Management of adverse reactions to COVID-19 vaccines by a Portuguese centre

Background: Since the introduction of COVID-19 vaccines, many reports have focused on adverse reactions. However, there is no global agreement on how to manage those patients. We aim to assess the management of adverse reactions by an immunoallergology department and its outcomes. Method(s): Retrospective analysis of the patients sent to our centre from January to October 2021 for adverse reactions to a COVID-19 vaccine, and who were considered ineligible for a 2nd dose by general practitioners. We collected data on the reported reactions, allergological study and outcomes. Result(s): 123 patients with adverse reactions were included (77% women, n = 95), mean age 55 years-old (min 12;max 92). Pfizer/ BioNTech Vaccine was inoculated in 64 patients (52%);Moderna in 15 (12%);AstraZeneca in 44 (36%). 65 patients (53%) presented symptoms compatible with allergic reactions: 86% (n = 56) with mucocutaneous symptoms, mainly urticaria-like lesions and/or angioedema;17% (n = 11) with suspected anaphylaxis and 5% (n = 3) with Steven-Johnson Syndrome. 19 patients performed skin testing with: PEG2000 (n = 17);polysorbate 80 (n = 15);COVID-19 vaccines (n = 21). Four patients had at least one positive test. 58 patients (47%) presented with non-allergic reactions. They showed great variability of symptoms. Most mild: 47% reported non-specific symptoms (such as malaise, headache, myalgia, fever, or fatigue) and 26% reported local reactions on the inoculation site. Some severe: 6 with deep vein or pulmonary thrombosis, 4 with myocarditis, 2 with stroke or myocardial infarction, and 1 with VITT. Patients with positive skin tests or severe previous reactions (n = 36, 29%) were referred for an alternative vaccine. Those with suspected allergic reaction but negative skin tests were premedicated with antihistamines before the 2nd dose. Follow-up showed: of the 81 patients (66%) who received an additional dose, 25% (n = 20) reported an adverse reaction, which was mild, and no case of anaphylaxis was reported. 16 (13%) refused a 2nd dose, and for 26 (21%) the information could not be obtained. Conclusion(s): The intervention of an allergologist had a significant positive impact on vaccination rates, with 2/3 of patients being reclassified as eligible for a 2nd dose. Allergological study and intervention identified vaccine-allergic patients and guided the decision on vaccine change and premedication, which resulted in a considerably lower number of adverse reactions to the 2nd dose, or at least its severity.

Prenatal and Neonatal Pulmonary Thrombosis as a Potential Complication of SARS-CoV-2 Infection in Late Pregnancy.

Neonatal venous thrombosis is a rare condition that can be iatrogenic or occur due to viral infections or genetic mutations. Thromboembolic complications are also commonly observed as a result of SARS-CoV-2 infections. They can affect pediatric patients, especially the ones suffering from multisystem inflammatory syndrome in children (MIS-C) or multisystem inflammatory syndrome in neonates (MIS-N). The question remains whether the maternal SARS-CoV-2 infection during pregnancy can lead to thromboembolic complications in fetuses and neonates. We report on a patient born with an embolism in the arterial duct, left pulmonary artery, and pulmonary trunk, who presented several characteristic features of MIS-N, suspecting that the cause might have been the maternal SARS-CoV2 infection in late pregnancy. Multiple genetic and laboratory tests were performed. The neonate presented only with a positive result of IgG antibodies against SARS-CoV-2. He was treated with low molecular weight heparin. Subsequent echocardiographic tests showed that the embolism dissolved. More research is necessary to evaluate the possible neonatal complications of maternal SARS-CoV-2 infection.

Clinical prediction model for pulmonary thrombosis diagnosis in hospitalized patients with SARS-CoV-2 infection.

Background and Aim: We aimed to develop a clinical prediction model for pulmonary thrombosis (PT) diagnosis in hospitalized COVID-19 patients. Methods: Non-intensive care unit hospitalized COVID-19 patients who underwent a computed tomography pulmonary angiogram (CTPA) for suspected PT were included in the study. Demographic, clinical, analytical, and radiological variables as potential factors associated with the presence of PT were selected. Multivariable Cox regression analysis to develop a score for estimating the pre-test probability of PT was performed. The score was internally validated by bootstrap analysis. Results: Among the 271 patients who underwent a CTPA, 132 patients (48.7%) had PT. Heart rate >100 bpm (OR = 4.63 [95% CI: 2.30-9.34]; P < 0.001), respiratory rate >22 bpm (OR = 5.21 [95% CI: 2.00-13.54]; P < 0.001), RALE score ≥4 (OR = 3.24 [95% CI: 1.66-6.32]; P < 0.001), C-reactive protein (CRP) >100 mg/L (OR = 2.10 [95% CI: 0.95-4.63]; P = 0.067), and D-dimer >3.000 ng/mL (OR = 6.86 [95% CI: 3.54-13.28]; P < 0.001) at the time of suspected PT were independent predictors of thrombosis. Using these variables, we constructed a nomogram (CRP, Heart rate, D-dimer, RALE score, and respiratory rate [CHEDDAR score]) for estimating the pre-test probability of PT. The score showed a high predictive accuracy (area under the receiver-operating characteristics curve = 0.877; 95% CI: 0.83-0.92). A score lower than 182 points on the nomogram confers a low probability for PT with a negative predictive value of 92%. Conclusions: CHEDDAR score can be used to estimate the pre-test probability of PT in hospitalized COVID-19 patients outside the intensive care unit. Relevance for Patients: Developing a new clinical prediction model for PT diagnosis in COVID-19 may help in the triage of patients, and limit unnecessary exposure to radiation and the risk of nephrotoxicity due to iodinated contrast.

Lung-on-chip: Its current and future perspective on pharmaceutical and biomedical applications

Organ-on-a-chip is a three-dimensional microfluidic system that simulates the cellular structure and biological milieu of an organ, that seemed to be constructed and studied substantially in the last decade. Microchips can be configured to suit disease states in a variety of organs, including the lung. When contrasted to traditional in vitro models like monolayer cell lineages, lung-on-a-chip models lays out a pragmatic portrayal of disease pathophysiology and pharmaceuticals' mode of action, and this is especially more prevailing in connection with the COVID-19 pandemic. Animal models have typically been used in pharmaceutical drug screening to assess pharmacological and toxicological reactions to a new entity. These adaptations, on the other hand, do not precisely represent biological reactions in humans. Present and prospective uses of the lung-on-a-chip model in the pulmonary system are highlighted in this overview. In addition, the constraints of existing in vitro systems for respiratory disease simulation and therapeutic discovery would be emphasized. Attributes of lung-on-a-chip transformative features in biomedical applications will be addressed to illustrate the relevance of this lung-on-chip model for medical science.Copyright © 2022

Mortality and Deep Vein Thrombosis in the Gamma Variant of Covid 19 and Lung Injury.

Purpose: The SARS-CoV-2 disease predisposes infected individuals to thrombosis, the underlying mechanisms of which are not fully understood. The balance between pro-coagulant factors and natural coagulation inhibitors in critically ill patients with Covid-19 is fundamental to the prevention and treatment of complications. The aim of the present study was to investigate the pulmonary injury patterns in Covid-19 having higher mortality in the presence of deep vein thrombosis in comparison to patients without venous thrombosis and determine the Gamma variant. Methods: A retrospective study was conducted involving the evaluation of 200 medical records of patients with Covid-19 and a clinical suspicion of deep vein thrombosis (DVT) at the intensive care unit of a public hospital. The sample was divided into two groups of patients were formed - those positive and those negative for DVT. Statistical analysis involved the use of Fisher's exact test, the paired t-test and chi-square test. Results: Patients with DVT had more severe lung injuries (greater than 70%) compared to those without DVT (p = 0.003). Lesions affecting 50% to 70% of the lung area occurred in little more half of the group with DVT and just under half in the group without DVT (p = 0.5). Pulmonary lesions affecting less than 50% of the lung occurred more in patients without DVT (p = 0.0001). The Gamma variant increased prevalence of the both DVT and mortality (p=0.0001). Conclusion: Deep vein thrombosis is an aggravating factor of mortality in patients with SARS-CoV-2, and the Gamma variant is an aggravating factor of both thrombotic events and mortality.

Lung ultrasound (LUS) for thrombosis in COVID-19 patients

Background: Lung thrombosis in hospitalized patients with COVID-19 pneumonia is a great problem. Angiopulmography is difficult to do because of epidemiologic circumstances and patients' oxygen dependency. Moreover, small focuses of thrombosis, which are common during COVID-19 may not visualized during CT scan. LUS is staying popular for diagnosing and dynamic observation of COVID-19 patients, but it is still unknown what parameters can be the really prediction of lung thrombosis. Aim(s): The aim was to estimate the diagnostic role of LUS during verification of COVID-19- associated lung thrombosis and during its dynamic observations. Method(s): We observed 40 patients (age -54.3 (48;65), men -6 (46.1%)) with severe COVID-19 pneumonia. General clinical analysis, LUS during hospitalization and in dynamic, statistical analysis applied. Result(s): 23 patients had signs of lung thrombosis on LUS: Subpleural triangular hypoechoic lesion (consolidations) with absent lung sliding and vascularization in Color regime (Figure 1). After strengthening of anticoagulation treatment 20 patients had positive dynamic on LUS: Decreasing of consolidation sizes and revascularization of lung tissue (Figure 2). Conclusion(s): 1) combination of LUS signs: Subpleural triangular hypoechoic lesion (consolidations) with absent lung sliding and vascularization in Color regime is quick, cheap, noninvasive test for verification of COVID-19- associated lung thrombosis 2) decreasing of consolidation sizes and revascularization of lung tissue during LUS could be the objective sign of adequate anticoagulant treatment. (Figure Presented).

COVID-19 and Pulmonary Thrombosis-An Unresolved Clinical Puzzle: A Single-Center Cohort Study.

Pulmonary thrombosis (PT) is a frequent complication of COVID-19. However, the risk factors, predictive scores, and precise diagnostic guidelines on indications for CT pulmonary angiography (CTPA) are still lacking. This study aimed to analyze the clinical and laboratory characteristics associated with PT in patients with COVID-19. We conducted a cohort study of consecutively hospitalized adult patients with COVID-19 who underwent CTPA at the University Hospital for Infectious Diseases in Zagreb, Croatia between 1 April and 31 December 2021. Of 2078 hospitalized patients, 575 (27.6%) underwent CTPA. PT was diagnosed in 178 (30.9%) patients (69.6% males, median age of 61, IQR 50-69 years). The PT group had a higher CRP, LDH, D-dimer, platelets, and CHOD score. PT was more frequent in patients requiring ≥15 L O2/min (25.0% vs. 39.7%). In multivariable analysis, only D-dimer ≥ 1.0 mg/L (OR 1.78, 95%CI 1.12-2.75) and O2 ≥ 15 L (OR 1.89, 95%CI 1.26-2.84) were associated with PT. PT was not associated with in-hospital mortality. In conclusion, our data confirmed a high incidence of PT in hospitalized patients with COVID-19, however, no correlation with traditional risk factors and mortality was found. CTPA should be performed in patients requiring high-flow supplemental oxygen or those with increased D-dimer levels.

Pulmonary Thrombus in Covid 19: A Case Series

Coronavirus disease 19 (COVID-19) increases the risk of thromboembolism by creating a prothrombotic state. COVID-19 and pulmonary embolism, both are associated with tachypnoea, hypoxemia, dyspnoea and increased D-dimer. Diagnosing pulmonary embolism in a patient with COVID-19 compared to a patient without it using conventional clinical and biochemical evidence is challenging. In this study, we report 8 cases affected by COVID-19 admitted to Medical Intensive Care Unit of a tertiary care centre in Udaipur. All the patients presented with fever, cough, shortness of breath. All the patients were hypoxic at the time of admission. Computed Tomographic Pulmonary Angiography (CTPA) was done in all of them when their hypoxia worsened, and D-dimer levels increased. All the patients were on therapeutic or prophylactic anticoagulation, yet they all developed pulmonary thrombus. Further studies are required to define the role of prophylactic and therapeutic anticoagulants in patients with COVID-19 infection.

Anticoagulant therapy monitoring in COVID-19 patients in the intensive care unit: thromboelastometry and echocardiography

Aim. To determine the effectiveness of thromboelastometry (TEM) and echocar-diography for anticoagulant therapy monitoring in patients with COVID-19. Material and methods. We analyzed treatment regimen of 92 patients with COVID-19. The patients were divided into two groups. In the control group (n=30), anticoagulant therapy with unfractionated heparin (UFH) was carried out under laboratory control of coagulation parameters. In the experimental group (n=62), anticoagulation was maintained by intravenous UFH under control of coagulation, echocardiography (Philips, Epiq 5) and TEM (ROTEM® delta). Echocardiography determined the pulmonary artery acceleration time (AT), mid-systolic notching (SN). The TEM method was used to study external (EXTEM) and internal (INTEM) pathways, differential tests (FIBTEM, HEPTEM) of coagulation. Statistical analysis was performed by calculating non-parametric statistics parameters, comparisons of differences in groups (Mann-Whitney test), area under the curve (AUC), and regression equations. Results. A high correlation level between echocardiographic and TEM parameters was determined. Their levels associated with a positive prognosis were calculated (AT>113,5 ms., AUC 0,979;p<0,0001;no SN, AUC 0,931;p<0,0001;FIBTEM ML (60 min) >1,12%, AUC 0,971, p<0,0001;INTEM ML (60 min) >2,01%, AUC 0,941, p<0,0001, EXTEM ML (60 min) >1,4%, AUC 0,934, p<0,0001;MCFfib not >26 mm, AUC 0,954;p<0,0001;MCFin not >56,6 mm, AUC 0,938;p<0,0001;MCFex not >47,9 mm, AUC 0,838, p<0,0001). In 33,9% of patients in the experimental group, heparin resistance was detected. In this connection, combined therapy with UFH and direct oral anticoagulants (DOACs) was used, followed by the switch to DOACs. In the control group, artificial ventilation was used in 50% of patients, mortality — 36,6%, myocardial infarction — 13,3%, deep vein thrombosis — 6,6%, pulmonary embolism — 6,6%, while in the experimental group, mechanical ventilation — 12,9%, myocardial infarction — 4,8%, mortality — 8,1%. Conclusion. The dynamic assessment of echocardiography and TEM parameters made it possible to monitor pulmonary thrombosis processes, significantly reduce complications, the use of artificial ventilation and mortality in COVID-19 patients.

A fatal case of COVID-19 pneumonia due to possible pulmonary thrombosis

The relationship between the severity of COVID-19, hyperinflammation, and intravascular coagulopathy is of critical importance. We report on a case of severe COVID-19 pneumonia treated with favipiravir during the earliest phase of the pandemic. The present case showed improvement in SARS-CoV-2 viral load and the presence of SARS-CoV-2 IgG with decreased radiological evidence of pulmonary infiltration. Moreover, the levels of serum IL-6 and TNF-α did not increase markedly. However, the hypoxia failed to recover, leading to the patient’s death due to possible pulmonary thrombosis, because D-dimer was markedly elevated, and an electrocardiogram showed typical changes. At present, the fact that some COVID-19 patients with mild to moderate symptoms suddenly die at home has become a major issue in Japan. These findings suggest that additional treatment with anti-coagulants should be considered in some COVID-19 patients at risk of hypercoagulation to prevent sudden death from pulmonary thrombosis.

Emerging complications of COVID-19 in a subset of Indian population: a pathological review with clinico-radiological case scenarios

Background: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was declared a pandemic by the World Health Organization on 11 March 2020 has been reported in most countries around the world since its origins in Wuhan, China. As of September 2021, there have been over 229 million cases of COVID-19 reported worldwide, with over 4.7 million COVID-19–associated deaths. Body: The devastating second wave of the COVID-19 pandemic in India has seen a rise in various extrapulmonary manifestations. One of key components in the pathogenesis of COVID-19 is downregulation of ACE-2, which is expressed on many organs and counterbalances the pro-inflammatory effects of ACE/angiotensin-II axis. This leads to influx of inflammatory cells into alveoli, increased vascular permeability and activation of prothrombotic mediators. Imaging findings such as ground glass opacities, interlobular septal thickening, vascular dilatation and pulmonary thrombosis correlate well with the pathogenesis. Conclusion: We hypothesize that the systemic complications of COVID-19 are caused by either direct viral invasion or effect of cytokine storm leading to inflammation and thrombosis or a combination of both. Gaining insights into pathobiology of SARS-CoV-2 will help understanding the various multisystemic manifestations of COVID-19. To date, only a few articles have been published that comprehensively describe the pathophysiology of COVID-19 along with its various multisystemic imaging manifestations.

Association of Nonalcoholic Fatty Liver Disease With COVID-19 Severity and Pulmonary Thrombosis: CovidFAT, a Prospective, Observational Cohort Study.

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease associated with systemic changes in immune response, which might be associated with coronavirus disease 2019 (COVID-19) severity. The aim of this study was to investigate the impact of NAFLD on COVID-19 severity and outcomes. Methods: A prospective observational study included consecutively hospitalized adult patients, hospitalized between March and June 2021, with severe COVID-19. Patients were screened for fatty liver by ultrasound and subsequently diagnosed with NAFLD. Patients were daily followed until discharge, and demographic, clinical, and laboratory data were collected and correlated to clinical outcomes. Results: Of the 216 patients included, 120 (55.5%) had NAFLD. The NAFLD group had higher C-reactive protein (interquartile range [IQR]) (84.7 [38.6-129.8] mg/L vs 66.9 [32.2-97.3] mg/L; P = .0340), interleukin-6 (49.19 [22.66-92.04] ng/L vs 13.22 [5.29-39.75] ng/L; P < .0001), aspartate aminotransferase (58 [40-81] IU/L vs 46 [29-82] IU/L; P = .0123), alanine aminotransferase (51 [32-73] IU/L vs 40 [23-69] IU/L; P = .0345), and lactate dehydrogenase (391 [285-483] IU/L vs 324 [247-411] IU/L; P = .0027). The patients with NAFLD had higher disease severity assessed by 7-category ordinal scale, more frequently required high-flow nasal cannula or noninvasive ventilation (26, 21.66%, vs 10, 10.42%; P = .0289), had longer duration of hospitalization (IQR) (10 [8-15] days vs 9 [6-12] days; P = .0018), and more frequently had pulmonary thromboembolism (26.66% vs 13.54%; P = .0191). On multivariable analyses, NAFLD was negatively associated with time to recovery (hazard ratio, 0.64; 95% CI, 0.48 to 0.86) and was identified as a risk factor for pulmonary thrombosis (odds ratio, 2.15; 95% CI, 1.04 to 4.46). Conclusions: NAFLD is associated with higher COVID-19 severity, more adverse outcomes, and more frequent pulmonary thrombosis.

Spontaneous iliopsoas hematoma: A warning for CoViD-19

Background: Patients with CoViD-19 are at high risk of thromboembolic events due to hemostatic changes directly related to the SARS-CoV-2 infection or to the consequence of cytokine storm. Anticoagulation with heparin is recommended to reduce the thrombotic risk. Spontaneous iliopsoas hematoma (IPH) is a potentially life-threatening complication of anticoagulation therapy described in CoViD-19 patients. Materials and Methods: We report two cases of association with IPH and SARS-CoV-2 pneumonia treated with heparin. Results: Over a 5-month period (November 2020-April 2021) 252 subjects with SARS-CoV-2 infection were admitted to our CoViD hospital. We found two cases of spontaneous IPH during the clinical course of CoViD-19. Diagnosis of IPH was made by CT angiogram. Coagulation parameters and platlet count were normal. One patient (an 83-year-old woman) was on prophylactic low weight molecular heparin (LWMH). The other patient (a 79-yearold man) received a therapeutic dosage with LWMH for pulmonary thrombosis and died, after urgent transarterial embolization, because of hemorrhagic hypovolemic shock. Conclusions: Although case reports are scarce for conclusion, our two cases, in addition to previous reports, suggest that CoViD-19 patients treated with anticoagulants are at risk of IPH. Given the indications to prescribe anticoagulation in CoViD-19 and the lack of solid evidences on the optimal dose and duration, it is important to be aware of IPH as a potentially serious complication. Rapid diagnosis and timely intervention are crucial to ensure good patient outcomes.

Electrical impedance tomography clues to detect pulmonary thrombosis in a teenager with COVID-19.

We report a case of pulmonary thrombosis in a teenager during a hypercoagulable state associated with COVID-19 (coronavirus disease 2019) caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). A condition rare in children and adolescents, pulmonary thrombosis underdiagnosis likely increases morbidity and mortality. A pulmonary thrombosis diagnosis requires a high level of suspicion and relies on the combination of clinical presentation, D-dimer elevation, and computed tomography (CT) pulmonary angiography or ventilation/perfusion scans, imaging techniques that are difficult to perform. Electrical impedance tomography (EIT) has gained attention, as it provides real-time ventilation distribution analysis. In addition, lung pulsatility images can be obtained through this technique using electrocardiogram gating to filter out ventilation. In this case report, the reduced EIT pulsatility corresponded to the perfusion defect found on the CT scan, information that was obtained at the bedside without radiation or contrast exposure.

Serial markers of coagulation and inflammation and the occurrence of clinical pulmonary thromboembolism in mechanically ventilated patients with SARS-CoV-2 infection; the prospective Maastricht intensive care COVID cohort.

BACKGROUND: The incidence of pulmonary thromboembolism is high in SARS-CoV-2 patients admitted to the Intensive Care. Elevated biomarkers of coagulation (fibrinogen and D-dimer) and inflammation (c-reactive protein (CRP) and ferritin) are associated with poor outcome in SARS-CoV-2. Whether the time-course of fibrinogen, D-dimer, CRP and ferritin is associated with the occurrence of pulmonary thromboembolism in SARS-CoV-2 patients is unknown. We hypothesise that patients on mechanical ventilation with SARS-CoV-2 infection and clinical pulmonary thromboembolism have lower concentrations of fibrinogen and higher D-dimer, CRP, and ferritin concentrations over time compared to patients without a clinical pulmonary thromboembolism. METHODS: In a prospective study, fibrinogen, D-dimer, CRP and ferritin were measured daily. Clinical suspected pulmonary thromboembolism was either confirmed or excluded based on computed tomography pulmonary angiography (CTPA) or by transthoracic ultrasound (TTU) (i.e., right-sided cardiac thrombus). In addition, patients who received therapy with recombinant tissue plasminogen activator were included when clinical instability in suspected pulmonary thromboembolism did not allow CTPA. Serial data were analysed using a mixed-effects linear regression model, and models were adjusted for known risk factors (age, sex, APACHE-II score, body mass index), biomarkers of coagulation and inflammation, and anticoagulants. RESULTS: Thirty-one patients were considered to suffer from pulmonary thromboembolism ((positive CTPA (n = 27), TTU positive (n = 1), therapy with recombinant tissue plasminogen activator (n = 3)), and eight patients with negative CTPA were included. After adjustment for known risk factors and anticoagulants, patients with, compared to those without, clinical pulmonary thromboembolism had lower average fibrinogen concentration of - 0.9 g/L (95% CI: - 1.6 - - 0.1) and lower average ferritin concentration of - 1045 µg/L (95% CI: - 1983 - - 106) over time. D-dimer and CRP average concentration did not significantly differ, 561 µg/L (- 6212-7334) and 27 mg/L (- 32-86) respectively. Ferritin lost statistical significance, both in sensitivity analysis and after adjustment for fibrinogen and D-dimer. CONCLUSION: Lower average concentrations of fibrinogen over time were associated with the presence of clinical pulmonary thromboembolism in patients at the Intensive Care, whereas D-dimer, CRP and ferritin were not. Lower concentrations over time may indicate the consumption of fibrinogen related to thrombus formation in the pulmonary vessels.

[Systemic consequences and clinical aspects of SARS-CoV-2 infection]. / Systemische Auswirkungen und klinische Aspekte der SARS-CoV-2-Infektion.

BACKGROUND: COVID-19 is considered a systemic disease. A severe course with fatal outcome is possible and unpredictable. OBJECTIVES: Which organ systems are predominantly involved? Which diseases are predisposed for a fatal course? Which organ changes are found with lethal outcome? MATERIALS AND METHODS: Data from published autopsy studies (28 cases by our group) with respect to organ changes and possible cause of death. RESULTS: The most severe alterations are found in the lungs by diffuse alveolar damage as a symptom of an acute respiratory distress syndrome (ARDS), in part with fibrosis. Thrombosis of small- to mid-sized pulmonary arteries is associated with hemorrhagic lung infarction. Frequent complications are bacterial pneumonias and less frequently fungal pneumonias by aspergillus. Pulmonary thromboembolism is found in 20-30% of lethal courses, also in the absence of deep venous thrombosis. Intestinal involvement of COVID-19 can be associated with intestinal ischemia, caused by shock or local thrombosis. In most cases, the kidneys display acute tubular injury reflecting acute renal failure, depletion of lymphocytes in the lymph nodes and spleen, and hyperplastic adrenal glands. The liver frequently reveals steatosis, liver cell necrosis, portal inflammation, and proliferation of Kupffer cells. Important preexisting diseases in autopsy studies are arterial hypertension with hypertensive and ischemic cardiomyopathy and diabetes mellitus but large population-based studies reveal increased risk of mortality only for diabetes mellitus not for arterial hypertension. CONCLUSIONS: Alterations of the pulmonary circulation with pulmonary arterial thrombosis, infarction, and bacterial pneumonia are important and often lethal complications of COVID-19-associated ARDS. Findings from autopsy studies have influenced therapy and prophylaxis.

Thrombotic Events in COVID-19 Are Associated With a Lower Use of Prophylactic Anticoagulation Before Hospitalization and Followed by Decreases in Platelet Reactivity.

Background: Coronavirus disease of 2019 (COVID-19) is associated with a prothrombotic state and a high incidence of thrombotic event(s) (TE). Objectives: To study platelet reactivity in hospitalized COVID-19 patients and determine a possible association with the clinical outcomes thrombosis and all-cause mortality. Methods: Seventy nine hospitalized COVID-19 patients were enrolled in this retrospective cohort study and provided blood samples in which platelet reactivity in response to stimulation with ADP and TRAP-6 was determined using flow cytometry. Clinical outcomes included thrombotic events, and all-cause mortality. Results: The incidence of TE in this study was 28% and all-cause mortality 16%. Patients that developed a TE were younger than patients that did not develop a TE [median age of 55 vs. 70 years; adjusted odds ratio (AOR) = 0.96 per 1 year of age, 95% confidence interval (CI) 0.92-1.00; p = 0.041]. Furthermore, patients using preexisting thromboprophylaxis were less likely to develop a thrombotic complication than patients that were not (18 vs. 54%; AOR = 0.19, 95% CI 0.04-0.84; p = 0.029). Conversely, having asthma strongly increased the risk on TE development (AOR = 6.2, 95% CI 1.15-33.7; p = 0.034). No significant differences in baseline P-selectin expression or platelet reactivity were observed between the COVID-19 positive patients (n = 79) and COVID-19 negative hospitalized control patients (n = 21), nor between COVID-19 positive survivors or non-survivors. However, patients showed decreased platelet reactivity in response to TRAP-6 following TE development. Conclusion: We observed an association between the use of preexisting thromboprophylaxis and a decreased risk of TE during COVID-19. This suggests that these therapies are beneficial for coping with COVID-19 associated hypercoagulability. This highlights the importance of patient therapy adherence. We observed lowered platelet reactivity after the development of TE, which might be attributed to platelet desensitization during thromboinflammation.

Tracking the time course of pathological patterns of lung injury in severe COVID-19.

BACKGROUND: Pulmonary involvement in COVID-19 is characterized pathologically by diffuse alveolar damage (DAD) and thrombosis, leading to the clinical picture of Acute Respiratory Distress Syndrome. The direct action of SARS-CoV-2 in lung cells and the dysregulated immuno-coagulative pathways activated in ARDS influence pulmonary involvement in severe COVID, that might be modulated by disease duration and individual factors. In this study we assessed the proportions of different lung pathology patterns in severe COVID-19 patients along the disease evolution and individual characteristics. METHODS: We analysed lung tissue from 41 COVID-19 patients that died in the period March-June 2020 and were submitted to a minimally invasive autopsy. Eight pulmonary regions were sampled. Pulmonary pathologists analysed the H&E stained slides, performing semiquantitative scores on the following parameters: exudative, intermediate or advanced DAD, bronchopneumonia, alveolar haemorrhage, infarct (%), arteriolar (number) or capillary thrombosis (yes/no). Histopathological data were correlated with demographic-clinical variables and periods of symptoms-hospital stay. RESULTS: Patient´s age varied from 22 to 88 years (18f/23 m), with hospital admission varying from 0 to 40 days. All patients had different proportions of DAD in their biopsies. Ninety percent of the patients presented pulmonary microthrombosis. The proportion of exudative DAD was higher in the period 0-8 days of hospital admission till death, whereas advanced DAD was higher after 17 days of hospital admission. In the group of patients that died within eight days of hospital admission, elderly patients had less proportion of the exudative pattern and increased proportions of the intermediate patterns. Obese patients had lower proportion of advanced DAD pattern in their biopsies, and lower than patients with overweight. Clustering analysis showed that patterns of vascular lesions (microthrombosis, infarction) clustered together, but not the other patterns. The vascular pattern was not influenced by demographic or clinical parameters, including time of disease progression. CONCLUSION: Patients with severe COVID-19 present different proportions of DAD patterns over time, with advanced DAD being more prevalent after 17 days, which seems to be influenced by age and weight. Vascular involvement is present in a large proportion of patients, occurs early in disease progression, and does not change over time.

Pulmonary thrombosis in Covid-19: before, during and after hospital admission.

Disordered coagulation, endothelial dysfunction, dehydration and immobility contribute to a substantially elevated risk of deep venous thrombosis, pulmonary embolism (PE) and systemic thrombosis in coronavirus disease 2019 (Covid-19). We evaluated the prevalence of pulmonary thrombosis and reported RV (right ventricular) dilatation/dysfunction associated with Covid-19 in a tertiary referral Covid-19 centre. Of 370 patients, positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 39 patients (mean age 62.3 ± 15 years, 56% male) underwent computed tomography pulmonary angiography (CTPA), due to increasing oxygen requirements or refractory hypoxia, not improving on oxygen, very elevated D-dimer or tachycardia disproportionate to clinical condition. Thrombosis in the pulmonary vasculature was found in 18 (46.2%) patients. However, pulmonary thrombosis did not predict survival (46.2% survivors vs 41.7% non-survivors, p = 0.796), but RV dilatation was less frequent among survivors (11.5% survivors vs 58.3% non-survivors, p = 0.002). Over the following month, we observed four Covid-19 patients, who were admitted with high and intermediate-high risk PE, and we treated them with UACTD (ultrasound-assisted catheter-directed thrombolysis), and four further patients, who were admitted with PE up to 4 weeks after recovery from Covid-19. Finally, we observed a case of RV dysfunction and pre-capillary pulmonary hypertension, associated with Covid-19 extensive lung disease. We demonstrated that pulmonary thrombosis is common in association with Covid-19. Also, the thrombotic risk in the pulmonary vasculature is present before and during hospital admission, and continues at least up to four weeks after discharge, and we present UACTD for high and intermediate-high risk PE management in Covid-19 patients.