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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-329729

ABSTRACT

SARS-CoV-2 remains an acute threat to human health, endangering hospital capacities worldwide. Many studies have aimed at informing pathophysiologic understanding and identification of disease indicators for risk assessment, monitoring, and therapeutic guidance. While findings start to emerge in the general population, observations in high-risk patients with complex pre-existing conditions are limited. To this end, we biomedically characterized quantitative proteomics in a hospitalized cohort of COVID-19 patients with mild to severe symptoms suffering from different (co)-morbidities in comparison to both healthy individuals and patients with non-COVID related inflammation. Deep clinical phenotyping enabled the identification of individual disease trajectories in COVID-19 patients. By the use of this specific disease phase assignment, proteome analysis revealed a severity dependent general type-2 centered host response side-by-side with a disease specific antiviral immune reaction in early disease. The identification of phenomena such as neutrophil extracellular trap (NET) formation and a pro-coagulatory response together with the regulation of proteins related to SARS-CoV-2-specific symptoms by unbiased proteome screening both confirms results from targeted approaches and provides novel information for biomarker and therapy development. Graphical Sars-CoV-2 remains a challenging threat to our health care system with many pathophysiological mechanisms not fully understood, especially in high-risk patients. Therefore, we characterized a cohort of hospitalized COVID-19 patients with multiple comorbidities by quantitative plasma proteomics and deep clinical phenotyping. The individual patient’s disease progression was determined and the subsequently assigned proteome profiles compared with a healthy and a chronically inflamed control cohort. The identified disease phase and severity specific protein profiles revealed an antiviral immune response together with coagulation activation indicating the formation of NETosis side-by-side with tissue remodeling related to the inflammatory signature.

2.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-329471

ABSTRACT

The immune system of most SARS-CoV-2 infected individuals limits viral spread to the upper airways without pulmonary involvement. This prevents the development of pneumonic COVID-19. However, the protective immunological responses causative of successful viral containment in the upper airways remain unclear. Here, we combine longitudinal single-cell RNA sequencing, proteomic profiling, multidimensional flow cytometry, RNA-Seq of FACS-sorted leukocyte subsets and multiplex plasma interferon profiling to uncover temporally resolved protective immune signatures in non-pneumonic and ambulatory SARS-CoV-2 infected patients. We compare host responses in a high-risk patient population infected with SARS-CoV-2 but without pulmonary involvement to patients with COVID-19 pneumonia. Our data reveal a distinct immunological signature of successful viral containment, characterized by an early prominent interferon stimulated gene (ISG) upregulation across immune cell subsets. In addition, reduced cytotoxic potential of Natural Killer (NK) and T cells, as well as a monocyte phenotype with immune-modulatory potential are hallmarks of protective immunity. Temporal resolution across disease trajectories highlights ISG upregulation as particularly prominent early in the disease and confirms increased expression also in comparison to healthy controls. We validate this distinct temporal ISG signature by in-depth RNA-seq of FACS-sorted leukocyte subsets in a large prospective ambulatory SARS-CoV-2 infected cohort confirming early and robust ISG upregulation particularly in monocytes and T cells. In conclusion, our data demonstrate a protective ISG phenotype in patients with successful containment of SARS-CoV-2 infection without progression to COVID-19. This early protective interferon response might be exploited as a therapeutic approach and for disease course prediction.

3.
Nat Commun ; 13(1): 1018, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1702467

ABSTRACT

The antiviral immune response to SARS-CoV-2 infection can limit viral spread and prevent development of pneumonic COVID-19. However, the protective immunological response associated with successful viral containment in the upper airways remains unclear. Here, we combine a multi-omics approach with longitudinal sampling to reveal temporally resolved protective immune signatures in non-pneumonic and ambulatory SARS-CoV-2 infected patients and associate specific immune trajectories with upper airway viral containment. We see a distinct systemic rather than local immune state associated with viral containment, characterized by interferon stimulated gene (ISG) upregulation across circulating immune cell subsets in non-pneumonic SARS-CoV2 infection. We report reduced cytotoxic potential of Natural Killer (NK) and T cells, and an immune-modulatory monocyte phenotype associated with protective immunity in COVID-19. Together, we show protective immune trajectories in SARS-CoV2 infection, which have important implications for patient prognosis and the development of immunomodulatory therapies.


Subject(s)
COVID-19/immunology , Adult , Aged , Aged, 80 and over , Ambulatory Care , Cytokines/blood , Female , Gene Expression Regulation , Gene Regulatory Networks , Humans , Interferons/immunology , Killer Cells, Natural/immunology , Longitudinal Studies , Male , Middle Aged , Monocytes/immunology , Nasopharynx/immunology , Nasopharynx/virology , SARS-CoV-2/physiology , T-Lymphocytes/immunology
4.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-314098

ABSTRACT

​​Since its recent zoonotic spill-over severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is constantly adapting to the human host as illustrated by the emergence of variants of concern with increased transmissibility and immune evasion. Prolonged replication in immunosuppressed individuals and evasion from spike-specific antibodies is known to drive intra-host SARS-CoV-2 evolution. Here we show for the first time the major role of CD8 T cells in SARS-CoV-2 evolution. In a patient with chronic, ultimately fatal infection, we observed three spike mutations that prevented neutralisation by convalescent plasma therapy. Moreover, at least four mutations in non-spike proteins emerged that hampered CD8 T-cell recognition of mutant epitopes, two of these occurred before spike mutations. A comparison with worldwide sequencing data showed that several of these T-cell escape mutations had emerged independently as homoplasies in multiple circulating lineages. We propose that human leukocyte antigen class I contributes to shaping the evolutionary landscape of SARS-CoV-2.

5.
Cell Rep ; 37(13): 110169, 2021 12 28.
Article in English | MEDLINE | ID: covidwho-1616407

ABSTRACT

The importance of pre-existing immune responses to seasonal endemic coronaviruses (HCoVs) for the susceptibility to SARS-CoV-2 infection and the course of COVID-19 is the subject of an ongoing scientific debate. Recent studies postulate that immune responses to previous HCoV infections can either have a slightly protective or no effect on SARS-CoV-2 pathogenesis and, consequently, be neglected for COVID-19 risk stratification. Challenging this notion, we provide evidence that pre-existing, anti-nucleocapsid antibodies against endemic α-coronaviruses and S2 domain-specific anti-spike antibodies against ß-coronavirus HCoV-OC43 are elevated in patients with COVID-19 compared to pre-pandemic donors. This finding is particularly pronounced in males and in critically ill patients. Longitudinal evaluation reveals that antibody cross-reactivity or polyclonal stimulation by SARS-CoV-2 infection are unlikely to be confounders. Thus, specific pre-existing immunity to seasonal coronaviruses may increase susceptibility to SARS-CoV-2 and predispose individuals to an adverse COVID-19 outcome, guiding risk management and supporting the development of universal coronavirus vaccines.


Subject(s)
COVID-19/immunology , Coronavirus/immunology , SARS-CoV-2/immunology , Adult , Antibodies/immunology , Antibodies, Viral/immunology , COVID-19/etiology , Coronavirus Infections/immunology , Coronavirus OC43, Human/immunology , Coronavirus OC43, Human/pathogenicity , Cross Reactions/immunology , Female , Germany , Humans , Immunity, Humoral/immunology , Immunoglobulin G/immunology , Longitudinal Studies , Male , Middle Aged , Pandemics , SARS-CoV-2/pathogenicity , Seasons , Severity of Illness Index , Spike Glycoprotein, Coronavirus/immunology
6.
Cell reports ; 2021.
Article in English | EuropePMC | ID: covidwho-1565013

ABSTRACT

Wratil et al. find specific antibody responses against seasonal human coronaviruses, which cause the common cold, to be elevated in patients with COVID-19 compared to pre-pandemic blood donors. This specific immunity is likely pre-existing in patients and increases their susceptibility to SARS-CoV-2 and severity of COVID-19.

7.
Euro Surveill ; 26(43)2021 10.
Article in English | MEDLINE | ID: covidwho-1547185

ABSTRACT

BackgroundIn the SARS-CoV-2 pandemic, viral genomes are available at unprecedented speed, but spatio-temporal bias in genome sequence sampling precludes phylogeographical inference without additional contextual data.AimWe applied genomic epidemiology to trace SARS-CoV-2 spread on an international, national and local level, to illustrate how transmission chains can be resolved to the level of a single event and single person using integrated sequence data and spatio-temporal metadata.MethodsWe investigated 289 COVID-19 cases at a university hospital in Munich, Germany, between 29 February and 27 May 2020. Using the ARTIC protocol, we obtained near full-length viral genomes from 174 SARS-CoV-2-positive respiratory samples. Phylogenetic analyses using the Auspice software were employed in combination with anamnestic reporting of travel history, interpersonal interactions and perceived high-risk exposures among patients and healthcare workers to characterise cluster outbreaks and establish likely scenarios and timelines of transmission.ResultsWe identified multiple independent introductions in the Munich Metropolitan Region during the first weeks of the first pandemic wave, mainly by travellers returning from popular skiing areas in the Alps. In these early weeks, the rate of presumable hospital-acquired infections among patients and in particular healthcare workers was high (9.6% and 54%, respectively) and we illustrated how transmission chains can be dissected at high resolution combining virus sequences and spatio-temporal networks of human interactions.ConclusionsEarly spread of SARS-CoV-2 in Europe was catalysed by superspreading events and regional hotspots during the winter holiday season. Genomic epidemiology can be employed to trace viral spread and inform effective containment strategies.


Subject(s)
COVID-19 , Cross Infection , Cross Infection/epidemiology , Genome, Viral , Genomics , Germany/epidemiology , Hospitals , Humans , Phylogeny , SARS-CoV-2
8.
J Extracell Vesicles ; 10(14): e12173, 2021 12.
Article in English | MEDLINE | ID: covidwho-1544291

ABSTRACT

Infection with SARS-CoV-2 is associated with thromboinflammation, involving thrombotic and inflammatory responses, in many COVID-19 patients. In addition, immune dysfunction occurs in patients characterised by T cell exhaustion and severe lymphopenia. We investigated the distribution of phosphatidylserine (PS), a marker of dying cells, activated platelets and platelet-derived microparticles (PMP), during the clinical course of COVID-19. We found an unexpectedly high amount of blood cells loaded with PS+ PMPs for weeks after the initial COVID-19 diagnosis. Elevated frequencies of PS+ PMP+ PBMCs correlated strongly with increasing disease severity. As a marker, PS outperformed established laboratory markers for inflammation, leucocyte composition and coagulation, currently used for COVID-19 clinical scoring. PS+ PMPs preferentially bound to CD8+ T cells with gene expression signatures of proliferating effector rather than memory T cells. As PS+ PMPs carried programmed death-ligand 1 (PD-L1), they may affect T cell expansion or function. Our data provide a novel marker for disease severity and show that PS, which can trigger the blood coagulation cascade, the complement system, and inflammation, resides on activated immune cells. Therefore, PS may serve as a beacon to attract thromboinflammatory processes towards lymphocytes and cause immune dysfunction in COVID-19.


Subject(s)
COVID-19/blood , Leukocytes, Mononuclear/metabolism , Phosphatidylserines/blood , Adult , Blood Platelets/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19/physiopathology , Cell-Derived Microparticles/metabolism , Flow Cytometry , Humans , Platelet Membrane Glycoprotein IIb , Severity of Illness Index , Transcriptome
9.
Infection ; 2021 Oct 30.
Article in English | MEDLINE | ID: covidwho-1491465

ABSTRACT

PURPOSE: To investigate the expression of the receptor protein ACE-2 alongside the urinary tract, urinary shedding and urinary stability of SARS-CoV-2 RNA. METHODS: Immunohistochemical staining was performed on tissue from urological surgery of 10 patients. Further, patients treated for coronavirus disease (COVID-19) at specialized care-units of a university hospital were assessed for detection of SARS-CoV-2 RNA in urinary samples via PCR, disease severity (WHO score), inflammatory response of patients. Finally, the stability of SARS-CoV-2 RNA in urine was analyzed. RESULTS: High ACE-2 expression (3/3) was observed in the tubules of the kidney and prostate glands, moderate expression in urothelial cells of the bladder (0-2/3) and no expression in kidney glomeruli, muscularis of the bladder and stroma of the prostate (0/3). SARS-CoV-2 RNA was detected in 5/199 urine samples from 64 patients. Viral RNA was detected in the first urinary sample of sequential samples. Viral RNA load from other specimen as nasopharyngeal swabs (NPS) or endotracheal aspirates revealed higher levels than from urine. Detection of SARS-CoV-2 RNA in urine was not associated with impaired WHO score (median 5, range 3-8 vs median 4, range 1-8, p = 0.314), peak white blood cell count (median 24.1 × 1000/ml, range 5.19-48.1 versus median 11.9 × 1000/ml, range 2.9-60.3, p = 0.307), peak CRP (median 20.7 mg/dl, 4.2-40.2 versus median 11.9 mg/dl, range 0.1-51.9, p = 0.316) or peak IL-6 levels (median: 1442 ng/ml, range 26.7-3918 versus median 140 ng/ml, range 3.0-11,041, p = 0.099). SARS-CoV-2 RNA was stable under different storage conditions and after freeze-thaw cycles. CONCLUSIONS: SARS-CoV-2 RNA in the urine of COVID-19 patients occurs infrequently. The viral RNA load and dynamics of SARS-CoV-2 RNA shedding suggest no relevant route of transmission through the urinary tract.

10.
PLoS Pathog ; 17(10): e1009742, 2021 10.
Article in English | MEDLINE | ID: covidwho-1456098

ABSTRACT

Disease manifestations in COVID-19 range from mild to severe illness associated with a dysregulated innate immune response. Alterations in function and regeneration of dendritic cells (DCs) and monocytes may contribute to immunopathology and influence adaptive immune responses in COVID-19 patients. We analyzed circulating DC and monocyte subsets in 65 hospitalized COVID-19 patients with mild/moderate or severe disease from acute illness to recovery and in healthy controls. Persisting reduction of all DC subpopulations was accompanied by an expansion of proliferating Lineage-HLADR+ cells lacking DC markers. Increased frequency of CD163+ CD14+ cells within the recently discovered DC3 subpopulation in patients with more severe disease was associated with systemic inflammation, activated T follicular helper cells, and antibody-secreting cells. Persistent downregulation of CD86 and upregulation of programmed death-ligand 1 (PD-L1) in conventional DCs (cDC2 and DC3) and classical monocytes associated with a reduced capacity to stimulate naïve CD4+ T cells correlated with disease severity. Long-lasting depletion and functional impairment of DCs and monocytes may have consequences for susceptibility to secondary infections and therapy of COVID-19 patients.


Subject(s)
COVID-19/immunology , Dendritic Cells/immunology , Regeneration/immunology , SARS-CoV-2/immunology , Adult , Antigens, CD/immunology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , COVID-19/pathology , Dendritic Cells/pathology , Female , Humans , Male , Middle Aged , Monocytes/immunology , Monocytes/pathology , Programmed Cell Death 1 Receptor/immunology
11.
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
12.
Infection ; 50(2): 359-370, 2022 Apr.
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.


Subject(s)
COVID-19 , Early Warning Score , Area Under Curve , COVID-19/diagnosis , Humans , Machine Learning , Retrospective Studies , SARS-CoV-2
13.
Hemasphere ; 5(7): e603, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1301392

ABSTRACT

The clinical and immunological impact of B-cell depletion in the context of coronavirus disease 2019 (COVID-19) is unclear. We conducted a prospectively planned analysis of COVID-19 in patients who received B-cell depleting anti-CD20 antibodies and chemotherapy for B-cell lymphomas. The control cohort consisted of age- and sex-matched patients without lymphoma who were hospitalized because of COVID-19. We performed detailed clinical analyses, in-depth cellular and molecular immune profiling, and comprehensive virological studies in 12 patients with available biospecimens. B-cell depleted lymphoma patients had more severe and protracted clinical course (median hospitalization 88 versus 17 d). All patients actively receiving immunochemotherapy (n = 5) required ICU support including long-term mechanical ventilation. Neutrophil recovery following granulocyte colony stimulating factor stimulation coincided with hyperinflammation and clinical deterioration in 4 of the 5 patients. Immune cell profiling and gene expression analysis of peripheral blood mononuclear cells revealed early activation of monocytes/macrophages, neutrophils, and the complement system in B-cell depleted lymphoma patients, with subsequent exacerbation of the inflammatory response and dysfunctional interferon signaling at the time of clinical deterioration of COVID-19. Longitudinal immune cell profiling and functional in vitro assays showed SARS-CoV-2-specific CD8+ and CD4+ T-effector cell responses. Finally, we observed long-term detection of SARS-CoV-2 in respiratory specimens (median 84 versus 12 d) and an inability to mount lasting SARS-CoV-2 antibody responses in B-cell depleted lymphoma patients. In summary, we identified clinically relevant particularities of COVID-19 in lymphoma patients receiving B-cell depleting immunochemotherapies.

14.
Eur Arch Otorhinolaryngol ; 278(12): 4855-4861, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1173904

ABSTRACT

PURPOSE: It has been established that the infection with SARS-CoV-2 may cause an impairment of chemosensory function. However, there is little data on the long-term effects of SARS-CoV-2 infection on chemosensory function. METHODS: Twenty three SARS-CoV-2-positive patients diagnosed in spring 2020 with subjective hyposmia (out of 57 positive patients, 40.3%) were compared to SARS-CoV-2-positive patients without hyposmia (n = 19) and SARS-CoV-2-negative patients (n = 14). Chemosensory function was assessed by the Brief Smell Identification Test (BSIT), Taste Strips (TS), Visual Analogue Scales (VAS), and the SNOT-22. The initial cohort with hyposmia were also examined at 8 weeks and 6 months after initial examination. RESULTS: There were no differences between the SARS-CoV-2-positive cohort without hyposmia and negative controls in terms of BSIT (8.5 ± 2.6 vs. 10.2 ± 1.8), TS (3.4 ± 0.6 vs. 3.9 ± 0.3) or VAS (2.1 ± 1.3 vs. 1.1 ± 0.5); yet the SNOT-22 was significantly elevated (27.7 ± 11.2 vs. 16.4 ± 10.8). The SARS-CoV-2-positive group with hyposmia performed significantly poorer in BSIT (4.0 ± 1.7 vs. 8.5 ± 2.6/10.2 ± 1.8), TS (2.6 ± 1.3 vs. 3.4 ± 0.6/3.9 ± 0.3), and VAS (7.9 ± 2.2 vs. 2.1 ± 1.3/1.1 ± 0.5) compared to both control groups. At week 8 and month 6 control, six and five patients, respectively, still suffered from subjectively and objectively impaired chemosensory function. The other patients had recovered in both respects. CONCLUSION: SARS-CoV-2 patients with subjectively impaired chemosensory function regularly perform poorly in objective measurements. About 70% of patients suffering from olfactory dysfunction in SARS-CoV-2 quickly recover-the rest still suffers from considerable impairment 6 months after infection.


Subject(s)
COVID-19 , Olfaction Disorders , Follow-Up Studies , Humans , Olfaction Disorders/diagnosis , Olfaction Disorders/etiology , SARS-CoV-2 , Smell , Taste Disorders
15.
Eur Respir J ; 58(1)2021 Jul.
Article in English | MEDLINE | ID: covidwho-1105685

ABSTRACT

A fraction of COVID-19 patients progress to a severe disease manifestation with respiratory failure and the necessity of mechanical ventilation. Identifying patients at risk is critical for optimised care and early therapeutic interventions. We investigated the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding relative to disease severity.We analysed nasopharyngeal and tracheal shedding of SARS-CoV-2 in 92 patients with diagnosed COVID-19. Upon admission, standardised nasopharyngeal swab or sputum samples were collected. If patients were mechanically ventilated, endotracheal aspirate samples were additionally obtained. Viral shedding was quantified by real-time PCR detection of SARS-CoV-2 RNA.45% (41 out of 92) of COVID-19 patients had a severe disease course with the need for mechanical ventilation (severe group). At week 1, the initial viral shedding determined from nasopharyngeal swabs showed no significant difference between nonsevere and severe cases. At week 2, a difference could be observed as the viral shedding remained elevated in severely ill patients. A time-course of C-reactive protein, interleukin-6 and procalcitonin revealed an even more protracted inflammatory response following the delayed drop of virus shedding load in severely ill patients. A significant proportion (47.8%) of patients showed evidence of prolonged viral shedding (>17 days), which was associated with severe disease courses (73.2%).We report that viral shedding does not differ significantly between severe and nonsevere COVID-19 cases upon admission to the hospital. Elevated SARS-CoV-2 shedding in the second week of hospitalisation, a systemic inflammatory reaction peaking between the second and third week, and prolonged viral shedding are associated with a more severe disease course.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , RNA, Viral , Respiratory System , Severity of Illness Index , Virus Shedding
16.
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
17.
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
18.
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
19.
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
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