1%). Cardiac magnetic resonance showed any myocardial tissue injury defined by elevated T1, extracellular volume, or late gadolinium enhancement with a nonischemic pattern in 16 patients (83.3%). Seven patients (38.9%) demonstrated myocardial edema in addition to tissue injury fulfilling the Lake-Louise criteria for myocarditis. Combining cardiac magnetic resonance with speckle tracking echocardiography demonstrated functional or morphological cardiac changes in 100% of investigated patients. Endomyocardial biopsy was conducted in 5 patients and revealed enhanced macrophage numbers in all 5 patients in addition to lymphocytic myocarditis in 1 patient. SARS-CoV-2 RNA was not detected in any biopsy by quantitative real-time polymerase chain reaction. Finally, follow-up measurements of left ventricular global longitudinal strain revealed significant improvement after a median of 52.0 days (-11.2% [-9.2% to -14.7%] versus -15.6% [-12.5% to -19.6%] at follow-up; P=0.041). CONCLUSIONS: In this small cohort of COVID-19 patients with elevated troponin levels, myocardial injury was evidenced by reduced echocardiographic left ventricular strain, myocarditis patterns on cardiac magnetic resonance, and enhanced macrophage numbers but not predominantly lymphocytic myocarditis in endomyocardial biopsies.


Subject(s)
COVID-19/complications , COVID-19/pathology , Myocarditis/etiology , Myocarditis/pathology , Myocardium/pathology , Aged , Biopsy , COVID-19/blood , Cohort Studies , Echocardiography/methods , Female , Germany , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged , Myocarditis/diagnostic imaging , Prospective Studies , SARS-CoV-2 , Troponin/blood
10.
J Thromb Haemost ; 19(2): 574-581, 2021 02.
Article in English | MEDLINE | ID: covidwho-939789

ABSTRACT

OBJECTIVE: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to severe pneumonia, but also thrombotic complications and non-pulmonary organ failure. Recent studies suggest intravascular neutrophil activation and subsequent immune cell-triggered immunothrombosis as a central pathomechanism linking the heterogenous clinical picture of coronavirus disease 2019 (COVID-19). We sought to study whether immunothrombosis is a pathognomonic factor in COVID-19 or a general feature of (viral) pneumonia, as well as to better understand its upstream regulation. APPROACH AND RESULTS: By comparing histopathological specimens of SARS-CoV-2 with influenza-affected lungs, we show that vascular neutrophil recruitment, NETosis, and subsequent immunothrombosis are typical features of severe COVID-19, but less prominent in influenza pneumonia. Activated neutrophils were typically found in physical association with monocytes. To explore this further, we combined clinical data of COVID-19 cases with comprehensive immune cell phenotyping and bronchoalveolar lavage fluid scRNA-seq data. We show that a HLADRlow CD9low monocyte population expands in severe COVID-19, which releases neutrophil chemokines in the lungs, and might in turn explain neutrophil expansion and pulmonary recruitment in the late stages of severe COVID-19. CONCLUSIONS: Our data underline an innate immune cell axis causing vascular inflammation and immunothrombosis in severe SARS-CoV-2 infection.


Subject(s)
COVID-19/immunology , Immunity, Innate , Influenza, Human/immunology , Lung/immunology , Neutrophils/immunology , Thrombosis/immunology , Vasculitis/immunology , COVID-19/diagnosis , COVID-19/virology , Diagnosis, Differential , Host-Pathogen Interactions , Humans , Influenza, Human/diagnosis , Influenza, Human/virology , Lung/pathology , Lung/virology , Neutrophils/virology , Predictive Value of Tests , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Thrombosis/virology , Vasculitis/virology
11.
Clin Res Cardiol ; 110(7): 1029-1040, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-932521

ABSTRACT

AIMS: SARS-CoV-2 infection is associated with adverse outcomes in patients with cardiovascular disease. Here, we analyzed whether specific biomarkers predict the clinical course of COVID-19 in patients with cardiovascular comorbidities. METHODS AND RESULTS: We enrolled 2147 patients with SARS-CoV-2 infection which were included in the Lean European Open Survey on SARS-CoV­2 (LEOSS)-registry from March to June 2020. Clinical data and laboratory values were collected and compared between patients with and without cardiovascular comorbidities in different clinical stages of the disease. Predictors for mortality were calculated using multivariate regression analysis. We show that patients with cardiovascular comorbidities display significantly higher markers of myocardial injury and thrombo-inflammatory activation already in the uncomplicated phase of COVID-19. In multivariate analysis, elevated levels of troponin [OR 1.54; (95% CI 1.22-1.96), p < 0.001)], IL-6 [OR 1.69 (95% CI 1.26-2.27), p < 0.013)], and CRP [OR 1.32; (95% CI 1.1-1.58), p < 0.003)] were predictors of mortality in patients with COVID-19. CONCLUSION: Patients with cardiovascular comorbidities show elevated markers of thrombo-inflammatory activation and myocardial injury, which predict mortality, already in the uncomplicated phase of COVID-19. Starting targeted anti-inflammatory therapy and aggressive anticoagulation already in the uncomplicated phase of the disease might improve outcomes after SARS-CoV-2 infection in patients with cardiovascular comorbidities. Elevated markers of thrombo-inflammatory activation predict outcome in patients with cardiovascular comorbidities and COVID-19 disease: insights from the LEOSS registry.


Subject(s)
COVID-19/complications , Cardiovascular Diseases/physiopathology , Inflammation/pathology , Thrombosis/pathology , Adult , Aged , Aged, 80 and over , Biomarkers/metabolism , Female , Humans , Male , Middle Aged , Registries , Young Adult
13.
Circulation ; 142(12): 1176-1189, 2020 09 22.
Article in English | MEDLINE | ID: covidwho-696368

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome corona virus 2 infection causes severe pneumonia (coronavirus disease 2019 [COVID-19]), but the mechanisms of subsequent respiratory failure and complicating renal and myocardial involvement are poorly understood. In addition, a systemic prothrombotic phenotype has been reported in patients with COVID-19. METHODS: A total of 62 subjects were included in our study (n=38 patients with reverse transcriptase polymerase chain reaction-confirmed COVID-19 and n=24 non-COVID-19 controls). We performed histopathologic assessment of autopsy cases, surface marker-based phenotyping of neutrophils and platelets, and functional assays for platelet, neutrophil functions, and coagulation tests, as well. RESULTS: We provide evidence that organ involvement and prothrombotic features in COVID-19 are linked by immunothrombosis. We show that, in COVID-19, inflammatory microvascular thrombi are present in the lung, kidney, and heart, containing neutrophil extracellular traps associated with platelets and fibrin. Patients with COVID-19 also present with neutrophil-platelet aggregates and a distinct neutrophil and platelet activation pattern in blood, which changes with disease severity. Whereas cases of intermediate severity show an exhausted platelet and hyporeactive neutrophil phenotype, patients severely affected with COVID-19 are characterized by excessive platelet and neutrophil activation in comparison with healthy controls and non-COVID-19 pneumonia. Dysregulated immunothrombosis in severe acute respiratory syndrome corona virus 2 pneumonia is linked to both acute respiratory distress syndrome and systemic hypercoagulability. CONCLUSIONS: Taken together, our data point to immunothrombotic dysregulation as a key marker of disease severity in COVID-19. Further work is necessary to determine the role of immunothrombosis in COVID-19.


Subject(s)
Coronavirus Infections/diagnosis , Pneumonia, Viral/diagnosis , Respiratory Insufficiency/etiology , Betacoronavirus/genetics , Betacoronavirus/isolation & purification , Blood Coagulation Disorders/diagnosis , Blood Coagulation Disorders/etiology , Blood Platelets/cytology , Blood Platelets/metabolism , Blood Platelets/pathology , COVID-19 , Case-Control Studies , Coronavirus Infections/complications , Coronavirus Infections/pathology , Coronavirus Infections/virology , Extracellular Traps/metabolism , Humans , Kidney/pathology , Lung/pathology , Neutrophils/cytology , Neutrophils/metabolism , Neutrophils/pathology , Pandemics , Phenotype , Platelet Activation , Pneumonia, Viral/complications , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Respiratory Insufficiency/diagnosis , SARS-CoV-2 , Severity of Illness Index , Thrombosis/complications , Thrombosis/diagnosis
14.
J Cardiovasc Pharmacol Ther ; 25(6): 497-502, 2020 11.
Article in English | MEDLINE | ID: covidwho-671676

ABSTRACT

In recent months, the new coronavirus SARS-CoV-2 has emerged as a worldwide threat with about 4.2 million confirmed cases and almost 300 000 deaths. Its major clinical presentation is characterized by respiratory symptoms ranging from mild cough to serve pneumonia with fever and potentially even death. Until today, there is no known medication to improve clinical symptoms or even prevent or fight the infection. The search for a useful vaccination is ongoing and it will probably not be available before the end of 2020. In this review, we highlight hydroxychloroquine (HCQ) as a potential agent to prevent coronavirus disease 2019 (COVID-19) and reduce as well as shorten clinical symptoms. Moreover, it might serve as a potential post-exposition prophylaxis. Although it has been used in the treatment of rheumatoid arthritis, discoid or systemic lupus erythematosus, and malaria prophylaxis and therapy for decades, knowledge on HCQ as a potential treatment for COVID-19 is limited and multiple clinical trials have just emerged. Especially, rare HCQ side effects which were of minor importance for use in selected indications might gain major relevance with population-wide application. These rare side effects include retinopathy and-even more important-QT prolongation leading to sudden cardiac death by malignant arrhythmias.


Subject(s)
Coronavirus Infections/drug therapy , Hydroxychloroquine/therapeutic use , Pneumonia, Viral/drug therapy , Arrhythmias, Cardiac/chemically induced , Betacoronavirus , COVID-19 , Coronavirus Infections/immunology , Humans , Hydroxychloroquine/adverse effects , Hydroxychloroquine/pharmacology , Pandemics , Pneumonia, Viral/immunology , Randomized Controlled Trials as Topic , Retinal Diseases/chemically induced , SARS-CoV-2
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