The fatal trajectory of pulmonary COVID-19 is driven by lobular ischemia and fibrotic remodelling.

BACKGROUND: COVID-19 is characterized by a heterogeneous clinical presentation, ranging from mild symptoms to severe courses of disease. 9-20% of hospitalized patients with severe lung disease die from COVID-19 and a substantial number of survivors develop long-COVID. Our objective was to provide comprehensive insights into the pathophysiology of severe COVID-19 and to identify liquid biomarkers for disease severity and therapy response. METHODS: We studied a total of 85 lungs (n = 31 COVID autopsy samples; n = 7 influenza A autopsy samples; n = 18 interstitial lung disease explants; n = 24 healthy controls) using the highest resolution Synchrotron radiation-based hierarchical phase-contrast tomography, scanning electron microscopy of microvascular corrosion casts, immunohistochemistry, matrix-assisted laser desorption ionization mass spectrometry imaging, and analysis of mRNA expression and biological pathways. Plasma samples from all disease groups were used for liquid biomarker determination using ELISA. The anatomic/molecular data were analyzed as a function of patients' hospitalization time. FINDINGS: The observed patchy/mosaic appearance of COVID-19 in conventional lung imaging resulted from microvascular occlusion and secondary lobular ischemia. The length of hospitalization was associated with increased intussusceptive angiogenesis. This was associated with enhanced angiogenic, and fibrotic gene expression demonstrated by molecular profiling and metabolomic analysis. Increased plasma fibrosis markers correlated with their pulmonary tissue transcript levels and predicted disease severity. Plasma analysis confirmed distinct fibrosis biomarkers (TSP2, GDF15, IGFBP7, Pro-C3) that predicted the fatal trajectory in COVID-19. INTERPRETATION: Pulmonary severe COVID-19 is a consequence of secondary lobular microischemia and fibrotic remodelling, resulting in a distinctive form of fibrotic interstitial lung disease that contributes to long-COVID. FUNDING: This project was made possible by a number of funders. The full list can be found within the Declaration of interests / Acknowledgements section at the end of the manuscript.

Inflammation and vascular remodeling in COVID-19 hearts.

A wide range of cardiac symptoms have been observed in COVID-19 patients, often significantly influencing the clinical outcome. While the pathophysiology of pulmonary COVID-19 manifestation has been substantially unraveled, the underlying pathomechanisms of cardiac involvement in COVID-19 are largely unknown. In this multicentre study, we performed a comprehensive analysis of heart samples from 24 autopsies with confirmed SARS-CoV-2 infection and compared them to samples of age-matched Influenza H1N1 A (n = 16), lymphocytic non-influenza myocarditis cases (n = 8), and non-inflamed heart tissue (n = 9). We employed conventional histopathology, multiplexed immunohistochemistry (MPX), microvascular corrosion casting, scanning electron microscopy, X-ray phase-contrast tomography using synchrotron radiation, and direct multiplexed measurements of gene expression, to assess morphological and molecular changes holistically. Based on histopathology, none of the COVID-19 samples fulfilled the established diagnostic criteria of viral myocarditis. However, quantification via MPX showed a significant increase in perivascular CD11b/TIE2 + -macrophages in COVID-19 over time, which was not observed in influenza or non-SARS-CoV-2 viral myocarditis patients. Ultrastructurally, a significant increase in intussusceptive angiogenesis as well as multifocal thrombi, inapparent in conventional morphological analysis, could be demonstrated. In line with this, on a molecular level, COVID-19 hearts displayed a distinct expression pattern of genes primarily coding for factors involved in angiogenesis and epithelial-mesenchymal transition (EMT), changes not seen in any of the other patient groups. We conclude that cardiac involvement in COVID-19 is an angiocentric macrophage-driven inflammatory process, distinct from classical anti-viral inflammatory responses, and substantially underappreciated by conventional histopathologic analysis. For the first time, we have observed intussusceptive angiogenesis in cardiac tissue, which we previously identified as the linchpin of vascular remodeling in COVID-19 pneumonia, as a pathognomic sign in affected hearts. Moreover, we identified CD11b + /TIE2 + macrophages as the drivers of intussusceptive angiogenesis and set forward a putative model for the molecular regulation of vascular alterations.

Determinants of survival in patients on extracorporeal membrane oxygenation therapy due to severe covid-19.

BACKGROUND: Severe acute respiratory distress syndrome (ARDS) due to Coronavirus Disease-19 (COVID-19) is associated with high mortality. Although survival on mechanical circulatory support has improved, determinants for better prognosis are still unclear. Here, we report on the outcome of our patient population with the need for mechanical circulatory support due to severe COVID-19 (sCOVID-19) induced ARDS. METHODS: All patients treated with extracorporeal membrane oxygenation (ECMO) for severe ARDS due to sCOVID-19 were analysed. Patients > 18 years of age at the time of initiation of ECMO were included. Pre-existing comorbidities, complications during ECMO implantation, and ECMO runtime were reviewed. The latency to intubation, proning, tracheotomy, and ECMO implantation was analysed. Furthermore, the survival and non-survival population were compared to determine factors in favour of a better outcome. RESULTS: In total, 85 patients were treated with veno-venous membrane oxygenation (vv-ECMO) for severe ARDS in our medical centre. The patient population was predominantly male (83.5%) with a mean patient age of 54.9 years. A history of cardiovascular disease (p = .01), smoking (p < .05), need for vasopressor- (p < .05), and renal replacement therapy (p < .001) was associated with a worse prognosis. Overall survival was 50%. The survival population was significantly younger (p = .004), had a significantly higher body weight (p = .02) and body mass index (BMI) (p = .01). Furthermore, survival was significantly better when vv-ECMO was initiated within 48 h after admission (p < .001). CONCLUSIONS: Pre-existing cardiovascular disease, higher age, history of nicotine abuse, and development of renal failure are associated with poor outcome. Early start of vv-ECMO therapy may lead to better survival in sCOVID-19 patients, although complications during ECMO therapy are associated with a worse prognosis.

Mathematical Modeling and Numerical Simulation of Atherosclerosis Based on a Novel Surgeon's View.

This paper deals with the mathematical modeling of atherosclerosis based on a novel hypothesis proposed by a surgeon, Prof. Dr. Axel Haverich (Circulation 135(3):205-207, 2017). Atherosclerosis is referred as the thickening of the artery walls. Currently, there are two schools of thoughts for explaining the root of such phenomenon: thickening due to substance deposition and thickening as a result of inflammatory overgrowth. The hypothesis favored here is the second paradigm stating that the atherosclerosis is nothing else than the inflammatory response of of the wall tissues as a result of disruption in wall nourishment. It is known that a network of capillaries called vasa vasorum (VV) accounts for the nourishment of the wall in addition to the natural diffusion of nutrient from the blood passing through the lumen. Disruption of nutrient flow to the wall tissues may take place due to the occlusion of vasa vasorums with viruses, bacteria and very fine dust particles such as air pollutants referred to as PM 2.5. They can enter the body through the respiratory system at the first place and then reach the circulatory system. Hence in the new hypothesis, the root of atherosclerotic vessel is perceived as the malfunction of microvessels that nourish the vessel. A large number of clinical observation support this hypothesis. Recently and highly related to this work, and after the COVID-19 pandemic, one of the most prevalent disease in the lungs are attributed to the atherosclerotic pulmonary arteries, see Boyle and Haverich (Eur J Cardio Thorac Surg 58(6):1109-1110, 2020). In this work, a general framework is developed based on a multiphysics mathematical model to capture the wall deformation, nutrient availability and the inflammatory response. For the mechanical response an anisotropic constitutive relation is invoked in order to account for the presence of collagen fibers in the artery wall. A diffusion-reaction equation governs the transport of the nutrient within the wall. The inflammation (overgrowth) is described using a phase-field type equation with a double well potential which captures a sharp interface between two regions of the tissues, namely the healthy and the overgrowing part. The kinematics of the growth is treated by classical multiplicative decomposition of the gradient deformation. The inflammation is represented by means of a phase-field variable. A novel driving mechanism for the phase field is proposed for modeling the progression of the pathology. The model is 3D and fully based on the continuum description of the problem. The numerical implementation is carried out using FEM. Predictions of the model are compared with the clinical observations. The versatility and applicability of the model and the numerical tool allow.

Time-Dependent Molecular Motifs of Pulmonary Fibrogenesis in COVID-19.

(1) Background: In COVID-19 survivors there is an increased prevalence of pulmonary fibrosis of which the underlying molecular mechanisms are poorly understood; (2) Methods: In this multicentric study, n = 12 patients who succumbed to COVID-19 due to progressive respiratory failure were assigned to an early and late group (death within ≤7 and >7 days of hospitalization, respectively) and compared to n = 11 healthy controls; mRNA and protein expression as well as biological pathway analysis were performed to gain insights into the evolution of pulmonary fibrogenesis in COVID-19; (3) Results: Median duration of hospitalization until death was 3 (IQR25-75, 3-3.75) and 14 (12.5-14) days in the early and late group, respectively. Fifty-eight out of 770 analyzed genes showed a significantly altered expression signature in COVID-19 compared to controls in a time-dependent manner. The entire study group showed an increased expression of BST2 and IL1R1, independent of hospitalization time. In the early group there was increased activity of inflammation-related genes and pathways, while fibrosis-related genes (particularly PDGFRB) and pathways dominated in the late group; (4) Conclusions: After the first week of hospitalization, there is a shift from pro-inflammatory to fibrogenic activity in severe COVID-19. IL1R1 and PDGFRB may serve as potential therapeutic targets in future studies.

Telemonitoring and Care Program for Left Ventricular Assist Device Patients During COVID-19 Outbreak: A European Experience.

Coronavirus disease 2019 (COVID-19) radically modified the organization of healthcare systems with shutdown of routine activities and outpatient clinics. Herein, we report our institutional experience with a Telemonitoring and Care Program (TC-Program) to monitor and support left ventricular assist device (LVAD) patients during COVID-19 outbreak. This single-arm cohort study analyzed 156 patients who entered the TC-Program at our institution between April and August 2020. The TC-Program was based on routine phone calls to patients and a 24/7 emergency line. In November 2020, patients were asked for feedback on the TC-Program and checked for survival, transplant, or explant. The primary endpoint was the rate of TC-Program-driven interventions. Patients (males: 82.8%) were 61 years old (interquartile range [IQR]: 53.0-67.5) and on LVAD support for 1,266 days (IQR: 475-2,211). Patients were included in the TC-Program for a median time of 99 days (min:15, max:120) and received a median number of six phone calls (min:1, max:14). Twenty-three patients (14.7%) were referred for clinical evaluation after phone contact. Two patients (1.27%) were diagnosed with COVID-19: one of them died after intensive care, and one remained paucisymptomatic and recovered. Three patients asked to exit the program considering it not useful while the others gave high rates in terms of usefulness (median: 9, IQR: 8-10), information (median: 9, IQR: 8-10), good medical care (median: 9, IQR: 8-10), and psychologic support (median: 8, IQR: 7-10). A TC-Program based on the four ICSA principles (Inform, Care, Support, and Adapt) is feasible in LVAD patients and can be rapidly implemented during the COVID-19 pandemic.

Impaired immune response mediated by prostaglandin E2 promotes severe COVID-19 disease.

The SARS-CoV-2 coronavirus has led to a pandemic with millions of people affected. The present study finds that risk-factors for severe COVID-19 disease courses, i.e. male sex, older age and sedentary life style are associated with higher prostaglandin E2 (PGE2) serum levels in blood samples from unaffected subjects. In COVID-19 patients, PGE2 blood levels are markedly elevated and correlate positively with disease severity. SARS-CoV-2 induces PGE2 generation and secretion in infected lung epithelial cells by upregulating cyclo-oxygenase (COX)-2 and reducing the PG-degrading enzyme 15-hydroxyprostaglandin-dehydrogenase. Also living human precision cut lung slices (PCLS) infected with SARS-CoV-2 display upregulated COX-2. Regular exercise in aged individuals lowers PGE2 serum levels, which leads to increased Paired-Box-Protein-Pax-5 (PAX5) expression, a master regulator of B-cell survival, proliferation and differentiation also towards long lived memory B-cells, in human pre-B-cell lines. Moreover, PGE2 levels in serum of COVID-19 patients lowers the expression of PAX5 in human pre-B-cell lines. The PGE2 inhibitor Taxifolin reduces SARS-CoV-2-induced PGE2 production. In conclusion, SARS-CoV-2, male sex, old age, and sedentary life style increase PGE2 levels, which may reduce the early anti-viral defense as well as the development of immunity promoting severe disease courses and multiple infections. Regular exercise and Taxifolin treatment may reduce these risks and prevent severe disease courses.

Mechanical circulatory support in coronavirus disease-2019-positive patients with severe respiratory failure.

OBJECTIVES: Treatment of severe acute respiratory distress syndrome (ARDS) induced by severe acute respiratory syndrome coronavirus 2 has been heavily debated. Our goal was to describe our findings in patients with severe ARDS due to severe coronavirus disease 2019 (sCOVID-19) treated with venovenous extracorporeal membrane oxygenation (vv-ECMO). METHODS: We retrospectively examined all patients treated with vv-ECMO for severe ARDS due to acute respiratory syndrome coronavirus 2. RESULTS: In total, 13 patients were treated with vv-ECMO in our medical centre. The mean patient age was 48.1 years. Most patients were obese (69%) and male (85%). All patients were mechanically ventilated before ECMO. The mean time from intubation to proning was 16.6 h; the time from start of prone therapy to vv-ECMO implantation was 155.1 h. The mean total ECMO run time was 358 h. Significant reduction of positive end-expiratory pressure (P = 0.02), peak pressure (P = 0.001) and minute volume (P = 0.03) could be achieved after implantation of vv-ECMO. All patients showed an inflammatory response. Overall mortality was 30.7%: 1 patient died of mesenteric ischaemia; 3 patients died of multiple organ failure. A worse prognosis was seen in patients with highly elevated concentrations of interleukin-6. CONCLUSIONS: The use of vv-ECMO in patients with sCOVID-19-induced ARDS is safe and associated with improved respiratory ventilation settings. The rate of immune system involvement plays a pivotal role in the development and outcome of sCOVID-19.