Procoagulant phenotype of virus-infected pericytes is associated with portal thrombosis and intrapulmonary vascular dilations in fatal COVID-19.

BACKGROUND & AIMS: The underlying mechanisms and clinical impact of portal microthrombosis in severe COVID-19 are unknown. Intrapulmonary vascular dilation (IPVD)-related hypoxia has been described in severe liver diseases. We hypothesised that portal microthrombosis is associated with IPVD and fatal respiratory failure in COVID-19. METHODS: Ninety-three patients who died from COVID-19 were analysed for portal microvascular damage (histology), IPVD (histology and chest-computed tomography, CT), and hypoxemia (arterial blood gas). Seventeen patients who died from COVID-19-unrelated pneumonia served as controls. Vascular lesions and microthrombi were phenotyped for endothelial (vWF) and pericyte (αSMA/PDGFR-ß) markers, tissue factor (TF), viral spike protein and nucleoprotein (SP, NP), fibrinogen, and platelets (CD41a). Viral particles in vascular cells were assessed by transmission electron microscopy. Cultured pericytes were infected with SARS-CoV-2 to measure TF expression and tubulisation of human pulmonary microvascular endothelial cells was assessed upon vWF treatment. RESULTS: IPVD was present in 16/66 patients with COVID-19, with available liver and lung histology, and was associated with younger age (62 vs. 78 years-old), longer illness (25 vs. 14 days), worsening hypoxemia (PaO2/FiO2 from 209 to 89), and an increased requirement for ventilatory support (63% vs. 22%) compared to COVID-19/Non-IPVD. IPVD, absent in controls, was confirmed by chest CT. COVID-19/IPVD liver histology showed portal microthrombosis in >82.5% of portal areas, with a thicker wall of αSMA/PDGFR-ß+/SP+/NP+ pericytes compared with COVID-19/Non-IPVD. Thrombosed portal venules correlated with αSMA+ area, whereas infected SP+/NP+ pericytes expressed TF. SARS-CoV-2 viral particles were observed in portal pericytes. In vitro SARS-CoV-2 infection of pericytes upregulated TF and induced endothelial cells to overexpress vWF, which expanded human pulmonary microvascular endothelial cell tubules. CONCLUSIONS: SARS-CoV-2 infection of liver pericytes elicits a local procoagulant response associated with extensive portal microthrombosis, IPVD and worsening respiratory failure in fatal COVID-19. IMPACT AND IMPLICATIONS: Vascular involvement of the liver represents a serious complication of COVID-19 infection that must be considered in the work-up of patients with long-lasting and progressively worsening respiratory failure, as it may associate with the development of intrapulmonary vascular dilations. This clinical picture is associated with a procoagulant phenotype of portal venule pericytes, which is induced by SARS-CoV-2 infection of pericytes. Both observations provide a model that may apply, at least in part, to other vascular disorders of the liver, featuring obliterative portal venopathy, similarly characterised at the clinical level by development of hypoxemia and at the histological level by phlebosclerosis and reduced calibre of the portal vein branches in the absence of cirrhosis. Moreover, our findings shed light on an overlooked player in the pathophysiology of thrombosis, i.e. pericytes, which may present a novel therapeutic target.

Liver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy.

BACKGROUND AND AIMS: COVID-19 is associated with liver injury and elevated interleukin-6 (IL-6). We hypothesized that IL-6 trans-signaling in liver sinusoidal endothelial cells (LSECs) leads to endotheliopathy (a proinflammatory and procoagulant state) and liver injury in COVID-19. METHODS: Coagulopathy, endotheliopathy, and alanine aminotransferase (ALT) were retrospectively analyzed in a subset (n = 68), followed by a larger cohort (n = 3,780) of patients with COVID-19. Liver histology from 43 patients with COVID-19 was analyzed for endotheliopathy and its relationship to liver injury. Primary human LSECs were used to establish the IL-6 trans-signaling mechanism. RESULTS: Factor VIII, fibrinogen, D-dimer, von Willebrand factor (vWF) activity/antigen (biomarkers of coagulopathy/endotheliopathy) were significantly elevated in patients with COVID-19 and liver injury (elevated ALT). IL-6 positively correlated with vWF antigen (p = 0.02), factor VIII activity (p = 0.02), and D-dimer (p <0.0001). On liver histology, patients with COVID-19 and elevated ALT had significantly increased vWF and platelet staining, supporting a link between liver injury, coagulopathy, and endotheliopathy. Intralobular neutrophils positively correlated with platelet (p <0.0001) and vWF (p <0.01) staining, and IL-6 levels positively correlated with vWF staining (p <0.01). IL-6 trans-signaling leads to increased expression of procoagulant (factor VIII, vWF) and proinflammatory factors, increased cell surface vWF (p <0.01), and increased platelet attachment in LSECs. These effects were blocked by soluble glycoprotein 130 (IL-6 trans-signaling inhibitor), the JAK inhibitor ruxolitinib, and STAT1/3 small-interfering RNA knockdown. Hepatocyte fibrinogen expression was increased by the supernatant of LSECs subjected to IL-6 trans-signaling. CONCLUSION: IL-6 trans-signaling drives the coagulopathy and hepatic endotheliopathy associated with COVID-19 and could be a possible mechanism behind liver injury in these patients. LAY SUMMARY: Patients with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection often have liver injury, but why this occurs remains unknown. High levels of interleukin-6 (IL-6) and its circulating receptor, which form a complex to induce inflammatory signals, have been observed in patients with COVID-19. This paper demonstrates that the IL-6 signaling complex causes harmful changes to liver sinusoidal endothelial cells and may promote blood clotting and contribute to liver injury.

Pulmonary Embolism and Deep Vein Thrombosis in COVID-19: A Systematic Review and Meta-Analysis.

Background The association of pulmonary embolism (PE) with deep vein thrombosis (DVT) in patients with coronavirus disease 2019 (COVID-19) remains unclear, and the diagnostic accuracy of D-dimer tests for PE is unknown. Purpose To conduct meta-analysis of the study-level incidence of PE and DVT and to evaluate the diagnostic accuracy of D-dimer tests for PE from multicenter individual patient data. Materials and Methods A systematic literature search identified studies evaluating the incidence of PE or DVT in patients with COVID-19 from January 1, 2020, to June 15, 2020. These outcomes were pooled using a random-effects model and were further evaluated using metaregression analysis. The diagnostic accuracy of D-dimer tests for PE was estimated on the basis of individual patient data using the summary receiver operating characteristic curve. Results Twenty-seven studies with 3342 patients with COVID-19 were included in the analysis. The pooled incidence rates of PE and DVT were 16.5% (95% CI: 11.6, 22.9; I2 = 0.93) and 14.8% (95% CI: 8.5, 24.5; I2 = 0.94), respectively. PE was more frequently found in patients who were admitted to the intensive care unit (ICU) (24.7% [95% CI: 18.6, 32.1] vs 10.5% [95% CI: 5.1, 20.2] in those not admitted to the ICU) and in studies with universal screening using CT pulmonary angiography. DVT was present in 42.4% of patients with PE. D-dimer tests had an area under the receiver operating characteristic curve of 0.737 for PE, and D-dimer levels of 500 and 1000 µg/L showed high sensitivity (96% and 91%, respectively) but low specificity (10% and 24%, respectively). Conclusion Pulmonary embolism (PE) and deep vein thrombosis (DVT) occurred in 16.5% and 14.8% of patients with coronavirus disease 2019 (COVID-19), respectively, and more than half of patients with PE lacked DVT. The cutoffs of D-dimer levels used to exclude PE in preexisting guidelines seem applicable to patients with COVID-19. © RSNA, 2020 Supplemental material is available for this article. See also the editorial by Woodard in this issue.

Pathological characteristics of liver sinusoidal thrombosis in COVID-19 patients: A series of 43 cases.

AIM: Coronavirus disease (COVID-19) is characterized by pneumonia with secondary damage to multiple organs including the liver. Liver injury (elevated alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) often correlates with disease severity in COVID-19 patients. The aim of this study is to identify pathological microthrombi in COVID-19 patient livers by correlating their morphology with liver injury, and examine hyperfibrinogenemia and von Willebrand factor (vWF) as mechanisms of their formation. METHODS: Forty-three post-mortem liver biopsy samples from COVID-19 patients were obtained from Papa Giovanni XXIII Hospital in Bergamo, Italy. Three morphological features of microthrombosis (sinusoidal erythrocyte aggregation [SEA], platelet microthrombi [PMT], and fibrous thrombi) were evaluated. RESULTS: We found liver sinusoidal microthrombosis in 23 COVID-19 patients (53%) was associated with a higher serum ALT and AST level compared to those without (ALT: 10-fold, p = 0.04; AST: 11-fold, p = 0.08). Of 43 livers, PMT and SEA were observed in 14 (33%) and 19 (44%) cases, respectively. Fibrous thrombi were not observed. Platelet microthrombi were associated with increased ALT (p < 0.01), whereas SEA was not (p = 0.73). In COVID-19 livers, strong vWF staining in liver sinusoidal endothelial cells was associated with significantly increased platelet adhesion (1.7-fold, p = 0.0016), compared to those with weak sinusoidal vWF (2-fold, p < 0.0001). Sinusoidal erythrocyte aggregation in 19 (83%) liver samples was mainly seen in zone 2. Livers with SEA had significantly higher fibrinogen (1.6-fold, p = 0.031) compared to those without SEA in COVID-19 patients. CONCLUSIONS: Liver PMT is a pathologically important thrombosis associated with liver injury in COVID-19, while SEA is a unique morphological feature of COVID-19 patient livers. Sinusoidal vWF and hyperfibrinogenemia could contribute to PMT and SEA formation.

Chest X-ray at Emergency Admission and Potential Association with Barotrauma in Mechanically Ventilated Patients: Experience from the Italian Core of the First Pandemic Peak.

Barotrauma occurs in a significant number of patients with COVID-19 interstitial pneumonia undergoing mechanical ventilation. The aim of the current study was to investigate whether the Brixia score (BS) calculated on chest-X-rays acquired at the Emergency Room was associated with barotrauma. We retrospectively evaluated 117 SARS-CoV-2 patients presented to the Emergency Department (ED) and then admitted to the intensive care unit (ICU) for mechanical ventilation between February and April 2020. Subjects were divided into two groups according to the occurrence of barotrauma during their hospitalization. CXRs performed at ED admittance were assessed using the Brixia score. Distribution of barotrauma (pneumomediastinum, pneumothorax, subcutaneous emphysema) was identified in chest CT scans. Thirty-eight subjects (32.5%) developed barotrauma (25 pneumomediastinum, 24 pneumothorax, 24 subcutaneous emphysema). In the barotrauma group we observed higher Brixia score values compared to the non-barotrauma group (mean value 12.18 vs. 9.28), and logistic regression analysis confirmed that Brixia score is associated with the risk of barotrauma. In this work, we also evaluated the relationship between barotrauma and clinical and ventilatory parameters: SOFA score calculated at ICU admittance and number of days of non-invasive ventilation (NIV) prior to intubation emerged as other potential predictors of barotrauma.

Pneumonia-related pneumatoceles in infants: CT assessment and image-guided treatment.

Lung pneumatoceles represent a potential life-threatening complication of pneumonia in infants, especially when they do not spontaneously reabsorb. In this category of patients, scientific literature lacks and no consensus guidelines for management have been proposed. Imaging plays a key role in the diagnosis, characterization, and follow-up of pneumatoceles. Image-guided percutaneous drainage can be considered a safe and effective treatment in children, although it is not widely recognized in newborns and infants. The aim of this case series review is to describe the main CT features of complicated or persistent pneumatoceles in infants and to highlight the potential role of image-guided percutaneous drainage as an effective approach for their treatment. Successful management of four infants affected by pneumonia-related pneumatoceles with percutaneous drainage is presented.

Ischemic and hemorrhagic abdominal complications in COVID-19 patients: experience from the first Italian wave.

PURPOSE: To report ischemic and haemorrhagic abdominal complications in a series of COVID-19 patients. To correlate these complications with lung involvement, laboratory tests, comorbidities, and anticoagulant treatment. METHODS: We retrospectively included 30 COVID-19 patients who undergone abdomen CECT for abdominal pain, between March 16 and May 19, 2020. Ischemic and haemorrhagic complications were compared with lung involvement (early, progressive, peak or absorption stage), blood coagulation values, anticoagulant therapy, comorbidities, and presence of pulmonary embolism (PE). RESULTS: Ischemic complications were documented in 10 patients (7 receiving anticoagulant therapy, 70%): 6/10 small bowel ischemia (1 concomitant obstruction, 1 perforation) and 4/10 ischemic colitis. Main mesenteric vessels were patent except for 1 superior mesenteric vein thrombosis. Two ischemia cases also presented splenic infarctions. Bleeding complications were found in 20 patients (all receiving anticoagulant treatments), half with active bleeding: hematomas in soft tissues (15) and retroperitoneum (2) and gastro-intestinal bleeding (3). Platelet and lymphocyte were within the normal range. D-Dimer was significantly higher in ischemic cases (p < 0.001). Most of the patients had severe lung disease (45% peak, 29% absorption), two patients PE. CONCLUSIONS: Ischemic and haemorrhagic abdominal complications may occur in COVID-19 patients, particularly associated to extended lung disease. CT plays a key role in the diagnosis of these potentially life- threatening conditions.

Superb Microvascular Imaging (SMI) Compared with Color Doppler Ultrasound for the Assessment of Hepatic Artery in Pediatric Liver Transplants: A Feasibility Study.

(1) Background: Despite progression in surgical techniques and immunological treatments, hepatic artery (HA) thrombosis and stenosis still develop as an early or late liver transplant (LT) complication. We aimed to compare superb microvascular imaging (SMI) with conventional Doppler imaging (CDI) in the assessment of HA in a cohort of pediatric patients undergoing follow-up ultrasound (US) for LT. (2) Methods: This prospective, observational study included 73 pediatric LT recipients (median age, 7 years; IQR, 5.8 years; 35 females) who underwent US during LT follow-up from March to December 2019. For each examination, CDI and SMI were separately assessed in terms of HA visibility and spectral waveform morphology (SWM). The former was scored based on HA discrimination from the blooming signal of the surrounding vessels, as follows: 0, not visible; 1, majority course hardly distinguishable; and 2, majority course clearly distinguishable. The latter was scored on a two-point scale: 0, combined venous and arterial SWM, and 1, pure arterial SWM. The patient's overall score was finally calculated by adding the two individual scores. (3) Results: Both the absolute scores and frequency of overall scores equal to 3 (maximum global score) were higher using SMI compared with CDI. The median overall score was 3 for SMI and 2 for CDI (p = 0.011; IQR = 1). An overall score equal to 3 was obtained in 74% and 49.3% of the study population using SMI and CDI, respectively (p = 0.002). This was attributable to a better score in HA visibility (p = 0.007). (4) Conclusions: SMI has shown promise for assessing HA in pediatric LT recipients, possibly serving as a complementary non-invasive tool of CDI in everyday practice.

Embolization in Pediatric Patients: A Comprehensive Review of Indications, Procedures, and Clinical Outcomes.

Embolization in pediatric patients encompasses a large spectrum of indications, ranging from the elective treatment of congenital diseases of the cardiovascular system to the urgent management of acute hemorrhagic conditions. In particular, the endovascular treatment of central and peripheral vascular malformations and hypervascular tumors represents a wide chapter for both congenital and acquired situations. Thanks to the progressive availability of low-profile endovascular devices and new embolic materials, the mini-invasive approach has gradually overtaken surgery. In this review, the main embolization procedures will be illustrated and discussed, with a focus on clinical indications and expected outcomes. The most recent mini-invasive techniques will be described, with hints on the cutting-edge devices and embolic materials.

Myeloma Spine and Bone Damage Score (MSBDS) on Whole-Body Computed Tomography (WBCT): Multiple Reader Agreement in a Multicenter Reliability Study.

Objective: To assess the reliability of the myeloma spine and bone damage score (MSBDS) across multiple readers with different levels of expertise and from different institutions. Methods: A reliability exercise, including 104 data sets of static images and complete CT examinations of patients affected by multiple myeloma (MM), was performed. A complementary imaging atlas provided detailed examples of the MSBDS scores, including low-risk and high-risk lesions. A total of 15 readers testing the MSBDS were evaluated. ICC estimates and their 95% confidence intervals were calculated based on mean rating (k = 15), absolute agreement, a two-way random-effects model and Cronbach's alpha. Results: Overall, the ICC correlation coefficient was 0.87 (95% confidence interval: 0.79-0.92), and the Cronbach's alpha was 0.93 (95% confidence interval: 0.94-0.97). Global inter- and intra-observer agreement among the 15 readers with scores below or equal to 6 points and scores above 6 points were 0.81 (95% C.I.: 0.72-0.86) and 0.94 (95% C.I.:0.91-0.98), respectively. Conclusion: We present a consensus-based semiquantitative scoring systems for CT in MM with a complementary CT imaging atlas including detailed examples of relevant scoring techniques. We found substantial agreement among readers with different levels of experience, thereby supporting the role of the MSBDS for possible large-scale applications. Significance and Innovations • Based on previous work and definitions of the MSBDS, we present real-life reliability data for quantitative bone damage assessment in multiple myeloma (MM) patients on CT. • In this study, reliability for the MSBDS, which was tested on 15 readers with different levels of expertise and from different institutions, was shown to be moderate to excellent. • The complementary CT imaging atlas is expected to enhance unified interpretations of the MSBDS between different professionals dealing with MM patients in their routine clinical practice.

Intestinal ischemic manifestations of SARS-CoV-2: Results from the ABDOCOVID multicentre study.

BACKGROUND: Intestinal ischemia has been described in case reports of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (coronavirus disease 19, COVID-19). AIM: To define the clinical and histological, characteristics, as well as the outcome of ischemic gastrointestinal manifestations of SARS-CoV-2 infection. METHODS: A structured retrospective collection was promoted among three tertiary referral centres during the first wave of the pandemic in northern Italy. Clinical, radiological, endoscopic and histological data of patients hospitalized for COVID-19 between March 1st and May 30th were reviewed. The diagnosis was established by consecutive analysis of all abdominal computed tomography (CT) scans performed. RESULTS: Among 2929 patients, 21 (0.7%) showed gastrointestinal ischemic manifestations either as presenting symptom or during hospitalization. Abdominal CT showed bowel distention in 6 patients while signs of colitis/enteritis in 12. Three patients presented thrombosis of main abdominal veins. Endoscopy, when feasible, confirmed the diagnosis (6 patients). Surgical resection was necessary in 4/21 patients. Histological tissue examination showed distinctive features of endothelial inflammation in the small bowel and colon. Median hospital stay was 9 d with a mortality rate of 39%. CONCLUSION: Gastrointestinal ischemia represents a rare manifestation of COVID-19. A high index of suspicion should lead to investigate this complication by CT scan, in the attempt to reduce its high mortality rate. Histology shows atypical feature of ischemia with important endotheliitis, probably linked to thrombotic microangiopathies.

Bone islands incidentally detected on computed tomography: frequency of enostosis and differentiation from untreated osteoblastic metastases based on CT attenuation value.

OBJECTIVE: The frequency of enostosis incidentally found on CT and CT attenuation value to distinguish them from untreated osteoblastic metastases (UOM). METHODS: Enostosis group: 46 polytrauma patients underwent thoracoabdominal CT. Inclusion criteria: age range 14-35 years. Exclusion criteria: cancer, previous fractures. UOM group: 20 patients with radiological diagnosis of UOM. Analyzed data: number, size, location and density of enostoses and metastases. The density was measured with the broadest possible region of interest at the center of the lesion by two radiologists independently. Receiver operatingcharacteristic analysis to determine the sensitivity and specificity, area under the curve 95% confidence intervals and cutoff values of CT density to differentiate metastases from enostoses. RESULTS: Patients were 28 ± 7 years old (72% males). 41 (89%) patients had 124 enostoses (2-15 mm) with an average density of 1007 ± 122 Hounsfiled unit (HU, observer1) and 1052 ± 107 (observer2). The most common sites of occurrence were the proximal femur (34%), the pelvis (22%), the acetabulum (20%), the proximal humerus (11%), the vertebrae (11%) and the rib (2%). 13 patients had 1 bone island, 8 patients had 2, 9 cases had 3 and 11 cases had more than 3 enostoses. Overall, 114 UOM were evaluated, their average density was 728 ± 163 HU (observer1) and 712 ± 178 HU (observer2). The area under the curve value of mean density to distinguish enostoses from UOM was 0,982. Using a cut-off of 881 HU for mean density, sensitivity was 98% and specificity 95%. CONCLUSION: The frequency of enostosis in this study is 89%. The average density identified can help to distinguish enostoses from UOM. ADVANCES IN KNOWLEDGE: We report the exact frequency of enostosis.

Quality of life in panic disorder: the influence of clinical features and personality traits.

OBJECTIVE: To identify which clinical features and personality traits are associated with quality of life (QoL) in panic disorder (PD) patients. METHODS: This was a cross-sectional study with PD patients. The brief version of the World Health Organization Quality of Life Questionnaire (WHOQOL-BREF) and the Big Five Inventory (BFI) were used to assess QoL and personality traits respectively. The strength of correlations was measured with Pearson's, Spearman's, and point-biserial correlation coefficients. We also performed multiple linear regressions, considering sociodemographic data and scores from clinical scales as independent variables and QoL scores as dependent variables. RESULTS: A total of 98 patients were evaluated. Depressive symptoms had a strong negative correlation with QoL and, to a lesser extent, panic and anxiety symptoms were also negatively correlated with QoL. While consciousness, extraversion, and agreeableness had mild positive correlations with QoL, neuroticism had a strong negative correlation. CONCLUSION: Symptoms of depression, anxiety, and panic seem to have a negative impact on the QoL of PD patients. Personality traits, especially neuroticism, may also influence QoL in these patients.

Quality of life in panic disorder: the influence of clinical features and personality traits / Qualidade de vida no transtorno de pânico: a influência de características clínicas e traços de personalidade

Abstract Objective To identify which clinical features and personality traits are associated with quality of life (QoL) in panic disorder (PD) patients. Methods This was a cross-sectional study with PD patients. The brief version of the World Health Organization Quality of Life Questionnaire (WHOQOL-BREF) and the Big Five Inventory (BFI) were used to assess QoL and personality traits respectively. The strength of correlations was measured with Pearson's, Spearman's, and point-biserial correlation coefficients. We also performed multiple linear regressions, considering sociodemographic data and scores from clinical scales as independent variables and QoL scores as dependent variables. Results A total of 98 patients were evaluated. Depressive symptoms had a strong negative correlation with QoL and, to a lesser extent, panic and anxiety symptoms were also negatively correlated with QoL. While consciousness, extraversion, and agreeableness had mild positive correlations with QoL, neuroticism had a strong negative correlation. Conclusion Symptoms of depression, anxiety, and panic seem to have a negative impact on the QoL of PD patients. Personality traits, especially neuroticism, may also influence QoL in these patients.

Resumo Objetivo Identificar quais características clínicas e traços de personalidade são mais associados à qualidade de vida (QdV) em pacientes com transtorno de pânico (TP). Métodos Este foi um estudo transversal, realizado em pacientes com TP. A versão breve do Questionário de Qualidade de Vida da Associação Mundial de Saúde (World Health Organization Quality of Life Questionnaire - WHOQOL-BREF) e o Inventário dos Cinco Grande Fatores (Big Five Inventory - BFI) foram utilizados para avaliar QdV e traços de personalidade, respectivamente. A força de associação foi medida através da correlação de Pearson, de Spearman ou ponto bisserial. Foram também realizadas regressões lineares múltiplas, considerando os dados sociodemográficos e escores obtidos nas escalas clínicas como variáveis independentes, e os escores de QdV como variáveis dependentes. Resultados Um total de 98 pacientes foram avaliados. Sintomas depressivos apresentaram uma forte relação negativa com QdV; em menor intensidade, sintomas de TP e ansiosos também se correlacionaram com QdV. Nos domínios de personalidade, enquanto conscienciosidade, extroversão e amabilidade apresentaram uma leve correlação positiva com QdV, neuroticismo apresentou forte correlação negativa. Conclusão Sintomas depressivos, ansiosos e de TP parecem ter forte impacto negativo na QdV dos pacientes com TP. Traços de personalidade, principalmente neuroticismo, podem influenciar QdV nesses pacientes.