Lung pathology

The series of autopsies reported since the beginning of the pandemic have highlighted several patterns of lung damage, both isolated and combined. The factors influencing the occurrence of these different tissue responses to viral aggression by SARS-CoV-2 have not yet been determined. In asymptomatic patients or patients with respiratory symptoms who were not ventilated, lymphocyte pneumonia associated with type II pneumocyte atypical hyperplasia and a few hyaline membranes or focal lesions of acute fibrinous pneumonia have been observed. In critically ill patients, the most frequent pattern is diffuse alveolar damage with interstitial lymphoid infiltration, type II pneumocyte atypia and, very often, capillary or arteriolar microthromboses and/or endothelitis. The precise description of these lesions, which is becoming more and more consensual, makes it possible to understand the favourable effects of corticosteroid therapy in seriously ill patients and the evolution under ventilation towards fibrosis.Copyright © ERS 2021.

SUBPOPULATION COMPOSITION OF PERIPHERAL BLOOD LYMPHOCYTES IN COVID-19.

The pathogenesis of severe coronavirus infection COVID-19 is associated with activation of immune system, cytokine storm, impaired blood clotting, microvascular thrombosis, organ ischemia and multiple organ dysfunction syndrome. The role of various lymphocyte subpopulations in COVID-19 is still debated. The aim of our study was to analyze the subpopulational profile of peripheral blood lymphocytes in COVID-19 patients as compared with healthy donors. The study included 20 COVID-19 patients (11 males and 9 females,) and 26 healthy donors. Average age of the patients was 52 and 56 years, respectively. Clinical examinations were performed by standard laboratory methods. Peripheral blood lymphocytes were isolated in the Ficoll gradient. The cells were stained with antibodies to specific antigens of main lymphocyte populations, endothelial cells, and apoptotic cell markers. The analysis was performed by flow cytometry. The results showed that all patients had elevated C-reactive protein (14- to 35-fold), ferritin (1.2- to 13-fold), D-dimers (1.2- to 90-fold). 55% of men had a decrease in the absolute number of lymphocytes, in women this index was at the low normal limit. Cytometric analysis showed that, among peripheral blood lymphocytes, the proportion of functional cells expressing the CD45 marker ranged from 2 to 12% in 70% of patients, as compared with 80-99% among the donors. The proportion of CD45+ lymphocytes significantly correlated with the level of hemoglobin, but not with the levels of inflammatory biochemical markers. Among the functional lymphocytes of patients, there was a decrease in the proportion of CD3+, CD4+, CD8+T cells, increased proportion of natural killer CD56+ and the apoptotic (AnnexinV+) cell contents, but the proportion of CD19 and HLA-DR+B cells was not changed. Analysis of the lymphocyte (LC) subpopulations that did not express CD45 marker showed that this fraction contained different lymphocyte subsets with reduced expression of CD4, CD8, CD19, CD56 etc. in the blood of patients and donors. Higher percentage of endothelial cells expressing CD62P marker made the difference between patients and donors. Laboratory determination of lymphocyte subsets in blood samples of COVID-19 patients does not reflect the real severity pattern of the disease, thus requiring studies of the CD45-expressing functional cell populations.Copyright © Svirshchevskaya E.V. et al., 2023 The article can be used under the Creative Commons Attribution 4.0 License.

Coagulopathy and thromboembolism in children with COVID-19 - pathophysiology, thrombotic risk, clinical manifestations, and management

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the beginning of the pandemic, it has been generally accepted that children infected with SARS-CoV-2 either stay asymptomatic or present benign symptoms. Yet SARS-CoV-2 is widely known to cause serious consequences in children and adolescents. Complications may develop during infection, several weeks afterwards, or in the course of multisystem inflammatory syndrome in children (MIS-C). MIS-C manifests with fever, gastrointestinal, cardiovascular and/or neurological symptoms. Moreover, thromboembolism is a relatively common complication of COVID-19 and MIS-C. The purpose of this work was to review current reports on thromboembolic complications among children who underwent SARS-CoV-2 infection. Among the published cases of MIS-C, thromboembolic incidents ranged from 1.4% to 6.5%, taking the form of a brain infarct, deep vein thrombosis, pulmonary embolism, or splenic infarct. Several mechanisms leading to thrombosis in COVID-19 in children are considered. The development of acute infection in the lungs results in local clot formation in the pulmonary microcirculation, leading to perfusion disturbances. ADAMTS13 activity is also mildly reduced in patients infected with SARS-CoV-2, increasing the risk of microthrombosis. COVID-19-associated coagulopathy is characterized by elevated D-dimers and fibrinogen levels. Significantly increased D-dimers probably represent activation of coagulation caused by viremia and cytokine storm, as well as possible organ dysfunction. The treatment of thromboembolism in children includes low and high molecular weight heparins and acetylsalicylic acid. Pediatricians should be aware of the possible multiple complications associated with COVID-19 in children, including thromboembolic incidents. Copyright © 2022 Sciendo. All rights reserved.

Herbs for Heart: Benefits for Post-Covid Cardiac Protection

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-caused coronavirus disease 2019 (COVID-19) pandemic, which began in early December 2019, has spread quickly over the world and presented an unprecedented threat to human health. The disease is characterized by cytokine storm, resulting in endothelial inflammation/dysfunction, micro- and macro-vascular thrombosis, which may damage organs other than the lung. COVID-19 substantially impairs the cardiovascular system. According to the study published in the journal Nature Medicine, patients with COVID-19 were more likely to have a wide range of cardiovascular conditions. Thus, one of the most useful tools in the therapeutic management of post-covid cardiovascular illnesses will be cardio-protection and treatment. Despite improvements in CVD management and therapy, CVDs continue to claim more lives than other cancer types combined. As a result, there has been significant enforcement of CVD prevention in recent years. Since ancient times, people have used herbs to treat cardiovascular conditions. The journal of Clinical Phytoscience published an article in 2021 that used cluster analysis to choose 128 plants. These herbs effectively protected the heart. This study and subsequent analysis revealed that herbal remedies like Arjuna, Tribulus, and Tinospora have potent cardioprotective characteristics. The evidence for these herbs' cardiovascular protection is highlighted in the current review.

WAS COVID A “BLESSING IN DISGUISE?” MAY-THURNER SYNDROME COMPLICATES COVID

CASE: A 30-year-old previously healthy male presented with three weeks of progressively worsening pain, erythema, swelling in his left thigh, inability to bear weight and associated fatigue, fever, and dyspnea on exertion. Four weeks prior, he experienced 1 week of anosmia, fatigue, and “even worse” dyspnea on exertion with a resting heart rate in excess of 110 bpm and felt he most likely had had COVID. He self-treated for symptoms, rested, isolated and felt he had improved from COVID. The pain and swelling in the left leg increased over the prior three weeks and he sought care. On exam the left thigh was warm to touch, erythematous, and painful. Ultrasound imaging revealed left lower extremity deep venous thrombosis (DVT) extending from his upper thigh to lower leg. Abdominal/thoracic CT w/ contrast noted diffuse pulmonary emboli and May-Thurner Syndrome (MTS). Treatment was started with IV heparin followed by thrombolytic therapy with higher dose heparin and alteplase for 3 days. Shortly after this therapy was initiated, he developed significant hypoxia and was transferred to the ICU. He was stabilized and on the final day of thrombolytic therapy, a left common iliac vein stent was placed and he was discharged two days later on Apixaban and aspirin. IMPACT/DISCUSSION: May-Thurner syndrome (MTS), is an anatomical variant that may lead to venous outflow obstruction due to extrinsic compression by the iliac arterial system against bony structures in the iliocaval venous territory. Most common in the left leg, MTS is present in about 20% of the population and is more commonly found in women. It can result in venous hypertension and venous thromboembolisms (VTE). In serious and untreated cases, these VTEs can progress to pulmonary embolisms with resultant serious injury, hospitalization, and death. In this case, a recent COVID infection unearthed an MTS anomaly. The activated proinflammatory state induced by COVID is known to result in blood clots in hospitalized patients and appears to be related to a cytokine storm. This inflammatory state induces endothelial damage, microvascular thrombosis, and possibly pro-thrombotic antiphospholipid antibodies. In hospitalized patients with more severe disease VTE is commonly diagnosed, however the risk of COVID related coagulopathy in the outpatient setting is unknown. It appears that when blood clots do develop in outpatients, 1/5 have had a recent COVID infection which indicates an association between inflammation from infection contributes to VTE. In this case, the COVID complication helped to uncover a May-Thurner anomaly. CONCLUSION: - Delayed presentation can exacerbate COVID-related complications, even after acute symptoms have diminished - more should be done to educate patients on the dangers of post COVID thromboembolic disease. - Despite its prevalence in females, May-Thurners Syndrome should be in the differential for males with DVT.

Utility of D-dimer as a Prognostic Factor in SARS CoV2 Infection: A Review.

Coronavirus Disease-2019 (COVID-19) is currently a public health emergency and has been listed by the World Health Organization (WHO) as a pandemic. It has commonly been associated with pulmonary manifestations and there is a growing body of evidence of multisystem involvement of the virus. As evidenced by various case reports and cohort studies, COVID-19-associated coagulopathy has been a common manifestation amongst the critically ill and has been associated with increased mortality. The presence of venous thromboembolic events in patients who are critically ill due to COVID-19 has prompted the adoption of anticoagulation regimens aimed at preventing thromboembolic phenomena. Coagulation abnormalities have also been implicated in the progression and the severity of COVID-19 related acute respiratory distress syndrome (ARDS) and disseminated intravascular coagulation (DIC). There is strong evidence that D-dimer levels help predict which patients are at risk of thromboembolic events, progression to ARDS, DIC, immune dysregulation and mortality. We will review the utility of D-dimer as screening tool and in the risk stratification of COVID-19 patients prone to developing thromboembolic events, DIC, immune dysregulation and death. To date, the studies that have been published show the presence of elevated D-dimer levels in both the adult and pediatric populations and the measured level correlates with disease severity. Studies have also shown the relative increase of D-dimer levels in non-survivors compared to survivors. The elevation of D-dimer levels has shown to guide clinical decision making, namely the initiation of therapeutic anticoagulation and mortality benefit in patients with severe COVID-19 pneumonia compared to severe non COVID-19 pneumonia. Although the current body of literature suggested the use of D-dimer as a risk stratification tool and as a test to augment clinical judgement regarding the initiation of anticoagulation, randomized control trials are needed to fully understand the relationship between COVID-19 infection and the efficacy of D-dimer assays in clinical decision making.

Pathogenetic and prognostic significance of inflammation and altered ADAMTS-13/vWF axis in patients with severe COVID-19

Introduction. Currently, endothelial dysfunction caused by inflammation and immunothrombosisis considered as one of the crucial mechanisms in developing the SARS-CoV-2 virus-mediated coronavirus disease 2019 (COVID-19). A mass endothelial damage followed by release of untypical large quantity of von Willebrand factor (vWF) multimers and subsequent consumption of metalloproteinase ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) is described during severe COVID-19. The activation of innate immune cells including neutrophils results in formation of neutrophil extracellular traps (NETs) and myeloperoxidase (MPO) release that, in turn, contributes to spread of inflammation and microvascular thrombosis. Aim: to evaluate a pathogenetic role and predictive significance for serum markers of inflammation, endothelial dysfunction and hemostatis activation such as vWF, ADAMTS-13 and MPO for in-hospital mortality in severe COVID-19 patients requiring mechanical lung ventilation. Materials and Methods. There was performed a single-center observational study with 129 severe COVID-19 patients on mechanical lung ventilation at the intensive care unit, by assessing serum in all subjects vWF, ADAMTS-13 as well as in 79 patients MPO level along with other potential predictors for in-hospital mortality. Results. A multivariate analysis revealed that increased serum level for vWF antigen (vWF:Ag) and MPO antigen (MPO:Ag) were significantly and independently related to high mortality probability: vWF:Ag (IU/ml) - adjusted odds ratio (OR) = 3.360;95 % confidence interval (95 % Cl) = 1.562-7,228 (р = 0,0019);MPO:Ag (ng/ml) - adjusted OR = 1.062;95 % = 1.024-1.101 (p = 0.0011). Such data allowed to obtained a simplified mortality score for categorizing patients as those having a higher or lower score compared with the median score level: a high score was associated with lower cumulative survival rate (p < 0.0001), with 50 % of the cases linked to lethal outcome on day 13 post-hospital admission. Conclusion. Severe COVID-19 patients requiring mechanical lung ventilation were found to have elevated level of serum MPO activity and vWF correlating with poor survival.

COVID-19 coagulopathy - what should we treat?

NEW FINDINGS: What is the topic of this review? Overview of the coagulation abnormalities, including elevated D-dimers widely reported with COVID-19, often labelled as COVID coagulopathy. What advances does it highlight? The review highlights the changes in bronchoalveolar haemostasis due to apoptosis of alveolar cells, which contributes to acute lung injury and acute respiratory distress syndrome; the pathophysiological mechanisms, including endothelial dysfunction and damage responsible for thrombosis of pulmonary microcirculation and potential contribution to the hypoxaemia of COVID-19 acute lung injury; and changes in coagulation proteins responsible for the hypercoagulability and increased risk of thrombosis in other venous and arterial beds. The rationale for anticoagulation and fibrinolytic therapies is detailed, and potential confounders that might have led to less than expected improvement in the various randomised controlled trials are considered. ABSTRACT: Coronavirus disease 19 (COVID-19) causes acute lung injury with diffuse alveolar damage, alveolar-capillary barrier disruption, thrombin generation and alveolar fibrin deposition. Clinically, hypoxaemia is associated with preserved lung compliance early in the disease, suggesting the lack of excessive fluid accumulation typical of other lung injuries. Notably, autopsy studies demonstrate infection of the endothelium with extensive capillary thrombosis distinct from the embolic thrombi in pulmonary arteries. The inflammatory thrombosis in pulmonary vasculature secondary to endothelial infection and dysfunction appears to contribute to hypoxaemia. This is associated with elevated D-dimers and acquired hypercoagulability with an increased risk of deep vein thrombosis. Hypercoagulability is secondary to elevated plasma tissue factor levels, von Willebrand factor, fibrinogen, reduced ADAMTS-13 with platelet activation and inhibition of fibrinolysis. Multi-platform randomised controlled studies of systemic therapeutic anticoagulation with unfractionated and low molecular mass heparins demonstrated a survival benefit over standard care with full-dose anticoagulation in patients with non-severe disease who require supplemental oxygen, but not in severe disease requiring ventilatory support. Late intervention and the heterogeneous nature of enrolled patients can potentially explain the apparent lack of benefit in severe disease. Improvement in oxygenation has been demonstrated with intravenous fibrinolytics in small studies. Inhaled anticoagulants, thrombolytic agents and non-specific proteolytic drugs in clinical trials for decreasing alveolar fibrin deposition might benefit early disease. Essentially, COVID-19 is a multi-system disorder with pulmonary vascular inflammatory thrombosis that requires an interdisciplinary approach to combination therapies addressing both inflammation and intravascular thrombosis or alveolar fibrin deposits to improve outcomes.

Severe headache after adenoviral-vector vaccination against coronavirus disease 2019: a case report

Background: Several cases of vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) following exposition to adenoviral- vector vaccines against SARS-CoV-2 were described. The risk of developing intracranial thrombosis is high in subjects with severe headache, thrombocytopenia and d-dimer increase. Clinical Case: In July 2021 a 20-year-old woman, without risk factors for thrombosis, presented to the emergency room with headache and hematomas in the lower limbs. Ten days earlier she had received the Ad26.CoV2 vaccine (Johnson & Johnson/Jansenn). The blood tests showed thrombocytopenia, increase in d-dimer value, normal level of hemoglobin. A CT scan with contrast enhancement of the head excluded thrombosis of the intracranial veins or hemorrhage. The patient was hospitalized in the internal medicine ward;on admission she reported severe headache with normal neurological examination. The laboratory studies showed: d-dimer 34.430 ng/ml, fibrinogen 64 mg/dl, platelet count 65 x 103/mcl. Upon diagnosis of VIPIT the patient was treated with high dose intravenous immunoglobulins (IVIG), 800 mg/kg for two days. On the second day after IVIG infusion platelet count was 143.000/mmc, d-dimer value 2369 ng/ml and the headache had resolved. Conclusions: The clinical presentation, the laboratory and instrumental findings, the response to the treatment supported a prothrombotic condition, potentially associated with microthrombosis in intracranial smaller veins. Our experience suggests that early use of IVIG can be efficacious in avoiding the evolution into manifest thrombosis.

Higher Frequency of Acute and Subacute Postmortem Neuropathologic Findings in Patients with COVID-19 Infection

Background: Increasing numbers of COVID-19 patients experience acute and chronic neurologic symptoms and complications. Despite ample clinical evidence of CNS involvement by COVID-19, reported neuropathological findings in the postmortem brain tissues of COVID19 patents include variety of hypoxic/ischemic changes, thrombosis, intracerebral and subarachnoid hemorrhage, nonspecific microglial activation and/or lymphocytic infiltration. But, there is no clear evidence whether these findings are specific to COVID19 infection or not. Design: Autopsy brains specimens from 94 COVID19 patients and 61 controls (COVID 19 negative PCR test at time of autopsy) were examined. Clinical data on the presence of comorbid conditions, such as hypertension, diabetes, hyperlipidemia, chronic cardiac, and renal disorders were collected for both groups. Using routine neuropathology approaches, the extents of vascular pathology;acute, subacute, and remote ischemic hemorrhagic lesions;microvascular thrombosis, cerebral edema, and intraparenchymal and subarachnoid hemorrhage were examined. For histopathologic examination hippocampus, frontal and parietal neocortices and white matter, basal ganglia, midbrain, pons, medulla, and cerebellum were selected. Results: Mean age in the COVID19 group was 63 years and 60 years in the control group. There were more males in both group than females (COVID19 - 2.8:1, Control - 1.5:1). There was no statistically significant difference between groups in the frequencies of systemic comorbid conditions. 93% of COVID19 cases and 87% of control cases had at least one gross and/or microscopic neuropathologic finding. COVID19 cases showed higher rate of combined acute findings, including brain edema, acute and subacute hypoxic/ischemic lesions, thrombosis, and hemorrhage (61% vs 39%, P value - 0.002). When compared these features separately, none of them reached statistical significance. Arteriolosclerosis (66% vs 66%), atherosclerosis (17% vs 26%), and remote infarcts (19% vs 18%) where quite common findings with similar frequencies in both groups. Conclusions: Our data shows higher tendency of acute and subacute events in the patients with COVID19 infection. These finding do not quite explain the clinical symptoms seen in patients with neurologic complications, and likely represent the sequela of COVID19 systemic complications. More comprehensive neuropathologic and molecular approaches are necessary to better understand the mechanisms of neurologic complications of COVID19 infection.

COVID-19 Patients with GI Manifestations May be Associated with Extensive Microthrombosis in the Small Intestine, a Study from 13 Autopsy Cases

Background: More than 20% of COVID-19 patients have gastrointestinal (GI) symptoms, among which diarrhea is the most commonly seen symptom. Studies have suggested that patients with severe disease are more likely to have abdominal manifestations. Recent studies have also implicated that coagulopathy and thromboembolic as the major pathophysiological event leading to higher mortality. Besides thrombus in larger vessels, microthrombi appears to occur systemically and plays an important role in multiple organ dysfunction. However, fewer studies have focused on microthrombosis in the GI system. Design: 13 bronchial SARS-CoV-2 PCR proven autopsy cases were included in the study. Small intestinal specimens were obtained, and processed to routine hematoxylin and eosin (H&E) and CD61 immunohistochemistry (IHC). Related clinical and laboratory data were collected from patient chats. H&E and IHC slides were reviewed by two GI pathologists to evaluate histopathology and microthrombi. The degree of microthrombosis was graded as no microthrombi, focal (1- 2 per 10x), scattered (3-5 per 10x), and diffuse (≥6 per 10x). Results: Out of 13 patients (11 males, 1 female, age range 22-89 years old), 6 had diarrhea as the initial GI symptom, while others (7 patients) did not report any GI manifestations. Sections from the small intestine showed no acute inflammation in all cases. CD61 positive microthrombi was seen in all small intestine specimens, mainly located in the microvasculature of mucosa, and occasionally submucosal tissue. Patients who had diarrhea, 4/6 (66.7%) showed diffuse (greater than 6 per 10x field) microthrombi in the small intestine. In contrast, patients without GI symptoms, only 2/7 (28.5%) had diffuse microthrombi. Data from lab tests showed the D-dimer appeared to be higher in patients with diarrhea (median, 4067, range from 867 to 10000 ng/ml) compared to patients without diarrhea (median, 2820, range from 298 to 10000 ng/ml). There was no significant difference between median levels of C-reactive protein, prothrombin time (PT) and partial thromboplastin time (aPTT) between patients with or without diarrhea. Conclusions: Our study highlights that microthrombi frequently occurs in the GI system as reported in other organs. COVID-19 patients with initial GI manifestations, may develop severe microthrombosis and progress to sever disease.

In Situ Pulmonary Thrombolysis and Perfusion Lung Angiography in Severe COVID-19 Respiratory Failure.

A proof-of-concept study using thrombolysis with catheter-directed tissue plasminogen activator (tPA) and pulmonary angiography imaging was performed to visualize perfusion deficits and reperfusion/therapeutic effects of tPA. DESIGN: A prospective, open-label, compassionate study. Descriptive statistics were presented for categorical variables and as means with sds for continuous variables. The Wilcoxon test was used to determine the differences between the two-related samples and a t test for continuous variables. Statistical significance was set at p value of less than 0.05. Agreement between observations was evaluated using the Kappa Cohen index and overall agreement using the Fleiss Kappa coefficient. SETTING: A single COVID-19 ICU of Mexico´s General Hospital Dr Eduardo Liceaga. SUBJECTS: Fifteen patients with severe Delta variant severe acute respiratory syndrome coronavirus 2 infection, 18-75 years old, requiring mechanical ventilation with a persistent Fio2 requirement of 70% or higher and Pao2/Fio2 ratio (or imputed ratio) less than 150 for more than 4 hours. The coagulation inclusion criteria were International Society on Thrombosis and Haemostasis score greater than 5, and presence of a d-dimer greater than 1,200, with viscoelastic testing using rotational thromboelastometry (Instrumentation Laboratories, Mexico City, Mexico) showing both hypercoagulability (EXTEM amplitude at 5 min > 65 FIBTEM > 30) and hypofibrinolysis (EXTEM maximum lysis < 8%). INTERVENTIONS: Catheter-directed tPA angiography and iFlow system analysis to assess pre-tPA baseline pulmonary perfusion and changes in response to thrombolysis. RESULTS: Nine patients had microvascular filling defects demonstrated by angiography, and good agreement was found with iFlow analysis (ƙ = 0.714). Statistically significant differences were identified in the area under the curve (AUC) region of interest/AUC reference tissue with and without filling defects in phase 2 DM -0.09206 (sd ± 0.16684) (p = 0.003). The Pao2/Fio2 values measured immediately and 48 hours after the procedure were significantly higher (p = 0.001 and p = 0.005, respectively). Statistically significant differences were found in d-dimer values (p = 0.007), Fio2 (p = 0.002), and oxygen saturation in arterial blood/Fio2 (p = 0.045), as well as in the number of patients who required prone positioning before, immediately after the procedure, and at 48 hours after the procedure (p = 0.002). CONCLUSIONS: Thrombolysis with catheter-directed tPA resulted in imaging evidence via pulmonary angiography and iFlow technology of improved lung perfusion in COVID-19 patients with severe respiratory failure.

Oxidative stress-induced endothelial dysfunction and decreased vascular nitric oxide in COVID-19 patients.

BACKGROUND: SARS-CoV-2 targets endothelial cells through the angiotensin-converting enzyme 2 receptor. The resulting endothelial injury induces widespread thrombosis and microangiopathy. Nevertheless, early specific markers of endothelial dysfunction and vascular redox status in COVID-19 patients are currently missing. METHODS: Observational study including ICU and non-ICU adult COVID-19 patients admitted in hospital for acute respiratory failure, compared with control subjects matched for cardiovascular risk factors similar to ICU COVID-19 patients, and ICU septic shock patients unrelated to COVID-19. FINDINGS: Early SARS-CoV-2 infection was associated with an imbalance between an exacerbated oxidative stress (plasma peroxides levels in ICU patients vs. controls: 1456.0 ± 400.2 vs 436 ± 272.1 mmol/L; P < 0.05) and a reduced nitric oxide bioavailability proportional to disease severity (5-α-nitrosyl-hemoglobin, HbNO in ICU patients vs. controls: 116.1 ± 62.1 vs. 163.3 ± 46.7 nmol/L; P < 0.05). HbNO levels correlated with oxygenation parameters (PaO2/FiO2 ratio) in COVID-19 patients (R2 = 0.13; P < 0.05). Plasma levels of angiotensin II, aldosterone, renin or serum level of TREM-1 ruled out any hyper-activation of the renin-angiotensin-aldosterone system or leucocyte respiratory burst in ICU COVID-19 patients, contrary to septic patients. INTERPRETATION: Endothelial oxidative stress with ensuing decreased NO bioavailability appears as a likely pathogenic factor of endothelial dysfunction in ICU COVID-19 patients. A correlation between NO bioavailability and oxygenation parameters is observed in hospitalized COVID-19 patients. These results highlight an urgent need for oriented research leading to a better understanding of the specific endothelial oxidative stress that occurs during SARS-CoV-2. FUNDING: Stated in the acknowledgments section.

Microvascular involvement in long-term CoViD-19: usefulness of nailfold videocapillaroscopy

Background: Endothelial dysfunction represents a key pathophysiological factor in CoViD-19. A significant proportion of patients (pts) who have been infected with SARS-CoV-2 continue to have symptoms for a long time (long-term CoViD-19). Nailfold videocapillaroscopy (NVC) is nowadays considered one of the best diagnostic techniques of non-invasive imaging, able to study the microcirculation in vivo. The aim of our study was to assess microvasculature by means of NVC in long-term CoViD-19 pts. Methods: We examined 18 pts (12 F and 6 M), aged 53.9 years (range 29-84) with recent diagnosis of CoViD-19 and two successive oropharyngeal swabs resulted negative for the SARS-CoV-2 genome, hospitalized in our ward for other acute pathologies or related to our NVC clinic. The control group consisted of 20 healthy subjects without previous or current SARS-CoV-2 infection with overlapping demographic characteristics. We used a VideoCap 3.0 (DS Medica), equipped with 200x optics to evaluate microcirculation and its elementary alterations. Results: Long-term CoViD-19 pts, compared to control subjects, showed a higher prevalence of meandering capillaries, enlarged capillaries, loss of capillaries, hemosiderin deposits expression of micro-hemorrhages and micro-thrombosis, sludge flow and pericapillary edema. Conclusions: Long-term CoViD-19 pts present greater microvascular abnormalities at NVC compared to healthy subjects. However, further studies with larger case series are needed to assess the clinical relevance of NVC in long-term CoViD-19.

Exploring the pathways of inflammation and coagulopathy in COVID-19: A narrative tour into a viral rabbit hole.

Worldwide COVID-19 pandemic has taken a huge toll of morbidity and mortality. In selected patients, classified as severe, the overwhelming inflammatory state imposed by this infection is accompanied by a hypercoagulable state, hallmarked by a unique pattern; a marked increase in D-dimer, out of proportion to other markers of coagulopathy. In this review, we turn a spotlight to this phenomenon, offering a unified conceptual model depicting the leading hypotheses of coagulopathy in COVID-19. The key players of the coagulation cascades accompanying the COVID-19 inflammation malfunction on virtually every level; tissue factor expression is amplified, physiological anti-coagulant pathways (anti-thrombin, protein C and S, and the inhibitor of the tissue factor pathway) are impaired and fibrinolysis is inhibited. Components of autoimmunity, the complement system amongst others, further contribute to the pathology. As data continue to gather, our model offers a pathophysiological overview of COVID-19 coagulopathy, defined by the resultant histopathology: either intra-vascular or extra-vascular. We hope this review will facilitate understanding and serve as a lead point to future therapeutic directives.

Is Microthrombosis the Main Pathology in Coronavirus Disease 2019 Severity?-A Systematic Review of the Postmortem Pathologic Findings.

This systematic review attempts to retrieve and report the findings of postmortem studies including the histopathologic data of deceased coronavirus disease 2019 patients and to review the manifestations of coronavirus disease 2019-associated thrombotic pathologies reported in the recent literature. DATA SOURCES: PubMed, Excerpta Medica Database, and Cochrane library between December 1, 2019, and August 26, 2020. STUDY SELECTION: Investigators screened 360 unique references, retrieved published autopsy series, and report on the postmortem histopathologic information on patients who had died of coronavirus disease 2019. DATA EXTRACTION: Investigators independently abstracted all available data including study design, participant demographics, key histopathologic findings, disease severity markers, duration of hospital stay, and cause of death. DATA SYNTHESIS: From the 65 eligible studies, 691 total completed autopsies were included in evidence synthesis. Histopathologic evaluation of the lungs revealed presence of diffuse alveolar damage in 323 of 443 patients and pulmonary microthrombi in 242 of 326 patients. Deep venous thrombosis and pulmonary embolism were found in 41% and ~15%, respectively, of the cadavers examined for thromboembolic events. d-dimer levels were generally higher in patients with severe clinical course of coronavirus disease 2019. Plasma levels of ferritin, lactate dehydrogenase, interleukin-6, and C-reactive protein were higher in nonsurvivors when compared with survivors. Overall, microthrombi and extensive angiogenesis of lung vasculature were the most common pathologic findings in the lungs and microthrombi in most of the assessed organ-tissue. CONCLUSIONS: Diffuse alveolar damage was the most predominant feature in the lungs of coronavirus disease 2019 patients who underwent postmortem assessment. Widespread pulmonary microthrombosis and extensive pulmonary angiogenesis, in addition to frequent pulmonary and extrapulmonary microthrombotic and thromboembolic findings in patients with coronavirus disease 2019, appear to be consistent with the disease-specific hypercoagulability. Further discovery efforts in assessing the link between coronavirus disease 2019, hypercoagulable state, and immunothrombosis are warranted. In the interim, increased attention to anticoagulant treatment approaches in coronavirus disease 2019 patients is needed.

[Microvascular thrombosis and clinical implications]. / Trombosis microvascular y sus implicaciones clínicas.

Thrombosis is often present in the microcirculation in a variety of significant human diseases, such as disseminated intravascular coagulation, thrombotic microangiopathy, sickle cell disease, and others. Microvascular thrombosis has also recently been demonstrated in patients with COVID-19 and has been proposed to mediate the pathogenesis of organ injury in the lung and other organs. In many of these conditions, microvascular thrombosis is accompanied by inflammation, an association referred to as thromboinflammation or immunothrombosis. A greater understanding of the links between inflammation and thrombosis in the microcirculation will provide new therapeutic options for human diseases accompanied by microvascular thrombosis.

D-dimer at hospital admission for COVID-19 are associated with in-hospital mortality, independent of venous thromboembolism: Insights from a French multicenter cohort study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has been associated with coagulation disorders, in particular high concentrations of D-dimer, and increased frequency of venous thromboembolism. AIM: To explore the association between D-dimer at admission and in-hospital mortality in patients hospitalised for COVID-19, with or without symptomatic venous thromboembolism. METHODS: From 26 February to 20 April 2020, D-dimer concentration at admission and outcomes (in-hospital mortality and venous thromboembolism) of patients hospitalised for COVID-19 in medical wards were retrospectively analysed in a multicenter study in 24 French hospitals. RESULTS: Among 2878 patients enrolled in the study, 1154 (40.1%) patients had D-dimer measurement at admission. Receiver operating characteristic curve analysis identified a D-dimer concentration>1128ng/mL as the best cut-off value for in-hospital mortality (area under the curve 64.9%, 95% confidence interval [CI] 60-69), with a sensitivity of 71.1% (95% CI 62-78) and a specificity of 55.6% (95% CI 52-58), which did not differ in the subgroup of patients with venous thromboembolism during hospitalisation. Among 545 (47.2%) patients with D-dimer concentration>1128ng/mL at admission, 86 (15.8%) deaths occurred during hospitalisation. After adjustment, in Cox proportional hazards and logistic regression models, D-dimer concentration>1128ng/mL at admission was also associated with a worse prognosis, with an odds ratio of 3.07 (95% CI 2.05-4.69; P<0.001) and an adjusted hazard ratio of 2.11 (95% CI 1.31-3.4; P<0.01). CONCLUSIONS: D-dimer concentration>1128ng/mL is a relevant predictive factor for in-hospital mortality in patients hospitalised for COVID-19 in a medical ward, regardless of the occurrence of venous thromboembolism during hospitalisation.