Relationship Between Pulmonary Vascular Dilatation and Clinical Symptoms on Chest Computed Tomography in Patients with Confirmed COVID-19

BACKGROUND: Chest computed tomography (CT) is important in establishing a diagnosis, including detecting pulmonary vascular dilatation as a radiological feature of COVID-19, and consequently in providing comprehensive treatment. AIM: This study aimed to analyze the relationship between pulmonary vascular dilatation and clinical symptoms on chest CT in patients with confirmed COVID-19. PATIENTS AND METHODS: This retrospective and cross-sectional study was conducted at the Radiology Department of Dr. Wahidin Sudirohusodo Hospital and Hasanuddin University Hospital, Makassar, Indonesia, from July to September 2021 in a total of 231 patients with confirmed COVID-19. The Chi-squared correlation test was used to analyze the data, with p < 0.05 considered significant. RESULT(S): Pulmonary vascular dilatation was observed in 31 (37.8%) of the 82 patients with confirmed COVID-19 with mild-to-moderate clinical symptoms and in 51 (69.8%) of the 73 patients with confirmed COVID-19 with severe-to-critical clinical symptoms. The incidence of pulmonary vascular dilatation increased in the patients with confirmed COVID-19 with severe-to-critical clinical symptoms. The chief complaints of most patients were cough, shortness of breath, and fever. In the patients with mild-to-moderate clinical symptoms, the most common chief complaint was cough (n = 53;64.63%), while in those with severe-to-critical clinical symptoms, the most common chief complaint was shortness of breath (n = 60;82.19%). CONCLUSION(S): Based on chest CT findings, pulmonary vascular dilatation is related to clinical symptoms in patients with confirmed COVID-19.Copyright © 2023 Sri Asriyani, Nikmatia Latief, Andi Alfian Zainuddin, Muzakkir Amir, Bachtiar Murtala, Hendra Toreh.

The evolving landscape of pulmonary arterial hypertension clinical trials

Although it is a rare disease, the number of available therapeutic options for treating pulmonary arterial hypertension has increased since the late 1990s, with multiple drugs developed that are shown to be effective in phase 3 randomised controlled trials. Despite considerable advancements in pulmonary arterial hypertension treatment, prognosis remains poor. Existing therapies target pulmonary endothelial dysfunction with vasodilation and anti-proliferative effects. Novel therapies that target proliferative vascular remodelling and affect important outcomes are urgently needed. There is need for additional innovations in clinical trial design so that all emerging candidate therapies can be rigorously studied. Pulmonary arterial hypertension trial design has shifted from short-term submaximal exercise capacity as a primary endpoint, to larger clinical event-driven trial outcomes. Event-driven pulmonary arterial hypertension trials could face feasibility and efficiency issues in the future because increasing sample sizes and longer follow-up durations are needed, which would be problematic in such a rare disease. Enrichment strategies, innovative and alternative trial designs, and novel trial endpoints are potential solutions that could improve the efficiency of future pulmonary arterial hypertension trials while maintaining robustness and clinically meaningful evidence.Copyright © 2022 Elsevier Ltd

Pleiotropic Effects of Nitric Oxide on SARS-CoV-2 Infections

Infection by beta-coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coron-avirus-2) alters the homeostasis of the vascular endothelium, promoting an inflammatory state which causes damage and favors the prothrombotic state. The direct viral cytotoxicity induced by the SARS-CoV-2 leads to endothelial cell death;thus, altering the vessel functions. Moreover, SARS-CoV infection induces endothelial dysfunction (ED) and reduces the levels of nitric oxide (NO);thus, aggravating the vascular injuries, which promotes thrombotic events due to an altera-tion in the homeostasis. NO is a pleiotropic molecule that induces vasodilation, regulates the immune response, inhibits platelet aggregation, and decreases the cellular adhesion to vascular en-dothelium. Moreover, NO acts directly against invasive agents, exhibiting antibacterial, antiviral, and antifungal activity. High levels of NO result in an increase in the ED, causing an inflammatory amplification that aggravates the disease through undesirable positive feedback. The objective of this review was to present and discuss the involvement of NO on ED in SARS-CoV-2 infections. This review may also highlight new perspectives for therapeutic interventions through the supple-mentation of exogenous NO. The maintenance of homeostatic NO levels could represent a useful approach in the prevention of coronavirus-induced ED.Copyright © 2021 Bentham Science Publishers.

ENDOTHELIAL INFLAMMATION AND DYSFUNCTION INDUCED BY SARS-COV-2 SPIKE PROTEIN 1 INVOLVE ADAM17 AND INTERFERON ACTIVATION PATHWAYS

Objective: COVID19 is associated with vascular inflammation. IFN-alpha (IFNa) and IFN-lambda3 (IFNl3) are potent cytokines produced in viral infections. Their effects involve interferon-stimulated genes (ISGs) and may influence expression of angiotensin-converting enzyme 2 (ACE2), the receptor for S-protein (S1P) of SARS-CoV-2. We hypothesized that S1P-induced immune/inflammatory responses in endothelial cells (EC) are mediated via IFN-activated pathways Design and methods: Human ECs were stimulated with S1P (1 mg/mL), IFNa (100ng/mL) or IFNl3 (100IU/mL). Because ACE2, ADAM17 and TMPRSS2 are important for SARS-CoV-2 infection, we used inhibitors of ADAM17 (marimastat, 3.8 nM), ACE2 (MLN4760, 440pM), and TMPRSS2 (camostat, 50 mM). Gene and protein expression was investigated by real-time PCR and immunoblotting, respectively. Vascular function was assessed in mesenteric arteries from wild-type (WT) normotensive and hypertensive (LinA3) mice and in ISG15-deficient (ISG15KO) mice. Results: S1P increased expression of IFNa (3-fold), IFNl3 (4-fold) and ISGs (2-fold) in EC (p < 0.05). EC responses to IFNa (ISG15: 16-fold) were greater than to IFNl3 (ISG15: 1.7-fold) (p < 0.05). S1P increased gene expression of IL-6 (1.3-fold), TNFa (6.2-fold) and IL-1b (3.3-fold), effects that were amplified by IFNs. Only the ADAM17 inhibitor marimastat inhibited S1P effects. IFNa and IFNl3 increase protein expression of ADAM17 (27%) and TMPRSS2 (38%). No changes were observed on ACE2 expression. This was associated with increased phosphorylation of Stat1 (134%), Stat2 (102%), ERK1/2 (42%). EC production of IL-6 was increased by IFNa (1,230pg/mL) and IFNl3 (1,124pg/mL) vs control (591pg/mL). Nitric oxide generation and eNOS phosphorylation (Ser1177) were reduced by IFNa (40%) and IFNl3 (40%). Vascular functional responses demonstrated that endothelium-dependent vasorelaxation (% Emax) in vessels from WT-mice stimulated with IFNa (67%) and IFNl3 (71%) were reduced vs control (82%) (p < 0.05). Responses were not altered in vessels from ISG15KO mice. Increased contraction was observed only in vessels from hypertensive mice treated with IFNa (9.1 ± 0.5mN vs control: 7.3 ± 0.3mN) (p < 0.05). Conclusions: In ECs, S1P, IFNa and IFNl3 increased ISG15 and IL-6 by mechanisms dependent on ADAM17. IFNs amplifies endothelial cell inflammatory responses and induced vascular dysfunction through ISG15-dependent mechanisms, with augmented effects in hypertension. Our findings demonstrate that S1P induces immune/inflammatory responses that may be important in endotheliitis associated with COVID-19. This may be especially important in the presence of cardiovascular risk factors, including hypertension.

Mechanisms of kidney injury in COVID-19 and diagnostic methods

The COVID-19 pandemic is a global healthcare crisis. The frequency of acute kidney injury (AKI) in patients with COVID-19 and the features of its diagnostics indicate the relevance of the topic. Objective of the review. To analyze mechanisms of AKI development in patients with COVID-19 and provide support for methodological approaches to ensure its timely diagnosis. Material and methods. The methodological approaches used in the review are based on a sufficient number of literature sources (more than 150 sources), of which 34 articles are included in the review: 15 original studies, 12 reviews, 2 meta-analyses, 5 re-ports, and letters to the editor. Results. The mechanisms of AKI development and progression, including the direct cytotoxic effect of the SARS-CoV-2 virus, dis-ruption of metabolic pathways of renal blood flow regulation, and the complement system, are considered. We also analyzed AKI risk factors in patients with acute respiratory distress: diabetes mellitus, chronic kidney injury, arterial hypertension with im-paired NOx production, and eNOS expression as significant factors of vasodilation in renal microcirculatory vessels. The analy-sis showed the most perspective directions in the diagnostics of AKI functional stages. These include molecular test methods (pro-teome and metabolome) in blood and urine;they helped define damage markers to proximal tubules and the glomerular system, thus improving the diagnostics accuracy and validity, therapy efficiency, and end points of disease prognosis. Conclusion. The Coronado study aims to assess the phenotypic features of patients with diabetes mellitus and COVID-19. More specific markers of the acute kidney injury functional stage were determined;these markers will improve the diagnostics accuracy and validity, therapy efficiency, and end points of disease prognosis.

HEPATO-PULMONARY SYNDROME: LOOK CLOSELY OR YOU MIGHT MISS IT

CASE: A Hispanic-speaking 63-year-old lady presented with left shoulder pain and dyspnea since two weeks. Past history was significant for cirrhosis due to autoimmune hepatitis and portal hypertension diagnosed 1.5 years prior. Upon further questioning, she revealed that she had exertional dyspnea for 2 years, which got progressively worse after her COVID-19 infection, 14 months prior. On initial exam, her hemoglobin levels were unchanged with previous. Troponin and BNP levels were unremarkable. CT Pulmonary Embolus scan and shoulder X-ray were negative. However, her SpO2 which was 90% on lying flat, fell to 84% on walking and she was admitted for further workup. On exam, she had a loud S2, spider angioma, and clubbing. ABG showed an alveolar-arterial oxygen gradient of 54.7 mm and PO2 of 61.7 mm. A contrastenhanced transthoracic echo with saline showed significant shunting with dilated pulmonary veins. Upon close inspection, she had a small right to left intracardiac shunt through an incidental PFO and a rather large intrapulmonary shunt. This was confirmed on trans-esophageal echo. Right heart catheterization showed a high cardiac index (5.3 L/min) suggestive of a high-output state, as typically seen with cirrhosis. It also revealed increased right-sided oxygen saturations, confirming the presence of a significant left to right shunt. Finally, pulmonary CT angiography was negative for AVMs. These findings were congruent with hepato-pulmonary syndrome (HPS) and based on her presenting symptoms she was referred to hepatology for consideration of liver transplantation. IMPACT/DISCUSSION: HPS is characterized by abnormal oxygenation due to intrapulmonary vascular dilations (IPVD) in the setting of advanced liver disease. Diagnosis needs an elevated A-a gradient (≥ 15mm or ≥ 20 mm if >64 years). IPVDs may not be seen on CT scans and are optimally detected on CE-TTE. The delayed appearance of injected microbubbles in the left heart, 3 or more cardiac cycles after visualization in the right heart signifies abnormally dilated pulmonary capillaries which don't trap the bubbles. TTE can help differentiate intracardiac and intrapulmonary shunts, by revealing the source of the microbubbles entering into the left atrium (across the atrial septum vs pulmonary veins). Shunting classically causes platypnea-orthodexia (worsening dyspnea on standing or sitting, alleviated by lying down). Alterations in lung parenchyma due to COVID-19 could have increased the flow through intrapulmonary AVMs and contributed to the worsening of symptoms. Management of HPS is supportive. Liver transplantation improves survival. CONCLUSION: Evaluation and management of HPS involves multiple modalities of testing and specialists in gastroenterology, cardiac imaging, interventional cardiology, interventional radiology, and transplant surgery. The diagnosis of HPS should escalate referral to a liver transplant center. Engaging medical interpreters can help elicit more detailed history and improve clinical outcomes.

IMPAIRED BETA-2ADRENERGIC ENDOTHELIUM-DEPENDENT VASODILATION IS REVERSED BY PHOSPHODIESTERASE INHIBITION IN PATIENTS PREVIOUSLY HOSPITALIZED WITH COVID-19

Objective: Endothelial dysfunction is thought to underlie many of the complications of COVID-19 but to what degree this persists after recovery is unknown. Here we examine endothelial function in subjects previously hospitalized with COVID- 19, those with mild symptoms who were not hospitalized and negative controls (absence of SARS-CoV-2-antibodies). Endothelial function was measured as pulse wave response to the β2 adrenergic agonist salbutamol (PWRS) which is mediated through the nitric oxide - cyclic guanosine monophosphate pathway (NO-cGMP). Design and method: Echocardiography was used to exclude subjects with cardiac abnormalities. Tonometry of the radial artery (SphygmoCor, AtCor Medical, Sydney, Australia) was performed in duplicate by a single operator before and after inhalation of 200 mcg of salbutamol using a spacer device. The PWRS was taken as the change from baseline in augmentation index (Aix) as calculated by the SphygmoCor system. In a sub-sample, PWRS was assessed in the presence and absence of the phosphodiesterase type 5 inhibitor sildenafil which inhibits the breakdown of cGMP. Results: We recruited 88 subjects (49 men) aged 47.9 ± 14.3 (mean ± SD) years of whom 32 were previously hospitalized with COVID-19 (~6 months). Subjects previously hospitalized with COVID-19 were all previously assessed in a dedicated pulmonary clinic. Age, gender, BMI, smoking status, diabetes and estimated 10-year cardiovascular risk (Q-RISKâ3) were similar between the groups. Administration of salbutamol reduced AIx in controls and those with mild COVID-19 but produced an increase in AIx in previously hospitalized COVID-19 cases (mean [95% CI]): -2.85 [-5.52, -0.188] %, -2.32 [-5.17,0.54] %, and 3.03 [0.06, 6.00] % respectively, P = 0.017 between the groups. In a sub-sample (11 hospitalized and 11 non-hospitalized) the PWRS was measured again 30 minutes after oral administration of sildenafil 25 mg. This produced a greater reduction in AIx: -5.28 [-9.00, -1.54] % in non-hospitalized and a reduction: -3.90 [-7.60, -0.21] % in hospitalized patients, and an overall improvement in the PWRS (P = 0.006). Conclusions: In subjects previously hospitalized with severe COVID-19, endothelial function is impaired for many months after hospital discharge and the impaired NO-cGMP mediated vasodilation may be reversed by sildenafil.

A Rare Cause of Angioedema - A Novel Case Report

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is well described as an etiology to severe acute respiratory distress syndrome (ARDS). However, rare immunologic and allergic manifestations may also occur from this infection. We report a novel case of angioedema occurring in the setting of COVID-19 infection in a fully vaccinated patient. Case Report: A 61-yearold COVID-19 vaccinated female with hypertension presented to the emergency department with tongue and lip swelling, odynophagia, dysphonia, and difficulty breathing. She denied personal or family history of allergies, anaphylaxis, or angioedema. Her home medications included Aspirin, methadone, Seroquel, and Klonopin, with no recent changes reported. Physical exam was notable for significant lip and tongue edema, audible dysphonia, and bilateral end-inspiratory wheezing. She was hypoxemic and placed on nasal cannula. Laboratory findings revealed lymphopenia, elevated inflammatory proteins, including C-reactive protein (57), Lactate dehydrogenase (LDH) (238), and D-dimer (11.52). Functional C1 esterase inhibitor levels (>91) were normal. Nasal PCR swab returned positive for SARS-CoV-2. Ear, nose, and throat specialist was consulted given concern for angioedema, and flexible nasolaryngoscopy was performed revealing uvular, epiglottic, and bilateral arytenoid edema concerning for impending airway compromise. The patient was initiated on intravenous methylprednisolone, epinephrine, antihistamines, tranexamic acid and admitted to the medical intensive care unit (ICU). She was monitored closely in the ICU with subsequent improvement of the angioedema and resolution of the hypoxemia. She was discharged with an oral steroid regimen and scheduled for a follow-up appointment with an allergist. Discussion: There exists only a handful of case reports describing angioedema in patients with COVID-19 infection. In those reports, patients also had normal C1 esterase inhibitor levels and no personal or family history of inherited angioedema. Interestingly, our patient was vaccinated six months prior to her presentation. The association between SARS-CoV-2 and angiotensinconverting enzyme 2 (ACE-2), the primary receptor for viral entry into the epithelial cells of the lungs, could be a potential explanation for the occurrence of angioedema. ACE-2 plays a pivotal role in inhibiting a potent ligand of bradykinin receptor 1, Arginine bradykinin. It has been postulated that SARS-CoV-2 downregulation of ACE-2 leads to elevated angiotensin II levels and subsequent activation of the bradykinin pathway. Excessive bradykinin production generates high levels of nitric oxide and prostaglandins, resulting in vasodilation, increased vascular permeability, and angioedema. This case highlights the importance of recognizing atypical and rare presentations of COVID-19 infection, especially angioedema, given its sudden onset and life-threatening complications.

A Safety Monitoring Framework for Critical Care Trials of Agents with Potential to Lower Blood Pressure

RATIONALE: Based on encouraging preliminary data, we undertook a randomized, placebo-controlled trial of synthetic vasoactive intestinal peptide (aviptadil) for treatment of COVID-19 acute respiratory distress syndrome (ARDS). Aviptadil may cause vasodilation and resultant hypotension. Given the high background incidence of hypotension from many causes (e.g., sedatives, sepsis, positive pressure ventilation) in critically ill patients, an ascertainment and grading strategy for postrandomization hypotension capable of distinguishing “signal” from “noise” is essential to the trial's conduct and interpretation. METHODS: We evaluated whether existing adverse event (AE) severity frameworks were adequate to characterize hypotension occurring in critically ill patients. Based on these findings, we developed and implemented a customized framework for hypotension-related safety monitoring and outcome collection during the Therapeutics for Severely Ill Inpatients with COVID-19 (TESICO) trial of aviptadil for COVID-19 ARDS (NCT04843761). RESULTS: Hypotension severity assigned to COVID-19 ARDS patients by existing AE frameworks - largely developed for outpatients - appeared misaligned with the frameworks' own generic/conceptual severity criteria. Existing frameworks' hypotension-specific AE grading tables lacked necessary detail and reporting guidance, over-graded mild hypotension, and missed safety signals suggested by increasing vasopressor requirements. We therefore developed a novel hypotension AE grading table aligned with conceptual AE severity criteria for critically ill patients (Figure). In addition to general severity criteria, the table adds criteria specific to the investigational agent's peri-infusion period and provides guidance for evaluating the “seriousness” of a hypotensive event in the context of subjects' preexisting critical illness. In combination with detailed reporting on the components of AE events, the study's protocol committee, sponsor, and data safety monitoring board approved the customized table for use in outcome measurement as well as real-time safety monitoring and AE reporting. We implemented a strategy to efficiently collect the hypotension-related data required for safety monitoring and allow automated hypotension AE grading according to both the adopted schema and existing AE frameworks. CONCLUSIONS: We developed a framework acceptable to diverse stakeholders for hypotension safety monitoring in COVID-19 ARDS patients receiving aviptadil or placebo. The monitoring framework will be validated in the ongoing TESICO trial and could be adapted for other trials of vasoactive investigational agents targeting critically ill patients. Comprehensive AE grading criteria designed specifically for critically ill patients could improve trials' ability to meaningfully monitor and report safety outcomes in this population.

Role of adenosine receptors in cardiovascular disorders and novel corona virus infection

Objective: To assess the importance of adenosine signaling in cardiovascular disorders (thrombosis, ischemia) and novel corona virus infection. Methodology: A specified web search was done to gather the relevant information using different scientific research forums and databases like WHO database, Pubmed and Google Scholar etc. Results: Adenosine receptors are P1 type of purinergic receptors and belong to G protein-coupled receptors (GPCRs), which is the largest family of integral membrane bound proteins receptors. Adenosine receptors are further classified into four subclasses known as A1, A2A, A2B, and A3. All four subclasses are being mediated by extracellular adenosine and perform a key role in a wide range of physiological functions such as immune system modulation, angiogenesis and sleep regulation. Adenosine receptors are thought to play a significant role in many pathophysiological conditions including cardiovascular disorders such as ischemia and thrombosis and novel corona virus infection making it a key target against these disorders. Conclusion: We suggest that modulation of adenosine receptor activity could increase the regenerative phase in these disorders by increasing the proliferation and differentiation rates of damaged tissue.

Assessment of COVID-19 Severity Using Chest CT Severity Score on High-Resolution Computed Tomography Chest in Pakistani Patients

Objective: The current review aims at portraying the high-resolution CT (HRCT) chest findings of corona virus pandemic that emerged in 2019 amongst the COVID-19 patients, admitted to the tertiary healthcare facilities in Punjab, Pakistan. It also aims to study the imaging features and dispensation of COVID-19 infection in different segments of the lungs. Moreover, a survey was also conducted for the job to analyze the chest CT severity score index (CT-SS) aims at identifying those patients with acute infections. Methods: This cross-sectional descriptive analysis led from May 15, 2020 to November 26, 2021, incorporates 97 diagnosed patients of the COVID-19 who received the HRCT scan in the tertiary healthcare facilities in Punjab, Pakistan. The HRCT chest of the infected patients was collected following the proper protocol. Each case was assessed for the presence of imaging features such as ground glass opacities (GGOs), consolidation, mixed pattern, crazy paving appearance and other findings along with their distribution in lung segments. Furthermore, to determine the CT-SS we divided each lung into 20 sub segments. The Linkert Score system of degree of 0,1 and 2 was provided. This indicates the intensity of involvement. It states that zero score indicates no involvement, whereas the Linkert figure 1 shows the involvement which is less than <50%. However, the remaining figure Linkert indicator figure 2 indicates the intensity of involvement if more than >50% by one zone. The total range of score for this test lies between 0-40. This score helps us to categories the patients based on their mild and severe cases. Here the score of less than <20 indicated mild infection, whereas, the score which appears more than >20 indicates the severity of the case. Results: The ground glass opacities which are trailed by consolidation of 49.4% and that of crazy paving by 21.64% was recorded as the most recognized finding. In most of the patients, the distribution of disease, with basal predilection, was recorded as bilateral, peripheral as well as multilobar. The ratio of vascular dilatation was recorded 19.5% and that of bronchiectasis was noted at 13.4% in patients. 3% of the patients showed the Halo, whereas reverse halo sign was noted in 1% of patients. None of the patients was seen to be carrying the Pleural effusion. Lung cavitation was seen in 2% of patients and isolated lobar consolidation without GGO was seen in 1% of patients. The segment which was most commonly involved bilaterally was the posterior segment of the lower lobes. As per the data collected from CT-SS, 80(82.4%) patients had mild and 17 (17.4%) patients had an acute disease symptoms respectively. Conclusion: GGOs are the most common imaging findings of COVID-19 pneumonia on HRCT chest having multilobar, bilateral and peripheral involvement with basal predilection. This proves CT-SS as a useful mechanism in placing pneumonia patients as mild and acute types. This helps categorizing the distinguishing the acute or severe patients from mild and to manage them accordingly.

Magnesium and COVID- 19 - cardiovascular implications

The novel coronavirus SARSCoV- 2 is causing an ongoing worldwide pandemic of COVID-19. The infection with this single-stranded RNA virus appears to be completely asymptomatic in a large fraction of people and many other patients may experience mild symptoms such as fever, cough, anosmia, and myalgia. Some patients need hospitalization and some will develop an acute respiratory distress syndrome (ARDS), and a significant subset will require treatment in the intensive care unit to provide respiratory ventilator support. Unfortunately, there is no causal curative treatment, so far. In this context, the potential prophylactic and therapeutic options for the novel SARS-CoV-2 infection and corresponding COVID-19, as well as interventions with special nutrients like zinc or vitamin D are discussed, especially due to their role in the immune system [1]. Possible drugs for the treatment of COVID-19 increase the risk of QT interval prolongation, e.g., chloroquine, hydroxychloroquine, azithromycin, lopinavir, ritonavir. QT prolongation can provoke life-threatening torsade-de-pointes arrhythmias (TdP) and sudden cardiac death. Mg deficiency and other electrolyte imbalances also belong to the known risk factors for QT prolongation and TdP. Consequently, it is recommended to obtain baseline assessment of Mg and other electrolytes and to correct deficiencies before using QT-prolonging drugs. Keeping serum potassium levels and Mg levels above 4 mmol/L and 3 mg/ dL (= 1.23 mmol/L), respectively, in COVID-19 patients treated with QT-prolonging drugs proved to be effective in preventing QT prolongation, and no arrhythmias or sudden cardiac arrest were registered. This is above the upper limit of the reference range (usually ∼ 1.1 mmol/L). In a single-center study (n = 524), a specially designed monitoring process in COVID-19 patients (with COVID-19-related medication) identified a high proportion of patients with QT prolongation (n = 103, corresponding to 19.7%). As part of the medical support, reaching Mg and potassium in the reference range was recommended [2, 3]. Administration of intravenous Mg sulfate is the therapy of choice for hemodynamically stable TdP, regardless of whether the patient is hypomagnesemic or has a normal serum Mg concentration. This may be a relevant reason why the German Federal Institute of Drugs and Medical Devices (BfArM) put Mg (parenteral) on a list with drugs whose need is greatly increased with treatment of COVID-19 patients in intensive care units [4]. On the other hand, hypomagnesemia generally is a common occurrence in intensive care patients (regardless of COVID-19) with a prevalence up to 65%, associated with an increased mortality rate, higher need for ventilator support, increased incidence of sepsis, and longer hospital stays [5]. There is increasing evidence that viral infection of the endothelial cells plays a key role in multiorgan participation and severe courses of COVID-19. This finding provides a rationale for therapies to stabilize the endothelium, in particular for vulnerable patients with pre-existing endothelial dysfunction which can be found for example in cardiovascular disease, diabetes, hypertension, obesity, all of which are associated with adverse outcomes in COVID-19. Interestingly, Mg is known to be crucial for endothelial function and its deficiency causes endothelial dysfunction with impaired endothelial-dependent vasodilation. In a meta-analysis of randomized, controlled trials (RCTs), oral Mg supplementation was shown to improve flow-mediated dilation as a marker of endothelial function. It is therefore plausible to assume that Mg deficiency further worsens the consequences of an infection with SARS-CoV-2 via induction of endothelial dysfunction. In this context, the frequent occurrence of thrombotic embolism in COVID-19 is worth mentioning. Animal and human data suggest that Mg functions as an antithrombotic agent. Hence, increased platelet reactivity and thrombosis are possible cardiovascular manifestations of Mg deficiency [6, 7]. Furthermore, increased inflammation in Mg deficiency has to be kept in mind. Experimental studies show an increased incidence of markers for inflammation in case of Mg deficiency, e.g., leukocyte and macrophage activation, pro-inflammatory molecules such as interleukin-1, interleukin-6, tumor necrosis factor, vascular cell adhesion molecule-1, plasminogen activator inhibitor-1, and excessive production of free radicals. Generally, Mg deficiency is considered as a significant contributor to chronic lowgrade inflammation and, therefore, risk factor for a variety of pathological conditions such as cardiovascular disease, hypertension, and diabetes. In meta-analyses of RCTs, Mg supplementation was shown to reduce C-reactive protein levels. Whether Mg deficiency or Mg supplementation may impact the inflammatory event in COVID-19 has to be investigated in clinical studies [7, 8]. To our knowledge, there are no systematic studies so far examining Mg status in COVID-19 patients. In a pooled analysis, Lippi et al. [6] confirmed that COVID-19 severity was associated with lower serum concentrations of sodium, potassium, and calcium. Therefore, measuring electrolytes at initial presentation and monitoring during hospitalization is recommended in order to be able to take appropriate corrective measures in good time. Unfortunately, serum Mg was not determined in the studies analyzed. In the above-mentioned study of Jain et al. [3], 30.1% of the COVID-19 patients with QT prolongation showed hypomagnesemia. Conclusion: In view of the relationships described, it is plausible to assume that Mg deficiency may decrease the resistance against infection with SARS-CoV-2 and, most notably, may worsen the course of COVID-19. Hence, Mg deficiency could be a risk factor for severe COVID-19, comparable to cardiovascular disease, diabetes, chronic respiratory disease, older age, obesity, amongst others. Interestingly, Mg deficiency is often associated with these risk factors or seen as comorbidity. However, more research questions need to be addressed before definitive conclusions can be drawn [8, 9].

Dermatological Manifestations in Patients with COVID-19 Pneumonia in Veracruz, Mexico

Background. A large number of viral infections are characterized by the presence of cutaneous manifestations. Multiple dermatological manifestations have been observed in patients with COVID-19. Dermatological lesions in patients infected by SARS-CoV-2 such as livedo reticularis, rash and vascular lesions may represent manifestations of secondary phenomena such as paraviral rashes or by participation of the innate or adaptive immune system that cause vasodilation, vascular leakage or procoagulant effects Methods. Descriptive and observational study, adult patients with COVID-19 pneumonia were selected, confirmed by RT-PCR and chest CT. General symptoms, hematic cytometry results, pneumonia severity, prognosis as well as dermatological manifestations are characterized. Results. 100 patients were entered into the study, with an average age of 49.4 years, 54% male. The general symptoms with the highest incidence were: fever, cough and dyspnea characteristic of SARS-CoV-2 infection, followed by chest pain, headache, anosmia and dysgeusia. The main alteration of the hemogram was lymphopenia, no leukopenia or plaquetopenia was demonstrated. 54% of those affected had mild pneumonia, the rest severe pneumonia. 75% progressed towards improvement and 25% died. Among the dermatological manifestations identified, all occurred in cases with severe pneumonia, the one with the highest incidence was the morbilliform viral exanthema in 18%, the presence of diffuse partial alopecia in 7% as well as manifestations of lividity and maceration in 1%. Regarding alopecia, in 6% it was reversible androgenetic alopecia, having manifested during the acute stage of pneumonia (all men), in 1% it presented alopecia areata (male) that has been persistent beyond the acute phase and in frank recovery Demographic and clinical variables Conclusion. The incidence of dermatological manifestations is low in this study population, the most frequent being the morbilliform viral exanthema expected in a virus, however they present manifestations of low incidence such as reversible androgenetic alopecia associated with severity of the disease, a finding that has been documented recently as a manifestation associated with COVID-19.

Preintubation echocardiographic assessment using subcostal-only view (easy) exam: A case series

INTRODUCTION/HYPOTHESIS: Induction and intubation can cause cardiovascular instability, hypoxemia, and cardiac arrest. The EASy exam is a subcostal four-chamber view (SC4C), followed by inferior vena cava (IVC) and upper lung field views performed in quick succession. The goal of this study was to evaluate the impact of single-day EASy training on management prior to induction and intubation. METHODS: EASy training consists of a combination of a web-based curriculum, live lecture, and 10 exams performed under direct supervision. The EASy protocol was performed before emergency intubation on five critically ill patients. In this case series, we describe findings and management based on the EASy phenotypes (pattern recognition). RESULTS: Five resident-obtained EASy studies were performed in the ICU for emergency intubation. Two patients had COVID-19. Three had hyperdynamic ventricles with a small left ventricular (LV) cavity size with a < 1.5cm fully collapsible IVC consistent with hypovolemia (two of which had thickened LV walls indicating likely diastolic dysfunction). These three patients received a 10 mL/kg IV fluid bolus to counteract vasodilation and decreased venous return, and were started on phenylephrine. The fourth had normal contractility and diastolic cavity size with a normal-sized collapsible IVC. The fifth patient had biventricular dilation with reduced systolic function and a plethoric IVC. For this patient, no fluid bolus was given, and a vasopressor with inotropic properties (norepinephrine) was started. Etomidate was used for induction and intubation. The mean time for completion was 3 minutes (range 2 to 4 minutes). Three studies were deemed “good” quality and two were deemed “adequate” by an attending physician proficient in critical care ultrasound. Vitals were monitored for 15 minutes post-intubation, and all patients maintained hemodynamic stability with MAP ≥ 65 mmHg. CONCLUSIONS: EASy exam aids clinical decision-making in the pre-induction and intubation period, where interventions can have deleterious and even fatal consequences.

Myocardial ischaemia of non-obstructive origin as a cause of new onset anginal chest pain in the long COVID syndrome

Background: New-onset chest pain occurs in around 20% of patients with long COVID syndrome (LCS). Being the vascular endothelium one of the targets of the SARS-CoV-2 virus, we hypothesized that new onset anginal symptoms in LCS could be due to endothelium dysfunction and other non-obstructive causes of myocardial ischaemia. Methods: We investigated 11 consecutive patients who developed new onset anginal chest pain, suggestive of myocardial ischaemia, after documented SARS-CoV-2 infection. Intracoronary assessment included endothelium-dependent evaluation with acetylcholine testing (Ach), and endothelium-independent assessment with coronary flow reserve (CFR) and microcirculatory resistance (MR). Criteria for positiveness of these tests and medical treatment recommendation were obtained from 2019 ESC guidelines and 2020 EAPCI consensus document on ischaemia with non-obstructive coronary arteries (INOCA). Results: Mean patient age was 56 years (SD ± 15);10 (91%) were female. In the acute COVID-19 phase, 4 patients (36%) had had pulmonary infiltrates and 2 (18%) required hospitalization. Conclusive non-invasive tests were obtained in 7 (64%), showing exercise-related myocardial ischaemia in 6 (86%). Coronary angiography ruled out obstructive epicardial stenoses in all the patients. Ach testing revealed abnormal endothelium-dependent responses in 9 (82%) patients: 5 (56%) had epicardial vessel and 4 (44%) microvascular spasm. Endothelium-independent assessment was abnormal in 6 (54%) cases, with abnormal CFR in 2 (33%), abnormal MR in 2 (33) and both abnormal CFR and MR in 2 (33%) patients. The most frequent endotype was combined endothelium dependent- and independent abnormalities (6/9, 67%). Stratified medical treatment according to endotype led to significant improvement in Seattle Angina Scores for angina frequency (+22 points, p=0.013) and a notable trend towards angina stability (+25 points, p=0.093) at a mean follow-up time of 222 days. Conclusions: Myocardial ischaemia of non-obstructive origin is common in patients with chest pain and LCS. Vasomotor abnormalities related to endothelial dysfunction occurred in 82% of patients, frequently associated to impaired microvascular vasodilation or high microvascular resistance. Stratified medical treatment led to significant improvement in angina stability and frequency.