Prolonged stay and endothelial dysfunction in hospitalized patients with covid-19

Introduction: COVID-19 is not only a respiratory disease, produces a severe systemic and multi-organ response. This illness generates vascular disorders, leading the patient to endothelial dysfunction. It acutely and chronically affects the patient's evolution, prolonging the patient's stay and worsening life prognosis. Objective(s): To evaluate differences in endothelial dysfunction present in patients hospitalized for COVID-19 who had a hospital stay longer than 18 days compared to those who did not. Method(s): A prospective cohort study was conducted. Hospitalized patients with confirmed SARS-COV 2 andolder than 18 years were included. Subjects in whom endothelial function markers could not be processed wereexcluded. Endothelial dysfunction was evaluated using E-selectin, endothelin-1, glutathione-s-transferase, arginase, and MDAM. A prolonged hospital stay was established >=18 days. Result(s): A total of 165 patients were evaluated, the average age of the population was 57.18 +/- 13.37 years, 73.33% were men. Subjects with prolonged hospital stay were older (59.38 +/- 12.08 vs 51.15 +/- 14.96, p=0.004), a higher number of patients required intubation (87.60 % vs 75, p=0.049) and e-selectin (1 [0.79 - 1.32] vs 0.88 [0.68 -1.14], p=0.0323) compared to subjects without prolonged hospital stay. Conclusion(s): Hospitalized patients over 18 days showed elevated levels of E-selectin reflecting endothelial damage, affecting vascular homeostasis, added to this, a significant number of them were intubated, increasing the risk of mortality, as well as future cardiovascular complications.

Evolution ofIL-6 as possible marker of viral control in Covid-19

Introduction: Persistence of SARS-Cov-2 leads to immunosuppression and lack of viral control. Better understanding of the immune response throughout the course of evolution is important for a better patient management. Method(s): Prospective observational longitudinal study of 91 hospitalised patients with different degrees of severity (moderate, severe, critical). In 72 we obtained >=2 blood samples and classified them into viral phase (1-9 days after clinical onset), early inflammatory (10-16), and late inflammatory (>17). We included clinical data, immune cell counts, proinflammatory cytokine levels, serum inflammatory markers, and tissue damage. Result(s): We observed higher serum IL-6 levels in the more severe groups, from the first sample. In inflammatory phases, we found a significant decrease in IL-6 and LDH in moderate, severe and survivors, and high persistence in critical and deceased patients. The biphasic behavior of IL-6 described, first neutrophil recruitment, epithelial and endothelial damage and then, after achieving viral control, CD4 differentiation, Th cells response and potentiation of Ac response, could explain these differences between those who do not achieve viral control (critical, deceased) and those who do. Conclusion(s): - IL-6 levels at 10-16 days may indicate whether or not viral control is achieved and whether there may be progression to critical stage/death.

Clinical Evidence and Therapeutic Treatments at the Time of the Coronaviruses Responsible for SARS: A Perspective and Points of view with a Focus on Vascular Endothelium

The clinical outcomes of COVID-19 patients highlight a significant minority of subjects with very rapid lethal outcomes subsequent to the almost complete healing after coronavirus infections for most of the subjects involved. In addition, the reckless use of some drugs and therapeutic protocols that have not shown any efficacy in reducing mortality in those patients where the progression of the disease was unstoppable suggests a different interpretative model in the pathogene-sis of severe cases. Starting from the clinical data already known for almost twenty years on the be-havior of human SARS coronaviruses, it is possible to develop a new hypothesis. The reference points taken into consideration are: i) the comparison of the histological evidence of the autoptic material;ii) the poor pharmacological response in subjects with severe phenotypes of the patholo-gy;iii) the common element of endotheliitis in a subgroup of the population characterized by harm-ful clinical outcomes during the evolution of the pathology. The tendency to develop widespread, massive endothelial lesions not responding to any drug therapy or other interventions necessarily plays a crucial role in the onset of the systemic and severe stage of the disease. The present perspective opens the door to a different therapeutic approach both to the full-blown phase of COVID-19 and to the preventive phase or the very first manifestations of the disease. It is imperative to pay more attention to the protection of the vascular endothelium in subjects who already have a predis-position to the development of a severe evolution of this ailment rather than to give a simple antiviral therapy together with symptomatic drugs.Copyright © 2021 Bentham Science Publishers.

Acute Mesenteric Thrombosis, Small Intestine Necrosis and Peritonitis as a Complication of Covid-19 - a Case Report

Introduction. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to a family of ribonucleic acid (RNA) viruses, causing novel coronavirus disease 2019 (COVID-19). Because of a global inflammatory response and endothelial damage, COVID-19 may predispose to coagulation disorders and severe thrombotic events. Case presentation. A 62-year-old man patient was admitted for COVID-19 pneumonia and abdominal pain for 10 days. Because of the rapid deterioration of the clinical status, shock and evidence of peritoneal irritation, the patient was consulted by a surgeon. The native spiral computed tomography (CT) of the abdomen detected enlarged colon filled with air collections and hydro-aeric levels. The surgical intervention revealed diffuse peritonitis with necrosis of the distal ileum secondary to mesenteric thrombosis. A partial resection of the ileum was done. The histological examination showed an infarcted small bowel, with hemorrhage, vascular thrombosis, and signs of necrotizing endovasculitis. Conclusions. SARS-CoV-2 binds to ACE2 receptor, which results in increased signalling by thrombin receptors on platelet and endothelial cells, leading to coagulopathy. In older patients presenting with abdominal pain, shock and peritonitis, the most common underlying cause is mesenteric thrombosis which could be a complication of COVID-19.Copyright © 2022 Balkan Medical Union.

Complete response to eculizumab in atypical hemolytic uremic syndrome with homozygous C3 mutation

Case Report: Atypical Hemolytic Uremic Syndrome (atypical HUS) is a rare and severe form of thrombotic microangiopathy (TMA) characterized by thrombocytopenia, intravascular hemolysis, and acute kidney injury with an incidence of 1 per million.1 Dysregulation and overactivation of the complement alternative pathway due to genetic mutations have been detected in 40-60% of patients with sporadic or familial atypical HUS.2,4 Triggers include viral illness, pregnancy, malignancy, sepsis, or sporadically with no known inciting event.1 Atypical HUS is a severe disease with a 2-10% risk of mortality, 33% risk of end-stage renal failure, and 50% chance of relapse.5 A 24-year-old female with prior history of atypical HUS at the age of 16 (with response to plasmapheresis) presented to the ER with a 5-day history of fever, chills, sore throat, nausea, vomiting, and dark urine. She tested positive for COVID-19. The exam revealed scleral icterus and scattered petechiae. Labs demonstrated nadir hemoglobin (Hgb) of 9.2 g/dL, platelet count of 52 000k/uL, haptoglobin < 30 mg/dL, peak LDH 1128U/L and creatinine 4.62 mg/dL. Urinalysis is consistent with hemoglobinuria. Schistocytes were noted on the peripheral smear. Rapid streptococcal antigen test and C3, C4, and IgA levels were unremarkable. Chest X-Ray, X-ray KUB, and ultrasound abdomen were unremarkable. The pregnancy test was negative. ADAMTS13 was >100%. Genetic analysis after the initial episode at age 16 revealed autosomal recessive inheritance c.193A > c gene mutations in C3. The patient received IV fluids, ceftriaxone for cystitis, and two units of Fresh Frozen Plasma. She initiated treatment with eculizumab. She also received the MENVEO and meningitis B vaccine per protocol due to the risk of meningitis from terminal complement deficiencies. After 4 infusions of eculizumab, patient's labs improved to platelet count of 307 000 k/uL, Hgb 12.2 g/ dL (nadir 9.2 g/dL), haptoglobin 78 mg/dL normalization of LDH and improved creatinine. Atypical HUS is a rare form of TMAwith mutations in C3 noted in 5% of cases. Complement cascade dysfunction leads to endothelial deposits and microvasculature damage. The resulting prothrombotic state causes obstructive microvascular thrombi predominantly affecting the kidneys but can cause multiorgan dysfunction. The SARS-CoV-2 virus may precipitate atypical HUS relapse due to endothelial damage and complement activation further intensified in patients with existing complement aberrations. Plasma exchange remains a standard of care for atypical HUS, as it effectively removes the antibodies and other proteins. Eculizumab a humanized monoclonal IgG antibody binds to complement proteins, preventing cleavage into C5a and C5b blocking C5b-9(MAC) activation. In patients with CFH, CFI, C3, and CFB mutations, eculizumab is the preferred intervention. Copyright © 2023 Southern Society for Clinical Investigation.

COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is presenting as a systemic disease associated with vascular inflammation and endothelial injury. Severe forms of SARS-CoV-2 infection induce acute respiratory distress syndrome (ARDS) and there is still an ongoing debate on whether COVID-19 ARDS and its perfusion defect differs from ARDS induced by other causes. Beside pro-inflammatory cytokines (such as interleukin-1 beta [IL-1beta] or IL-6), several main pathological phenomena have been seen because of endothelial cell (EC) dysfunction: hypercoagulation reflected by fibrin degradation products called D-dimers, micro- and macrothrombosis and pathological angiogenesis. Direct endothelial infection by SARS-CoV-2 is not likely to occur and ACE-2 expression by EC is a matter of debate. Indeed, endothelial damage reported in severely ill patients with COVID-19 could be more likely secondary to infection of neighboring cells and/or a consequence of inflammation. Endotheliopathy could give rise to hypercoagulation by alteration in the levels of different factors such as von Willebrand factor. Other than thrombotic events, pathological angiogenesis is among the recent findings. Overexpression of different proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) or placental growth factors (PlGF) have been found in plasma or lung biopsies of COVID-19 patients. Finally, SARS-CoV-2 infection induces an emergency myelopoiesis associated to deregulated immunity and mobilization of endothelial progenitor cells, leading to features of acquired hematological malignancies or cardiovascular disease, which are discussed in this review. Altogether, this review will try to elucidate the pathophysiology of thrombotic complications, pathological angiogenesis and EC dysfunction, allowing better insight in new targets and antithrombotic protocols to better address vascular system dysfunction. Since treating SARS-CoV-2 infection and its potential long-term effects involves targeting the vascular compartment and/or mobilization of immature immune cells, we propose to define COVID-19 and its complications as a systemic vascular acquired hemopathy. Copyright © 2021, The Author(s), under exclusive licence to Springer Nature B.V.

Assessing endothelial activation and risk of bleeding in patients receiving VV-ECMO supportive therapy for COVID-19 using non-standard laboratory assays

Background: Critically ill patients infected with the SARS-CoV- 2 virus are known to have a coagulopathy with a risk of thrombosis due to endothelial activation and systemic inflammation. Veno-venous extracorporeal membrane oxygenation (VV ECMO) is recommended by the World Health Organisation (WHO) as a supportive therapy for patients with severe COVID-19 infection when conventional ICU methods have proven ineffective. VV ECMO comes with haematological complications, including loss of high molecular weight von Willebrand factor multimers, consumption of clotting factors and premature activation of platelets. Laboratory methods to characterise haemostasis in these patients are required and may be clinically useful in predicting clinical outcome. Aim(s): Can non-standard methods provide clinically meaningful results in COVID-19 positive patients supported by VV ECMO? Methods: Tissue plasminogen activator and von Willebrand factor were quantified via Abcam SimpleStep ELISA in VV ECMO supported Covid-19 patients and normal controls. Fibrinogen antigen concentration was quantified via Liaphen Fibrinogen Antigen assay in VV ECMO supported Covid-19 patients and normal controls. VW Select ristocetin cofactor assay was used to assess von Willebrand Factor activity in VV ECMO supported COVID-19 patients. Result(s): Tissue plasminogen activator and von Willebrand factor concentrations are significantly increased in COVID-19 patients supported by VV ECMO compared to healthy controls, which reflects endothelial damage displayed in critically unwell COVID patients. Fibrinogen levels were not significantly different between the two patient groups. The VW Select ristocetin cofactor assay detected patients with low vWF activity that would have otherwise been overlooked by standard methods. Conclusion(s): Non-conventional laboratory methods can be used to represent the extent of endothelial damage and risk of bleeding in patients who are COVID-19 positive and anticoagulated on VV ECMO support. The assays help to characterise pathology of COVID-19 used in conjunction with standard tests by providing clinically relevant results. (Figure Presented).

SARS-CoV-2 S Protein Is a Competitive Inhibitor of Furin Mediated ENaC Activation

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19 (Coronavirus disease 19). SARS-CoV-2 causes a multisystemic infection, which frequently presents with pulmonary oedema, endothelial damage and electrolytic abnormalities. An essential physiopathological feature of SARSCoV-2 involves cleavage of its S protein by furin or furin-like enzymes. It has been shown by sequence-based evidence that the S protein polybasic aminoacid sequence is identical to the consensus sequence for furin cleavage present in the human alpha subunit of the epithelial sodium channel (ENaC). Furin and furin-like enzymes are also involved in the posttranslational regulation of ENaC in many tissues, including the lung, endothelium, and the kidney, where cleavage is associated with increased activity of the channel. ENaC is involved in the regulation of fluid clearance, Na+, K+ and acid-base homeostasis, and endothelial function. Thus, we hypothesized that the S protein competes with ENaC for furin-mediated cleavage and activation. Method(s): We injected synthetic mRNA encoding WT S protein and mutant S protein lacking the furin consensus sequence (DELTA-Spike) into X. laevis oocytes with alphabetagamma-ENaC subunits. We then performed whole-cell voltage-clamp experiments and protein analysis by western blot. Result(s): We observed an interdependent competitive effect on the cleavage of both the S protein and ENaC when co-expressed, which was partially prevented with the injection of DELTA-Spike. We also found a decrease in the amiloride-sensitive sodium current in oocytes injected with the WT S protein but not with DELTA-Spike. This suggests diminished function of ENaC in the presence of WT S protein that depends on its furin cleavage site. Conclusion(s): These findings show evidence of a competitive interaction between the S protein and ENaC for furin-like enzymes. This suggests that SARS-CoV-2 infection may impair ENaC activity in human epithelia, which gives a plausible explanation to pulmonary oedema, endothelial damage, and electrolyte disturbances in patients with COVID-19.

A HARD PILL TO SWALLOW

SESSION TITLE: COVID-19 Case Report Posters 3 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Epiglottitis is an inflammation of the epiglottis which can be life-threatening in the absence of prompt intervention. Although primarily a pediatric condition, streptococcus pneumonia has been identified as a common pathogen in adults. SARS-CoV 2 has been known to affect a multitude of systems including the upper respiratory tract, but rarely the epiglottis. CASE PRESENTATION: A 66-year-old female with a past history of hypertension, and hypothyroidism presented with acute onset pharyngodynia and dysphagia with a feeling of throat closing up due to swelling and difficulty speaking. She had a recent COVID-19 diagnosis and was doing well except for mild fatigue. Upon presentation, she was hemodynamically stable. Physical exam revealed posterior pharyngeal edema without any exudate, mildly edematous uvula, and no stridor. Laboratory data was pristine except for elevated inflammatory markers. Rapid streptococcal test and MRSA swab were negative. Sputum culture showed usual respiratory flora and blood cultures were negative. A neck CT showed diffuse edema without any evidence of abscess. Laryngoscopy performed by the ENT surgeon revealed diffuse edema including epiglottitis. Emergent intubation revealed supra and epiglottis edema sparing the vocal cords. The patient was given Decadron and Benadryl to help with the edema along with clindamycin and subsequently transferred to ICU for further care. She was treated with Ceftriaxone for 7 days due to a chest X-ray finding of pneumonia. As for COVID 19 treatment, she received a course of Remdesivir and Decadron. Decadron was given at an increased interval to reduce edema around the epiglottis. Her ICU course was complicated with hypotension requiring intermittent vasopressor support, and acute kidney injury from ischemic acute tubular necrosis which slowly improved. Repeat CT chest showed bibasilar consolidations with peripheral ground-glass opacities. In view of hospital-acquired pneumonia, she was started on Ertapenem. Her clinical condition improved and she was successfully extubated. She was shifted to the floors from where she was discharged without any further complications. DISCUSSION: There are only two other reported cases of COVID 19 epiglottitis. The patient's advanced age and obesity were non-modifiable risk factors, but the COVID-19 infection played a role. The virus can lead to excessive upregulation of the host inflammatory response through repeat epithelial and endothelial damage leading to a cytokine storm, which may be responsible for this presentation. A great level of attention is to be maintained while attending to these patients given the multitude of systems that can be affected. CONCLUSIONS: COVID-19 is a potential cause of life-threatening acute epiglottitis. Early suspicion and direct visualization of the epiglottis is the key to success for early management. Reference #1: Emberey J, Velala SS, Marshall B, et al. Acute Epiglottitis Due to COVID-19 Infection. Eur J Case Rep Intern Med. 2021;8(3):002280. Published 2021 Mar 3. doi:10.12890/2021_002280 Reference #2: Smith C, Mobarakai O, Sahra S, Twito J, Mobarakai N. Case report: Epiglottitis in the setting of COVID-19. IDCases. 2021;24:e01116. doi: 10.1016/j.idcr.2021.e01116. Epub 2021 Apr 7. PMID: 33842206;PMCID: PMC8025537. DISCLOSURES: No relevant relationships by Arunava Saha

COMPARATIVE EFFECTIVENESS OF INHALED NITRIC OXIDE IN ARDS AND VIRAL PNEUMONIA WITH AND WITHOUT COVID-19

SESSION TITLE: ECMO and ARDS in COVID-19 Infections SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/17/2022 12:15 pm - 1:15 pm PURPOSE: Inhaled nitric oxide (iNO) is a potent vasodilator of pulmonary vasculature improving perfusion to ventilated alveoli in ARDS and other lung pathologies. During the pandemic, intensivists turned to iNO as “salvage” therapy in COVID-19 patients. Rationale was driven by vasodilatory effect and antiviral properties despite lack of evidence of clear benefit even in patients without COVID. We hypothesized that iNO would provide reduced increases in pulmonary perfusion and subsequent gas exchange improvement in COVID-19 patients due to extensive endothelial damage and coagulopathy throughout the pulmonary vasculature. METHODS: Our IRB exempt analysis examined patients hospitalized with and without COVID-19 from January 2020 to September 2021 who received at least 24h of invasive mechanical ventilation with iNO (15-20ppm). Effectiveness outcomes were PaO2/FIO2 ratio(PFR), PEEP/CPAP level, and PaCO2 serially measured and observed up to 24 hours prior to initiation of iNO and for up to 120h post iNO administration. Data were statistically controlled for age, sex, race, time to initiation of therapy and COVID-19 directed treatment. RESULTS: From January 2020 and September 2021, 42 patients were admitted to the ICU and received invasive mechanical ventilation and iNO. Results are sequenced as ARDS COVID-negative, ARDS COVID-positive, viral pneumonia COVID-negative, viral-pneumonia COVID-positive. Patient n = 8/14/6/14. Median age was 56/55/63/62 years. Demographics split 64-62% male vs 36-38% female in ARDS without/with COVID, 50%/83% male vs 50%/17% female in viral pneumonia without/with COVID. Racial distribution resulted 75%/93%/86%/83% White vs 25%/0%/17%/14% Black. Other races constituted less than 7% of patient total in any category. PFR delta from -24h to +120h post-iNO = +35/+35/+41/+22. PEEP/CPAP delta from -24h to +120h = -4/-1/-3/-2. PaCO2 delta mmHg from -24h to +120h = -21/-23/-9/-13. Median Hospital LOS = 26/26.5/17/19 days. Median ICU LOS = 15.8/19.0/13.8/17.6 days. Hospital mortality = 100% across all 4 subgroups. CONCLUSIONS: ARDS patients with or without COVID showed similar rates of PFR response to iNO, however viral pneumonia patients with COVID exhibited a blunted PFR response vs those without COVID. No statistically significant difference was observed with respect to PEEP/CPAP levels, PaCO2 mmHg, hospital or ICU LOS, or mortality. CLINICAL IMPLICATIONS: Our findings suggest that the presence of COVID-19 did not significantly inhibit response to iNO in ARDS or other viral pneumonia patients. Further evaluation of other indirect markers of gas exchange could provide further evidence of responsiveness. DISCLOSURES: No relevant relationships by Katherine Burns No relevant relationships by Karen Hamad No relevant relationships by Bobby Malik No relevant relationships by Richard Walo Jr No relevant relationships by Wilhelmine Wiese-Rometsch No relevant relationships by Stephanie Williams

COMMONLY USED MAGNESIUM SULFATE UNCOMMONLY CAUSING PULMONARY EDEMA

SESSION TITLE: Drug-Induced Critical Care SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: Intravenous magnesium sulfate (MgSo4) is commonly used for inpatient magnesium repletion. However, it is infrequently shown to be associated with the development of pulmonary edema. We present a case of acute hypoxic respiratory failure due to pulmonary edema after starting magnesium infusion in a patient recovering from COVID-19. CASE PRESENTATION: 60 year old female with a history of metastatic breast cancer presented with hypoxic respiratory failure due to COVID-19. CT angiogram of her chest showed diffuse bilateral ground-glass opacities with no evidence of pulmonary embolism. She had prolonged weaning from high flow nasal cannula and was treated with antibiotics, remedesivir, and dexamethasone. Following treatment, her inflammatory markers significantly improved. On day thirty, she was on 25 L at 45% FiO2 on high flow nasal cannula. Her magnesium level was low at 1.5 mg/dl, and 2 grams of intravenous MgSo4 was given for replacement. A few minutes after starting the infusion, the patient complained of metallic taste, severe shortness of breath, and tachypnea with a drop in oxygen saturation to 67%, which improved with increasing oxygen. CXR showed worsening perihilar infiltrates compared to prior, suggesting acute pulmonary edema. An echocardiogram showed normal function without evidence of structural abnormalities. Thyroid function was normal. She did not receive any blood products or opioids prior to this event. She responded very well to diuresis, was weaned to 5L nasal cannula in three days, and was eventually discharged on 2L supplemental oxygen. DISCUSSION: Pulmonary edema is due to the movement of excess fluid into the alveoli. It can be due to cardiogenic and noncardiogenic causes. Noncardiogenic pulmonary edema is due to a rise in transcapillary filtration, causing an increase in capillary permeability due to several factors, most importantly direct endothelial damage due to inflammation. Mechanisms for MgSo4 induced pulmonary edema are unknown, but theories include direct capillary damage or transient cardiac depression. It is seen in studies to be an independent risk factor for the development of pulmonary edema in pregnancy. Higher risk is associated with faster MgSo4 infusion, less concentrated MgSo4, and infection[1]. She was on abemaciclib for breast cancer before her admission, known to cause pneumonitis but was thought unlikely to cause her acute decompensation. The lack of other etiologies explaining sudden respiratory failure, her rapid improvement on stopping magnesium, and her response to diuretics supported our diagnosis. CONCLUSIONS: Treatment of noncardiogenic pulmonary edema involves addressing the underlying cause of the event and is mainly supportive. Given how commonly Mgso4 is used for repletion in the inpatient setting, MgSo4 induced pulmonary edema should be in the differential for acute hypoxic respiratory failure and promptly addressed. Reference #1: Samol JM, Lambers DS. Magnesium sulfate tocolysis and pulmonary edema: the drug or the vehicle? Am J Obstet Gynecol. 2005 May;192(5):1430-2. doi: 10.1016/j.ajog.2005.02.093. PMID: 15902128. DISCLOSURES: No relevant relationships by Nasir Alhamdan No relevant relationships by Harshitha Mergey Devender No relevant relationships by Abira Usman No relevant relationships by Vishruth Vyata No relevant relationships by Harika Yadav

AORTIC THROMBUS DESPITE THERAPEUTIC DOSE OF ANTICOAGULATION IN A PATIENT POSITIVE FOR COVID-19

SESSION TITLE: Extraordinary Cardiovascular Reports SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 01:35 pm - 02:35 pm INTRODUCTION: Hypercoagulability is a well-known complication of COVID-19, with the most common vascular events being pulmonary embolism and deep vein thrombosis (1). Arterial thrombotic events, specifically aortic thrombosis, are rarely observed in COVID-19 infections. Literature review reveals less than 10 cases of aortic thrombosis have been reported in patients with COVID-19 infection. Here, we report a unique case of acute aortic thrombosis despite administration of therapeutic anticoagulation. CASE PRESENTATION: A 77 y.o. female with no known medical history presented to the hospital after a diagnosis of COVID-19 five days prior. Upon arrival, she was hypoxic requiring supplemental oxygen via non-rebreather (NRB) mask. CT chest with contrast revealed bilateral ground-glass opacities without evidence of pulmonary embolism or aortic thrombus. She was treated with remdesivir, dexamethasone, baricitinib and enoxaparin 40mg BID (essentially therapeutic dosing based on patient's body weight of 45kg). Adequate oxygenation was maintained with nasal cannula and NRB. However, on day eight of admission she was noted to desaturate to 80% requiring BiPAP. D-dimer and CRP drastically increased from 0.36ug/ml to 1.75ug/ml and 13.0 to 102.2, respectively. Repeat CT chest with contrast revealed multiple intraluminal thrombi in the distal thoracic aorta. Treatment with clopidogrel was initiated, however patient remained BiPAP dependent. Due to DNR/DNI status, intubation was not pursued. Ultimately, patient was transitioned to comfort care and expired. DISCUSSION: Thrombotic events are poorly understood but remain a well-documented sequela of COVID-19 infection. The pathophysiology of thrombosis in COVID-19 patients has not been fully elucidated, however, it likely involves amplification of the hypercoagulable state due to viral infection. Some of the proposed theories regarding this effect include endothelial dysfunction secondary to direct virus invasion and immuno-thrombosis due to viral mediated endothelial inflammation with resultant platelet activation (2,3). Regarding COVID-19 associated arterial thrombi, myocardial infarction and stroke are the most commonly encountered events. The few reported cases of aortic thrombi occurred almost exclusively in males with significant cardiovascular risk factors and not on anticoagulation (1,3). CONCLUSIONS: Due to the increased risk of venous thromboembolic events, prophylaxis is routinely used in patients with COVID-19. However, in our case, the patient developed multiple aortic thrombi without any typical risk factors for endothelial lesions despite being fully anticoagulated. This case highlights the need for continued research and trials related to appropriate anticoagulation therapies in hospitalized patients with COVID-19. Additionally, physicians should be aware of potential arterial thrombi in patients infected with COVID-19. Reference #1: de Carranza M, Salazar DE, Troya J, et al. Aortic thrombus in patients with severe COVID-19: review of three cases. J Thromb Thrombolysis. 2021;51(1):237-242. doi:10.1007/s11239-020-02219-z Reference #2: Loo J, Spittle DA, Newnham MCOVID-19, immunothrombosis and venous thromboembolism: biological mechanismsThorax 2021;76:412-420. doi:10.1136/ thoraxjnl-2020-216243 Reference #3: Woehl B, Lawson B, Jambert L, Tousch J, Ghassani A, Hamade A. 4 Cases of Aortic Thrombosis in Patients With COVID-19. JACC Case Rep. 2020;2(9):1397-1401. doi:10.1016/j.jaccas.2020.06.003 DISCLOSURES: No relevant relationships by Chelsey Bertrand- Hemmings No relevant relationships by Alyssa Foster No relevant relationships by Kyle Foster No relevant relationships by Yelena Galumyan No relevant relationships by Veronica Jacome No relevant relationships by Viet Nguyen

A PATIENT WITH COVID-19 PNEUMONIA, PULMONARY EMBOLISM, AND OSA

SESSION TITLE: Global Case Reports in Critical Care SESSION TYPE: Global Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Thrombotic complications in patients diagnosed with COVID-19 pneumonia are emerging as an important and significant morbidity and mortality burden, with overwhelming inflammation, hypoxia, immobilization, and diffuse intravascular coagulation among possible causes of a procoagulant state (1). Obstructive sleep apnea (OSA), with intermittent arterial oxygen desaturation, may in its turn contribute to a procoagulant state, causing hemodynamic alterations as polycythemia and sluggish blood flow (2). Here we report on a case of sudden and massive non-lethal pulmonary thromboembolism (PTE) in a patient with COVID-19 severe pneumonia, for whom OSA was suspected and documented as a possible concurrent mechanism of thromboembolic complication during follow-up. CASE PRESENTATION: A 55-year-old male non-smoker obese (BMI 33 Kg/m2) was admitted to our hospital after 9 days of fever. In the Emergency Room, a chest HRCT scan showed bilateral diffuse ground glass opacities. He was treated with subcutaneous Tocilizumab (324 mg) single shot, Remdesivir (200 mg/day for first day and 100/daily for further 4 days), methyl-prednisolone 40 mg/daily, Enoxaparin 6000 UI/twice daily, azithromycin 500 mg/daily, high flow nasal cannula oxygen (50 L/min, TC 34°C, FiO2 35%) for moderate acute respiratory failure due to COVID-19 pneumonia (pO2: 58 mmHg, PCO2 34 mmHg pH 7.50, P/F 275). After 10 days, patient's clinical conditions worsened, needing non-invasive respiratory support;D-dimer increased abruptly, rising to 10 ng/mL, with findings consistent with PTE at a computed tomographic angiography (CTA, Fig 1). The patient was successfully treated with 10 mg/daily subcutaneous fondaparinux for 12 days, while assisted in the Intensive Care Unit, being discharged home in room air shortly later with oral anticoagulants. At the 3-month follow-up visit, OSA was suspected due to reported excessive daytime sleepiness and weakness, snoring, disturbed night sleep, morning headache in the last 4 years. The patient underwent a home sleep apnea test (HSAT) overnight. Test results revealed an AHI of 50 events/h, with several prolonged episodes of obstructive sleep apnea (307 apnea and hypopnea (A+H) events, 70 obstructive apnea and 233 hypopnea events, with a mean duration of 10% and an average arterial saturation of 93% (Fig. 2). He was adapted to CPAP therapy, with benefit and good correction of polygraphic indexes. DISCUSSION: The pathogenetic mechanisms of COVID 19 and OSA could have played a synergistic effect on endothelial damage, thus increasing the risk of thromboembolism. CONCLUSIONS: The presence of underdiagnosed comorbidities may well worsen the clinical course and complication of COVID-19;an earlier diagnosis of OSA is a prerequisite for timely treatment and, potentially, improved long-term clinical outcomes. Reference #1: Suh YJ, et al. Pulmonary embolism and deep vein thrombosis in COVID 19: a systematic review and meta-analysis. Radiology 2021;298 (2): E70-E80. Reference #2: Alfonso-Fernandez A., Garcia Surquia A., de la Pena M. OSA is a risk factor for recurrent VTE Chest. 2016;150 (6): 1291-1301. DISCLOSURES: no disclosure on file for Antonietta Esposito;no disclosure on file for Antonella Frattari;no disclosure on file for Giustino Parruti;no disclosure on file for Giorgia Patrizio;no disclosure on file for Pierpaolo Prosperi;no disclosure on file for Giorgia Rapacchiale;No relevant relationships by ANTONELLA SPACONE no disclosure on file for Giacomo Zuccarini;

THE ROLE of IL-6 in ENDOTHELIAL DYSFUNCTION: RHEUMATOID ARTHRITIS and COVID-19, TWO PATHOGENIC MODELS in COMPARISON

Background: Rheumatoid arthritis (RA) is the most common systemic autoimmune disease that primarily affects joints but is also often characterized by extra-articular involvement1. Cardiovascular diseases are the most important causes of sudden death in these patients, which present a risk of developing cardiovascular events increased by 48%2. The causes of increased cardiovascular risk are several and not completely understood, but recent evidence supports the key role of endothelial dysfunction in pathogenesis. In this complex scenario, it is known that IL-6 receptors are present at the endothelial level and can be activated leading to endothelial dysfunction. SARS-Cov-2 is a coronavirus responsible for the disease called 'coronavirus disease 2019' (CoViD-19) characterized by clinical manifestations ranging from a flu-like syndrome up to severe lung damage associated with systemic hyper cytokine syndrome that can lead to multiple organ failure and death. Therefore, both RA and Covid-19 are associated with an increased pro-thrombotic and cardiovascular risk and IL-6 might be crucial in the patho-physiological mechanisms of both diseases. Objectives: The main hypothesis of this study was to evaluate the possible role of IL-6 as a promoter of endothelial dysfunction in RA and CoViD-19. Methods: In vitro experiments were conducted on the endothelial cell line EA. hy926. Cells were treated for 24 h with fetal bovine serum (FBS), a pool of RA patients' sera or a pool of CoViD-19 patients' sera. The expression levels of adhesion molecules (V-CAM1/CD-106, I-CAM/CD-54, p-selectine/CD-62, tissue factor/CD-142) and apoptosis were analyzed using cytofuorimetric technique. In addition, the autophagy level, using the autophagy markers p62 and LC3II, were evaluated through a western-blot analysis. The same experiments were conducted co-treating cells with the same pool of sera in addition to tocilizumab (TCZ), an anti-IL-6 drug, to verify the reversibility of the process and test the role of the aforementioned cytokine. Data are reported as interquartile median values. The Kruskal Wallis test was used for unpaired samples and the Mann-Whitney test for paired samples. P<0.05 values were considered statistically signifcant. Results: EA. hy926 cells, when treated with both RA and CoViD-19 patients' sera, showed increased levels of activation molecules and apoptosis compared to FBS treated cells. In addition, we observed increased levels of both p62 and LC3 proteins after both rheumatoid arthritis and CoViD-19 patients' sera treatment. All these fndings were reversible in the presence of TCZ. The results are presented in Figure 1. Conclusion: Our data showed that treatment with RA and CoViD-19 patients' sera increase the activation and death of endothelial cells in vitro. The increased level of cells death is possibly due to a block of autophagy. The reversibility of the process after blocking IL-6 with TCZ co-treatment confrms the hypothesis that IL-6 can play a key role in the pathogenesis of endothelial damage in patients with RA and CoViD-19.

DISSECTING COVID-19 - A RARE CASE OF SPONTANEOUS CORONARY ARTERY DISSECTION IN THE SETTING OF RECENT COVID-19 INFECTION

CASE: A 67 year old woman with no known cardiac history presented after acute onset chest pain while watching TV. The pain was described as a burning, substernal pain associated with shortness of breath and nausea. She had no prior history of similar chest pain and was recently exercising with no complaints. Her pain was not relieved by Tums, so she presented to the ED. A COVID-PCR test was positive on admission, however the patient stated she had the infection three weeks prior to presentation and was asymptomatic. She was given sublingual nitroglycerin which improved her pain. Vital signs and physical exam were unremarkable. Electrocardiogram demonstrated ST elevations in leads V3 and V4 with an initial troponin of 0.1 ng/ml (reference range <0.80 ng/ml). She subsequently was loaded with aspirin, a heparin bolus, and was taken to the cath lab. There, she was found to have a distal LAD spontaneous coronary artery dissection and underwent POBA with restoration of vessel flow. IMPACT/DISCUSSION: Spontaneous coronary artery dissection (SCAD) is a condition predominantly seen in women without conventional risks for coronary disease and an often missed cause of non-atherosclerotic ACS. Most often, patients present with typical chest pain and dynamic ECG changes. Diagnosis of SCAD is made during coronary angiogram, at times with the aid of intravascular ultrasound or OCT. Often, these patients will have associated conditions such as fibromuscular dysplasia, pregnancy/postpartum status, or connective tissue diseases. We describe a unique case of a patient without any cardiac risk factors presenting with SCAD after the resolution of an asymptomatic COVID-19 infection. Cardiac complications of COVID-19 have been extensively described, from myocarditis, myocardial infarction, heart failure, and arrhythmias. However, published literature on the association between COVID-19 and SCAD is sparse, with a few case reports reporting a possible connection. Among these, the majority of patients were acutely symptomatic with COVID-19 and subsequently developed angina during the hospitalization. There was one similar case describing a patient developing SCAD after the resolution of a COVID infection 3 months prior to presentation. However, this patient had factors which could have contributed to the SCAD. SCAD is associated with inflammatory diseases that lead to vessel wall weakness. COVID-19 induces a marked inflammatory and immune response during infection, which has been found to cause endothelial and smooth muscle damage. It is possible the inflammatory response from the infection could promote fragility of coronary vessels and lead to dissection. CONCLUSION: As the relationship between SCAD and COVID-19 continues to be explored, providers must be mindful of the potential cardiac manifestations of the virus. An index of suspicion for SCAD should be maintained in patients with COVID-19 or a history of COVID-19 presenting with acute myocardial infarction with few or no atherosclerotic risk factors.

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.

Hypoalbuminemia in COVID-19 Patients: A Predictor of Disease Severity and Guarded Outcome

Background: Pandemic of COVID-19 is spreading in all continents. There have been lots of article published on different aspects of this infection. Finding low Albumin levels in the patients of COVID-19 disease regardless of their degree of severity of infection has surprised us from the beginning. Aim: To review the hypoalbuminemia and its extent in local population presented with COVID-19 and to determine the relationship of degree of hypoalbuminemia with the severity of infection. Place and duration of study: Bahria International Hospital Lahore and Services Institute of Medical Sciences, Lahore from 1stMay 2021 to 30thSeptember 2021. Methodology: Medical records 400 COVID-19 patient's related symptoms such as cough, flu, fever, headache, tiredness, distress in breathing were included. Serum Albumin, AST and ALT as clinical bioindicators in COVID-19 patients were reviewed. Results: A significant decrease in serum albumin levels with the means and standard deviation (2.692±0.302), (χ2=344.69, df=16, p<0.001) was recorded. Whereas, a significant increase AST (U/L) and ALT (U/L) with the means and standard deviations (45.130±31.138), (χ2=214.30, df=72, p<0.001) was also noted. Analysis between survivors and non-survivors shows the level of albumin and AST/ALT was inversely proportional. Conclusion: Low albumin is associated with disease severity and poor outcomes in terms of prolonged admissions and worse respiratory failure due to alveolar endothelial damage in COVID-19.

Umbilical cord vascular thrombosis: literature review and two clinical cases

Thrombosis of the umbilical cord vessels is a rare complication of pregnancy, combined with a high level of perinatal morbidity and mortality. Anomalies of vascular attachment (velamentous attachment), pathology of the umbilical cord (hyperspiralization, short or long umbilical cord), intrauterine infections, maternal diabetes mellitus and preeclampsia as well as meconium found in the amniotic fluid are among the risk factors of developing thrombosis in the umbilical cord vessels. Here we present two clinical observations of umbilical vein thrombosis at full-term pregnancy. In both cases, during pregnancy and childbirth, no signs of umbilical cord pathology were found according to cardiotocography and Doppler ultrasound;despite this, the children were born in hypoxic state. Both newborns were transferred to the second stage of treatment due to suspected intrauterine pneumonia. Velamentous attachment, intrauterine infections as well as meconium found in the amniotic fluid were the risk factors of developing umbilical vein thrombosis described in case 1 and case 2, respectively. During pregnancy, both female patients suffered from clinically confirmed novel coronavirus infection (COVID-19) and contacted patients with COVID-19 in the third trimester of gestation. It is likely that endothelial damage caused by the novel coronavirus SARS-CoV-2 was one of the risk factors for the development of umbilical vein thrombosis, but this issue requires to be further explored.

ENDOTHELIAL CELLS AND BLOOD VESSELS – CRITICAL TARGETS FOR COVID-19-INDUCED TISSUE INJURY AND SPREAD TO DISTANT ORGANS. UNDERLYING MECHANISMS INCLUDE ENDOTHELIAL DYSFUNCTION AND INJURY

Endothelial cells (ECs) lining the blood vessels of all organs express the SARS-CoV2 receptor. In the absence of preexisting tissue damage, the virus would need to pass through the ECs to blood vessels to infect other tissues. Thus, EC are a target for SARS-CoV-2 infection and a conduit for viral dissemination to distant organs. We hypothesized that ECs infection and/ or injury are the mechanisms of COVID-19 pathology and multi-organ dissemination and injury. Methods: Human studies: We used lung, heart, kidney, and small bowel specimens obtained during autopsies (n=5) from COVID-19 patients and uninfected subjects. Studies: 1) histologic evaluation of endothelial damage and endotheliitis, 2) immunohistochemistry for vWF, PAI-1, VCAM-1, & ICAM-1. Studies in cultured human microvascular ECs (HMVECs): We cultured lung and cardiac HMVECs in the presence or absence of SARSCoV- 2 S1 and/or S2 protein (10 ng/ml) for 0 - 24 hr. Studies:1) cell viability and proliferation;2) angiogenesis on Matrigel and cell migration;3) mitochondrial membrane potential (MMP);4) RNA seq analysis;5) Western blotting for vWF, PAI-1, VCAM-1, and ICAM-1. We examined the protective effect of melatonin, Coenzyme Q10 and nerve growth factor on S1/S2 protein induced HMVEC cell damage. Results: Histopathologic examination revealed presence of endothelial abnormalities and endotheliitis with marked presence of inflammatory cells in vessel wall & lumen, and fibrinous microthrombi) in lung, heart & kidney in autopsy specimens of COVID-19 patients. Immunostaining visualized increased vWF, PAI-1, VCAM- 1, & ICAM-1 in COVID-19. In in vitro study, S1 and S2 proteins induced endothelial injury, reduced angiogenesis and phosphorylated/activated Erk and Akt proteins in cultured HMVECs. Treatment of HMVECs for 1 & 4 hours with S2 but not S1 protein increased ICAM-1 levels by 1.4- to 1.8-fold (P < 0.001). RNA Seq analysis showed that treatment of HMVECs with S1 and S2 proteins upregulated VCAM-1, ICAM-1 and E-selectin mRNA in cultured HMVECs. Melatonin, Coenzyme Q10 and NGF stimulated angiogenesis in HMVECs by 2.4-, 1.3-&1.4-fold (all P < 0.001). Conclusions: 1) Significant endothelial abnormalities, blood vessel damage and endotheliitis are present in lung, heart and kidney autopsy specimens of COVID-19 patients, 2) There is increased expression of vWF, PAI-1, VCAM-1, and ICAM- 1 in lung, heart, and kidney specimens of COVID-19 patients, 3) Treatment of cultured HMVECs with SARS-CoV-2 S1 and S2 proteins upregulates VCAM-1, ICAM-1 and Eselectin expression, 4) SARS-CoV-2 S1 and S2 proteins induce endothelial injury in cultured HMVECs, and 5) melatonin, Coenzyme Q10 and NGF stimulated EC function. These studies uncovered novel mechanism – endothelial dysfunction underlying SARS-CoV-2 and identified melatonin, Coenzyme Q10 and NGF as potential drugs for treatment of COVID- 19-induced EC injury

Potential of the triad of fatty acids, polyphenols, and prebiotics from cucurbita against COVID-19 in diabetic patients: A review

Though the scientific community of the entire world has been struggling to create preventive and therapeutic drugs for coronavirus disease 2019 (COVID-19), the role of nutraceuticals has been hitherto neglected. Established role of fatty acids and polyphenols in combating lifestyle disease can be harnessed to play a significant role in the prevention of this disease. The synergistic effect of these phytonutrients and prebiotics is anticipated to prove beneficial for prevention as well as attenuation of COVID-19 infection. Presence of fatty acids, polyphenols and prebiotics in vegetables from the Cucurbitaceae family makes them an attractive choice for being used as a nutritional supplement during COVID-19. These are known to attenuate the excessive immune response which may prove to be beneficial in preventing and mitigating COVID-19. Use of prebiotics to promote the growth of probiotics has also been recommended for the prevention and cure of COVID-19. However, no such report exists in literature that throws light on such role of cucurbita plants. The present review focuses on the role of the triad of fatty acids, prebiotics and polyphenols present in cucurbita plants in controlling systemic inflammation and endothelial damage, the two main etiopathological factors involved in COVID-19. Cucurbita plants are rich in all these components and their inclusion in diet would be an effective strategy to combat COVID-19. The main focus of the review is to discuss the role of various components of the plants of Cucurbita family, taken as dietary component, in prevention and control of the ongoing pandemic COVID19.