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Like the challenges and skepticism that faced the antibody therapeutics field over a decade ago, RNA therapeutics is facing the same. And, like the antibody therapeutics field, we are beginning to realize the clinical impact of RNA therapeutics amiss these challenges. This is most clearly highlighted with the recent approval of mRNA vaccines to prevent against SARS-CoV-2 and the first FDA approved RNAi drugs targeted to the liver. Unfortunately, RNA-based drugs targeted to cancer cells is lagging behind, even with countless years of work that has revealed the power of using RNAi for treating oncological diseases. Lack of success in this space is attributed to inability to deliver RNAi safely and effectively. A successful delivery agent requires multiple features. First, the agent must deliver the RNA specifically to the intended cells. Second, the agent must have a large therapeutic window, meaning that toxicity, if observed, should occur at doses that are orders of magnitude higher than the therapeutic dose. Third, if delivery of the RNA is by way of a specific ligand and receptor pair, as is the case herein, the RNA must successfully escape the endosome. Simply swelling the endosome is not enough if noncovalent interactions between the ligand and the receptor cannot be disrupted. Fourth, the RNA should include appropriate stabilizing modifications to increase intracellular half-life that will reduce dosing and cost. Through hard work and dedication in this space, we have come up with an inclusive, easily synthesized, intramolecular molecule that achieves all of these essential features. Moreover, the ligand used to achieve successful delivery is also being evaluated for imaging tumors localized in the central nervous system. Here, the challenges we face, the hurdles we have overcome, and the barriers that still remain to achieve success in revealing the clinical potential of miRNA as anti-cancer therapeutics will be presented.
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Infection with severe acute respiratory syndrome coronavirus (SARS-CoV-2) and the resultant syndrome COVID-19 has wrecked the entire world. The disease mostly manifests as mild viral pneumonia but in a small proportion of patients it can produce an intense inflammatory and prothrombotic state leading to multiorgan failure and even death. Varying incidences of venous thromboembolism (VTE) have been found in COVID-19 patients. This review describes the role of various pharmacological agents used prophylactically as well as therapeutically for thromboembolism in such patients. The anticoagulants which are administered as antithrombotic therapy can be used parenterally (heparin and direct thrombin inhibitors) or orally (direct oral thrombin inhibitors). The mechanism of action, pharmacology, usage, and adverse effects of such agents has been discussed especially in the context of ongoing COVID-19 pandemic. As a result of various completed and ongoing clinical trials, scientific community has collected promising evidence and formulated guidelines regarding the role of anticoagulants in COVID-19 patients. © The Author(s), under exclusive licence to Springer Nature Singapore Pte Ltd. 2021.
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In April 2020 in order to prevent the spread of the new coronavirus infection COVID-19 on the territory of the Russian Federation, strict quarantine measures were introduced. In the shortest possible time, a large number of general hospitals were repurposed into COVID hospitals, recommendations were issued on the management of patients with a new coronavirus infection based on the existing global experience. The limited resources of the healthcare system in a pandemic require research into the pharmacoeconomic aspects of COVID-19. In the course of the study, a continuous retrospective analysis of the case histories of 6255 patients admitted to the Central Clinical Hospital RZD-Medicine was carried out. During the study period, 22% of patients received biological therapy. The average mortality rate of patients on biological therapy is 11.6%. An individual selection of the therapeutic dose of low molecular weight heparins was carried out, which showed high clinical efficacy. The developed methods were assessed from the perspective of pharmacoeconomics. The increase in the degree of damage to the lung tissue in patients with COVID-19, as well as the presence of concomitant diseases, entails an increase in the cost of treatment. Biotherapy can reduce the cost of treating patients with CT-4 by 16% by reducing the length of stay in the intensive care unit, the need for mechanical ventilation and reducing mortality.Copyright © 2021 Infectious Diseases: News, Opinions, Training. All rights reserved.
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Background: COVID-19 carries a high risk of vascular thrombosis. This joint analysis of two randomized-controlled trials (RCTs) aims to assess the safety and efficacy of enoxaparin at therapeutic dose compared to prophylactic dose in people hospitalized with COVID-19. Method(s): A joint analysis of two RCTs, COVID-19 HD (NCT044082359) and EMOS-COVID (NCT04646655), was performed. Both studies enrolled inpatients with COVID-19- associated respiratory compromise (as identified by respiratory rate >=25 breaths/min or arterial oxygen saturation <=93% at rest or PaO2/FiO2 <=300 mmHg for COVID-19 HD and by PaO2/FiO2 <=250 mmHg for EMOS-COVID) and/or coagulopathy (D-dimer > 2000 ng/ml for both RCTs or sepsis-Induced coagulopathy score >4 for COVIDHD). In both RCTs patients were randomly assigned to two arms: enoxaparin at prophylactic dose (standard 4.000 IU;in the EMOS-COVID 6000 IU if body weight >100 kg) and at therapeutic dose (70 U/Kg every 12 h). The primary efficacy endpoint of the joint analysis was clinical worsening, defined as the occurrence of at least one among: in-hospital death;acute myocardial infarction;symptomatic arterial or venous thromboembolism;need of either Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) in patients who were in standard oxygen therapy at randomization;need for IMV in any patient. The primary outcome was assessed as time-to-event, described with hazard ratio (HR) and with Kaplan-Meier survival estimate. The primary safety endpoint was major bleeding for both trials and for the joint analysis. Result(s): COVID-19 HD enrolled 142 people between July 2, 2020 and February 15, 2022, while EMOS-COVID enrolled 141 people from July 27, 2020 to June 5, 2021, resulting in 283 patients included in this joint analysis. Two-hundredseven (73.1%) were males, with a mean age of 61.1 years (SD +/-10.7), a mean BMI of 29.7 kg/m2 (SD +/-5.0), and 115 (40.6%) were on NIV or Cpap at randomization, with no significant difference between the study groups. 21/139 people in the high dose group reached the primary endpoint compared to 32/144 in the prophylactic group (HR 0.63, 95%CI 0.36 to 1.10). Figure 1 shows the Kaplan- Meier survival estimates of clinical worsening. No major bleeding was observed during the study time. Conclusion(s): The results of this joint analysis did not highlight significant differences in clinical worsening between COVID-19 patients that received enoxaparin at therapeutic compared to prophylactic dose. (Figure Presented).
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Introduction Edoxaban is a non-vitamin K dependent oral anticoagulant (NOAC) licensed for venous thromboembolism (VTE) treatment or stroke prevention in atrial fibrillation (SPAF). Major surgical procedures are not uncommon in anticoagulated patients but data on perioperative edoxaban management are scarce. Method Using data from the prospective DRESDEN NOAC REGISTRY we extracted data on major surgical procedures in patients who took edoxaban within the preceding 7 days. Periinterventional edoxaban management patterns and rates of outcome events were evaluated until day 30 after procedure. Results Between 2011 and 2021, 3448 procedures were identified in edoxaban patients, including 287 (8.3 %) major procedures. Overall, patient characteristics were comparable for major and non-major procedures, but significant differences existed with regard to gender, concomitant antiplatelet therapies and the proportion of patients with a CHA2DS2-VASc score >= 2 (Table 1). Major procedures consisted of orthopaedic/trauma surgery (44.3 %);open pelvic, abdominal or thoracic surgery (30.4 %), central nervous system surgery and procedures (13.9 %), vascular surgery (9.1 %) and extensive wound revision surgery (2.4 %). A scheduled interruption of edoxaban was observed in 284/287 major procedures (99 %) with a total median edoxaban interruption time of 11.0 days (25- 75th percentile 5.0-18.0 days). Heparin bridging was documented in 183 procedures (46 prophylactic dosages, 111 intermediate and 26 therapeutic dosages). Overall, 7 (2.4 %;95 %-CI 1.2 %-4.9 %) major cardiovascular events (5 VTE, 2 arterial thromboembolic events) occurred and 63 bleeding events were observed in 287 major procedures (22.0 %;95 %-CI 17.6 %-2.71 %), comprising of 38 ISTH major bleeding events (13.2 %;95 %-CI 9.8 %-17.7 %) and 25 ISTH CRNM bleedings (8.7 %;95 %-CI 6.0 %-12.5 %). Rates of major cardiovascular events with or without heparin bridging were comparable (6/183;3.3 %;95 %-CI 1.5 %-7.0 % vs. 1/36;2.8 %;95 %-CI 0.5 %-14.2 %;p = 0.7173). ISTH major bleeding occurred numerically more frequent in patients receiving heparin bridging (30/183;16.4 %;95 %-CI 11.7 %-22.4 %) versus procedures without heparin bridging (2/36;5.6 %;95 %-CI 1.5 %-18.1 %;p = 0.1542) (Fig. 1). Within 30 days of follow up, 6 patients died (2.1 %;95 %-CI 1.0 %-4.5 %) with causes of death being a ruptured truncus coeliacus following palliative angioplasty for an infiltrating pancreas cancer (ruled as fatal bleeding), septic organ failure, pneumocystis jirovecii pneumonia, COVID-19-pneumonia, septic complications following clipping of a ruptured cerebrovascular aneurism or terminal malignant disease. No fatal cardiovascular event occurred. Conclusion Within the limitations of our study design, periprocedural edoxaban management seems effective and safe in routine care. Use of heparin bridging seems to have limited effects on reducing vascular events but may increase bleeding risk. (Table Presented).
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Background: Coagulopathy-associated thrombotic events, leading to venous and arterial thromboembolism are highly prevalent among COVID-19 patients. While pharmacologic thromboprophylaxis are the mainstays of treatment, the consideration for an escalated therapeutic dose anticoagulation in the non-critically ill remained a highly debated issue. Objective(s): This meta-analysis sought to evaluate whether therapeutic dose anticoagulation among hospitalized non-critically ill COVID-19 patients reduce the composite primary efficacy outcome (VTE, ATE or death), and the secondary outcomes of major bleeding risk and progression to intubation and mechanical ventilation compared to prophylactic dose anticoagulation. Methodology: After extensive search, screening based on predefined inclusion and exclusion criteria and critical appraisal by 3 independent reviewers 3 eligible open label RTCs with a total of 1492 patients were included in the study. The event rates of the primary and secondary outcomes were assessed after 21-30 days of hospitalization. Result(s): The Risk Ratio for VTE, ATE and death is higher in the prophylactic dose anticoagulation (RR 1.42;95% CI 1.08-1.86), p-value <0.05) compared to therapeutic dose anticoagulation. The risk for major bleeding (RR 0.70;95% CI 0.30-1.62, p-value >0.05) and progression to intubation and mechanical ventilation (RR of 1.13;95% CI 0.93-1.38, p-value >0.05) were not significantly different between the dosing regimens. Conclusion(s): Therapeutic-dose regimen among non-critically ill admitted COVID-19 patients conferred lower risk for the composite primary outcome of VTE, ATE and death with similar risk for bleeding compared to prophylactic dose regimen. Due to this outcome advantage, therapeuticdose anticoagulation can be considered as initial regimen in the noncritically ill COVID-19 patients in the absence of contraindications.
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Background COVID-19 has been previously associated with thromboembolism. We present a unique case of a patient who was compliant with warfarin and yet developed breakthrough Deep Venous Thrombosis after recently being diagnosed with COVID-19. Case A 49-year-old female with past medical history of rheumatic fever complicated with mitral stenosis and treated with mechanical mitral valve replacement in 2003, presented with right-sided leg swelling, warmth, and pain for the past 1 week. She tested positive for COVID-19 almost 2 weeks ago but was not hospitalized or treated due to minimal symptoms. She had been on warfarin for the last 19 years due to underlying mechanical valve with an INR (international normalized ratio) goal of 2.5-3.5. On examination, the right calf was swollen and tender to palpation. Homan sign was positive. INR was elevated to 9.88 (a month ago it was within the therapeutic range of 2.5-3.5). The rest of the lab work up including fibrinogen levels, PT, aPTT, CBC, and CMP was unremarkable. A lower extremity venous duplex was performed that came back remarkable for acute right popliteal DVT. Decision-making Warfarin was held considering elevated risk of bleeding. INR was repeated daily and once it was below 2.5, therapeutic dose of enoxaparin 1mg/kg twice daily was started for 3 months. Due to limited anticoagulation options, a shared decision was made to place the patient back on warfarin, since she was out of the window of COVID-19 infection. She was not a candidate for DOAC's considering her mechanical valvular heart disease history and patient did not want to consider invasive interventions as well. Conclusion Our case study is the first ever reporting warfarin failure with supratherapeutic INR due to COVID-19 infection. It also raises concerns if warfarin is safe to use in COVID-19 patients, which might need further research studies to have clear answers. In patients with mechanical heart valves and supratherapeutic INR who present with concerns of warfarin failure, treatment options are limited. Recommended management is holding warfarin to achieve therapeutic INR levels, switch to enoxaparin temporarily, and eventually placement of IVC filter.Copyright © 2023 American College of Cardiology Foundation
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Introduction: The optimal anticoagulant treatment regimen in hospitalized COVID-19 patients is debated amid studies investigating the effectiveness of different dosing strategies. Aims and Objectives: The aim of this study was to compare the rates of disease progression and mortality in patients treated with LMWH according to a protocol based on baseline D-dimer levels (prophylactic dose when level is below 1000 ng/mL, intermediate dose between 1000 and 3000 ng/mL, therapeutic dose when levels exceed 3000 ng/mL)(on-protocol) and those treated with a fixed-dose regimen (off-protocol). Method(s): This was a retrospective analysis of all patients admitted to a university hospital for COVID-19 pneumonia during a one-year period. Out of a total of 384 patients (mean age 61.5+/-15.9y, 216 male), 294 patients with complete data composed the study group. Result(s): 174 patients were treated on-protocol and 120 patients were off-protocol. The on-protocol group had higher CRP, ferritin, LDH and D-dimer levels and lower SpO2/FiO2 levels at admission. Disease progression developed in 44 out of 174 on-protocol patients (25.3%) vs 53 of 120 off-protocol patients (44.2%) during the follow-up (p=0.001) and 29 (16.7%) vs 32 (26.7%), respectively, died in hospital (p=0.041). Logistic regression analysis was performed and included age, presence of comorbidities, LMWH regimen, baseline SpO2/FiO2, CRP and LDH levels as independent variables. The presence of cardiac comorbidity, age and LDH levels, but not LMWH treatment regimen, were associated with both disease progression and mortality. Conclusion(s): A d-dimer-driven LMWH treatment protocol is not associated with better clinical outcomes in hospitalized COVID-19 patients.
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Since it first surfaced, the new Coronavirus has multiplied and mutated into different forms, leading to a significant impact on people's lives. COVID-19's long-term impact is not completely known: It can only be hypothesized based on the prior outbreak of severe acute respiratory syndrome (SARS). Avascular necrosis (AVN) is one of these consequences, which if left untreated can lead to catastrophic events and bone collapse. It's important to remember that individuals who have recovered from COVID-19 infection are still at risk of developing AVN. The pathological findings in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are very similar to those seen in severe acute respiratory syndrome coronavirus (SARS-CoV) infection. We present cases of 27- and 69-years old men with no comorbidities admitted with complaints of bilateral hip pain post Covid treatment with corticosteroids and antivirals. The diagnosis was established based on history, physical examination, and magnetic resonance imaging (MRI). The use of corticosteroids in the treatment of SARS-CoV-2 infection has saved many lives, and it is still advised for moderate to severe cases on a short-term basis. The long-term use of corticosteroids is associated with numerous side effects. One of the most prevalent side effects of steroids is avascular necrosis of the femoral head, which is aggravated by the disease process. Early detection of avascular necrosis is very crucial in its management due to its high progression rate. Low therapeutic doses of corticosteroids with minimal effective duration remain the key to halting its occurrence.
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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
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SESSION TITLE: Treatment Debates in Critical Care SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/17/2022 12:15 pm - 1:15 pm PURPOSE: Studies have reported various estimates of the incidence of venous thromboembolism (VTE) and major bleeding among hospitalized patients with COVID-19, with varying doses and types of anticoagulation used in each study. While patients hospitalized with COVID-19 may have a higher incidence of VTE, there may also be an increased incidence of bleeding. The risk of VTE needs to be weighed against the increased risk of bleeding when considering higher than standard dose prophylactic anticoagulation. This review examines the incidence and risk of thromboembolism and major bleeding in hospitalized patients with COVID-19 pneumonia across randomized controlled trials. METHODS: Online databases including PubMed, CINAHL, Ovid, and Cochrane were searched from the inception of literature through January 11th, 2022, following the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines. Only articles published in the English language were included. s, case reports, and case series were excluded from this systematic analysis. Out of 168 studies, 8 randomized controlled trials were selected for a systematic review. RESULTS: In the 8 studies considered for this review, a total of 4,913 COVID patients were randomized to either prophylactic or therapeutic dose anticoagulation. Thrombotic events, major bleeding, and overall mortality were set as endpoints. Seven out of eight studies used heparin/low molecular weight heparin and only one used rivaroxaban. All except one study (Perepu et. al) reported a lower percentage of thrombotic events in the therapeutic group. Similarly, all except one study (Sholzberg et. al) reported a higher percentage of major bleed in the therapeutic group. In 4 out of 8 studies higher overall mortality was reported in the therapeutic group. However, only two values reported were statistically significant. Syropoulos et al reported a lower thrombotic event percentage in the therapeutic group with a p-value of <0.001% and Sholzberg et al reported a lower mortality percentage in the therapeutic group with the p-value of 0.006%. CONCLUSIONS: Therapeutic anticoagulation in COVID is a double-edged sword, decreased incidence of thrombotic events and an increased incidence of major bleeding was seen in the patients on therapeutic dose anticoagulation. Only one study reported a statistically significant decreased mortality in the therapeutic group and none of the studies reported a statistically significant major bleeding in the therapeutic group. CLINICAL IMPLICATIONS: Based on the finding of this study we would recommend against the use of therapeutic anticoaguation in hospitalized patients with COVID-19. DISCLOSURES: No relevant relationships by Faiz Anwer No relevant relationships by Ahmed Elkhapery No relevant relationships by Unaiza Faizan No relevant relationships by Deeptanshu Jain
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Objective. To clarify the features of the defect in the function of NK cells, T lymphocytes, the interferon system in patients with moderate and severe COVID-19. Patients and methods. Tests of the peripheral blood of 50 COVID-19 patients aged 61(57–71) and having the moderate and severe disease were performed. The following parameters were measured: the quantity of CD3+CD19–, CD3+CD4+, CD3+CD8+ T lymphocytes, NK – (CD3–CD16+CD56+), and TNK – CD3+CD16+CD56+ with expression density considered membrane receptors (MFI) (FC 500 Beckman Coulter, USA), the levels of IFN-α, IFN-γ, IL-6, TNF-α cytokines (IFA). Results. Combined immunodeficiency associated with quantitative and functional defects in NK, T lymphocytes and their subsets was revealed in moderate and severe COVID-19. An imbalance of cytokines has been established: blockade of the production of IFN-α and IFN-γ against the background of a significant increase in IL-6 and TNF-α, which negatively affects both the number and functionality of the participants in the immune response and is associated with a severe course and poor prognosis of COVID-19. Conclusion. The data obtained demonstrate the need to develop new strategies and tactics for the treatment of COVID-19, including replacement systemic therapy with recombinant IFN-α2b in combination with antioxidants (Viferon®) in adequate therapeutic doses, aimed at restoring the normal functioning of T lymphocytes, NK and the interferon system.
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Introduction: The difference between the end-tidal carbon dioxide (ETCO2) and arterial carbon dioxide (PaCO2) represents alveolar dead space. This is commonly characterised as the alveolar dead space fraction (AVDSf), which is calculated using the equation (PaCO2 -ETCO2)/PaCO2. The AVDSf can be easily calculated in the intensive care unit using routinely documented data. Pulmonary embolism (PE) increases dead space and so it is hypothesised that AVDSf may be a useful diagnostic tool for PE. Research in the Emergency Department setting has shown that AVDSf can help exclude PE when combined with other diagnostic tests. Patients with COVID-19 are at high risk of concurrent PE but diagnosis in invasively ventilated patients is challenging due to limitations with routine assessment, infection control issues and clinical instability. No studies have assessed the potential role of AVDSf in this diagnostic process. Objective: We sought to investigate the diagnostic utility of AVDSf prior to Computed Tomography Pulmonary Angiogram (CTPA) in invasively ventilated patients with COVID-19 and suspected PE. Methods: This was a retrospective, single-centre cohort study, delivered as a service evaluation with formal R&D approval and oversight (Ref: S20HIP17). All invasively ventilated patients with confirmed COVID-19 who underwent CTPA between March 2020 and April 2021 at a large UK intensive care unit were included. AVDSf values were derived from routine data taken at the closest available timepoint prior to the CTPA. Consultant radiologist reporting of the CTPA images was used as the reference standard for PE diagnosis. Results: 48 CTPAs were included in the final analysis. Therapeutic-dose anticoagulation was given before CTPA in 45.8% (n=22) of cases. The mean pre-CTPA PaO2/FiO2 (P/F ratio) was 134 mmHg (IQR 56.1). The 28-day mortality was 70.4%. 52.1% of CTPAs demonstrated a PE (n=25). Of these PEs, 8 were classified as central or lobar, 11 as segmental and 6 as subsegmental. The mean difference in AVDSf between PE positive CTPA and PE negative CTPA was 0.02 (0.34 vs 0.32). This difference was not statistically significant (p=0.255). At a threshold of 0.33 the sensitivity was 0.56 and specificity was 0.48. AVDSf did not provide diagnostic utility at any cut-off point (AUC=0.561). Conclusion: This study is the first to investigate the utility of AVDSf in diagnosing PE in COVID-19 patients. Our findings suggest there is no value in using single AVDSf values to guide decisions on diagnostic imaging in patients with severe COVID-19 and suspected PE. Given research has demonstrated the potential for AVDSf to reduce imaging requests in patients with a low pre-test probability of PE, further research may be appropriate in ambulatory COVID-19 patients. Additionally, the interpretation of trends in AVDSf, rather than its calculation at a single timepoint, could be investigated as a diagnostic tool for PE in critically unwell, ventilated patients.
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A 68-year-old man was referred to the general surgeons on account of his abdominal pain of unknown cause. He had contracted COVID-19, 9 days prior. CT chest abdomen and pelvis revealed an extensive thrombus extending from the portal vein to the superior mesenteric vein. Further investigation ruled out haematological causes, and COVID-19 was determined to be the cause. He was treated with an extended course of therapeutic dose low molecular weight heparin under the guidance of the haematology team. He was discharged once he was clinically stable and pain-free, with a plan to be followed up by both the surgeons and haematologists. This case highlights the different ways in which COVID-19 presents, and the need for clearer guidance on the treatment and prevention of thromboembolism in COVID-19.
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Aim and background: The high mortality associated with the thrombotic events in hospitalised COVID-19 patients resulted in the usage of anticoagulants in varying doses. Whether the high-dose anticoagulants have led to better outcomes or higher incidence of clinically significant bleeding events is still debatable. Objectives: To find the incidence of clinically significant bleeding events in moderate to severe COVID-19 patients on therapeutic anticoagulation and the factors influencing these events. Materials and methods: In our retrospective, single-centre, cohort study of 155 critically ill COVID-19 patients we observed the incidence of clinically significant bleeding. Multivariate regression models were used to evaluate the association between anticoagulant regimen, coagulation, and inflammatory markers with the incidence of bleeding and thrombotic events. Results: The incidence of Clinically Relevant Non-Major Bleeding (CRNMB) was 33.5% (26.17-41.46%,) and major bleeding was 9.03% (5.02-14.69%). The anticoagulation intensity at baseline had a very high odds of major bleeding when Enoxaparin and dual antiplatelet therapy were used together (adjusted OR of 434.09 [3.81-49502.95], p < 0.05). At admission, bleeders had a poorer P/F ratio with more patients on invasive ventilation. At the time of bleeding, the bleeders had a higher d-dimer, ferritin, CRP, and procalcitonin. The subhazard ratio (SHR) for death in bleeders was 3.35 (95% CI, 1.97-5.65;p < 0.001). Conclusion: The incidence of bleeding in critically ill COVID-19 patients on therapeutic anticoagulation increases with the severity of the disease as well as with concurrent use of dual antiplatelets. Major bleeding may also contribute to higher mortality.
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Background: Multiple sclerosis (MS) is a chronic disabling disease associated with negative effects on quality of life (QoL), including physical and mental health. The objective of this investigation was to evaluate the change in QoL for patients with highly active relapsing MS at 1 year after initiating treatment with cladribine tablets (CladT), by assessing changes in the physical and mental health composite scores of Multiple Sclerosis Quality of Life-54 (MSQoL-54). Material(s) and Method(s): In CLARIFY-MS (NCT03369665), patients with highly active relapsing MS were assigned to receive CladT 3.5 mg/kg cumulative dose over 2 years. Patients were recruited as per the EU label. Results in this interim analysis, conducted prior to the second year of treatment, were assessed using a mixed-effects linear model. Analyses were also conducted for cohorts separated by treatment naïve/prior disease-modifying therapy (DMT), and MSQoL reporting performed before/after the start of the COVID-19 pandemic, as defined as the first reported fatality within each country. Result(s): Of the 482 patients treated with CladT, 70.1% were female and the mean age was 37.4 years. Of the 426 patients who provided MSQoL-54 data, statistically significant (p<0.0001) improvements from Baseline to Month 12 were observed for physical and mental health composite scores with estimated changes of 4.51 (95% confidence interval [CI] 3.24–5.77) and 4.53 (95% CI 3.00–6.05), respectively. Similar trends were apparent for treatment naïve (n=121) and prior DMT (n=305) cohorts. There was no indication that the start of the COVID-19 pandemic had an impact on MSQoL-54 reporting. Regarding safety, 322 patients (66.8%) experienced at least one treatment-emergent adverse event, most commonly headache (16%), nasopharyngitis (9%), and lymphopenia (9%). The majority of observed post-baseline lymphopenia events were grade 1–2;fewer patients reported grade 3 lymphopenia, no grade 4 lymphopenia was observed. Conclusion(s): With only half a therapeutic dose of CladT, this interim analysis demonstrates a statistically significant improvement in the physical and mental health composite scores of MSQoL-54 at 1 year. No new safety concerns were found in this 1-year interim analysis, with no new severe or opportunistic infections that could have an impact on the established benefit:risk profile of CladT in MS.
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Lead Author's Financial Disclosures: Nothing to disclose. Study Funding: None. Background/Synopsis: Extensive evidence exists in support of a causal association of elevated triglyceride-rich lipoprotein (TRL) levels with the risk of atherosclerosis progression. Hypertriglyceridemia has been established as a risk factor for venous thrombosis, including a 2- fold increase in the risk of venous thrombosis in postmenopausal women. However, there is limited data on the role of hypertriglyceridemia in the arterial thrombosis. Objective/Purpose: Not Applicable. Methods: Case description: A 51-year-old white female with hypertension and type 2 diabetes (hemoglobin A1C, 7.4%) was transferred for further management of newly diagnosed bilateral renal and splenic infarcts. No risky habits were elicited except for the use of combined hormonal contraceptives over the past two years to control menorrhagia. Family history was significant for hypertriglyceridemia. Her physical exam was unremarkable. Testing for COVID-19 was negative. An extensive hypercoagulable and autoimmune work-up was unremarkable. Fasting lipid profile was significant for elevated levels of triglycerides, 1,274 mg/dL (replicated on two separate occasions), very low-density lipoprotein-cholesterol, 255 mg/dL, and non-high-density lipoprotein-cholesterol, 214 mg/dL, directly measured low-density lipoprotein cholesterol, 39 mg/dL and lipoprotein(a), 6 mg/dL. There was no structural pathology on the echocardiogram, including no interatrial shunt or intracardiac thrombus. Her whole-body computed tomography angiography revealed a focal calcified protruding thrombus in the distal thoracic aorta. No significant plaque was seen elsewhere in the aorta. Results: Decision-making. The posterior thrombus in the distal thoracic and proximal abdominal aorta was determined as a culprit for the visceral organ infarcts. Over the course of the hospital stay her abdominal pain gradually resolved. Treatment with low dose aspirin and therapeutic dose of low-molecular weight heparin was initiated followed by apixaban and aspirin on discharge. She was started on atorvastatin 40 mg, fenofibrate 145 mg, icosapent ethyl 4 g, resulting in a 70% reduction in the triglycerides levels (306 mg/dL). In 3 months, her repeat CT angiography showed significant resolution of the aortic atherothrombosis with no signs of aortic wall inflammation. At the 6-month follow-up visit she was switched to dual antiplatelet therapy with a plan to repeat imaging in 6 months. Conclusions: This case illustrates challenges in managing patients with arterial thrombosis in the setting of familial hypertriglyceridemia. Apart from severely elevated triglycerides no other etiology was evident. We propose further investigation of the prothrombotic properties of TRL and the role of targeted triglyceride-lowering therapies on atherothrombotic outcomes.
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INTRODUCTION: Covid- 19 has been associated with various fungal infections in immunocompetent/immunocompromised patients. We report the second case of PCP pneumonia coinfection in a HIV- uninfected man with COVID-19. CASE: A 52 y/o man with PMH of hyperlipidemia, gout, viral myocarditis and no prior immunodeficient conditions was admitted to hospital for COVID-19 SARS (Severe Acute Respiratory Syndrome) CoV- 2 Pneumonia. He was initially treated with Dexamethasone 6mg/day, Remdesivir and Tocilizumab x 2doses and oxygen therapy. On day 4, he was transferred to ICU for acute hypoxemic respiratory failure requiring NIV eventually requiring intubation with Fio2-60-90%. His course was complicated by AKI, septic shock requiring pressor for BP support. He received empiric ceftriaxone and Hydrocortisone for suspected adrenal insufficiency. Despite antibiotics, labs showed increasing WBC count with decreasing procalcitonin. Blood/urine cultures: no growth. Tracheal cultures: Ceftriaxone-sensitive E.coli therefore was continued on ceftriaxone. On ICU day3, he was still febrile so was started on prophylactic Bactrim for PCP suspecting immunosuppression although he was never treated with long term high dose steroids. Fungal cultures, Aspergillus, HIV, Beta-D glucan - negative. He was afebrile after 7days of antibiotics and PCP testing was done to discontinue Bactrim. Tracheal aspirate culture reported positive for PCP diagnosed with IFA stain. LDH - 471 but is an unreliable marker in the setting of covid pneumonia. HRCT was not attained due to unstable hemodynamics. Prophylactic Bactrim was then switched to therapeutic dose and also started on Prednisone 40mg twice daily on tapered dose. DISCUSSION: PCP is an infection commonly seen in immunocompromised individuals but may colonize healthy individuals remaining asymptomatic and serving as a reservoir to transmit and affect immunocompromised hosts with immunodeficiency syndromes/malignancy/organ transplant. Diagnosis is made via identification of organism via staining/PCR. Based on previous case series reported by Mayo Clinic amongst HIV- uninfected individuals, an average dose of steroids was 30mg/ day (minimum-16mg/ day) for an average duration of 12 weeks (minimum-8weeks) to acquire PCP infection. Our subject was treated with Hydrocortisone dose equivalent to a prednisone dose ∼ 75mg/day x 1 week which may have induced immunosuppression or due to COVID-19 infection itself making him susceptible for PCP infection. First case of PCP pneumonia coinfection in COVID-19 (recovered) was reported in March 2021. CONCLUSION: Our case report is unique for two reasons, PCP diagnosis via tracheal aspirate and two, detected in COVID-19 infected patient post prophylaxis. PCP coinfection with COVID-19 should be identified and treated.
ABSTRACT
Background: There is significant evidence to support that patients with the Coronavirus disease 2019 (COVID-19) have a higher propensity to develop thrombotic events. COVID-19 patients in intensive care units (ICU) have an increased rate of venous thromboembolism (VTE), ranging from 17% to 25%. Apart from acute respiratory failure, coagulopathy remains a common abnormality in these patients, within creased levels of both fibrinogen and D-dimers. Anticoagulation using subcutaneous heparin is known to reduce the incidence of thromboembolic events;although concern regarding over-anticoagulation resulting in excessive bleeding remains an impediment. Objective: Study Design: Retrospective study Place and Duration of Study: Bahria International Hospital Lahore from 1st May 2020 to 31st October 2020. Methodology: One hundred and eight patients admitted in the ICU were enrolled. The incidence of thrombotic and bleeding events in patients treated with subcutaneous heparin during their admission with moderate to severe COVID19 in the ICU. All patients were given therapeutic dosed anticoagulation universally unless contraindicated. Results: Thromboembolic events were seen in 10 patients while 98 patients did not have any such event. 3 patients had a bleeding event during their stay. Conclusions: Using prophylactic therapeutic dose anti-coagulation therapy is an effective and safe strategy in COVID-19 patients and it is associated with improved outcomes in terms of reducing morbidity and mortality.
ABSTRACT
Anticoagulant therapy becomes critical to preventing further complications caused by the hypercoagulative state in COVID-19 patients. The optimal dose and time-dependent administration of anticoagulants for COVID-19 patients remains unknown. The purpose of this study was to determine the mortality and bleeding risks of anticoagulants administered based dose dependent and time-dependent manner for COVID-19 patients. We collected data from articles that compared prophylactic and therapeutic anticoagulants in COVID-19 patients recorded online from studies that were published around 2020 to 2021. We were obtained the articles from a scientific database such as ScienceDirect, Cochrane, ProQuest, PubMed, and Google Scholar based on the inclusion criteria. Data analysis was conducted using Review Manager Version 5.4.1. Based on time dependent-manner, therapeutic anticoagulant showed no benefit in reducing mortality (RR = 0.69;95% CI = 0.47 to 1.02). Beside, based on dose-dependent manner, prophylactic anticoagulant was found beneficial to prevent mortality (RR = 0.49;CI 95%;p = 0.02) compared to therapeutic. Therapeutic anticoagulants also showed higher risk of bleeding (RR = 0.27;CI 95%;p < 0.000001) compared to prophylactic. Therapeutic have no significantly benefit over prophylactic dose in reducing mortality rates. Therapeutic anticoagulant has a higher risk of bleeding in patients with COVID-19. Administer prophylactic dose is recommended due to the fewer side effects compared to the therapeutic dose.