Metabolic dysfunction associated fatty liver disease and coronavirus disease 2019: clinical relationship and current management.

The coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). At present, the COVID-19 has been prevalent worldwide for more than a year and caused more than four million deaths. Liver injury was frequently observed in patients with COVID-19. Recently, a new definition of metabolic dysfunction associated fatty liver disease (MAFLD) was proposed by a panel of international experts, and the relationship between MAFLD and COVID-19 has been actively investigated. Several previous studies indicated that the patients with MAFLD had a higher prevalence of COVID-19 and a tendency to develop severe type of respiratory infection, and others indicated that liver injury would be exacerbated in the patients with MAFLD once infected with COVID-19. The mechanism underlying the relationship between MAFLD and COVID-19 infection has not been thoroughly investigated, and recent studies indicated that multifactorial mechanisms, such as altered host angiotensin converting enzyme 2 (ACE2) receptor expression, direct viral attack, disruption of cholangiocyte function, systemic inflammatory reaction, drug-induced liver injury, hepatic ischemic and hypoxic injury, and MAFLD-related glucose and lipid metabolic disorders, might jointly contribute to both of the adverse hepatic and respiratory outcomes. In this review, we discussed the relationship between MAFLD and COVID-19 based on current available literature, and summarized the recommendations for clinical management of MAFLD patients during the pandemic of COVID-19.

Response to the first awake prone positioning relates with intubation rate in SARS-CoV-2 patients suffering from acute respiratory failure with moderate to severe hypoxaemia: a retrospective study.

AIMS OF THE STUDY: Awake prone positioning (aPP) in non-intubated patients with severe SARS-CoV-2-related pneumonia improves oxygenation and reduces the intubation rate, but no early predictors for success or failure of the strategy have been described. The main objective of this study was to assess whether response to the first aPP in terms of PaO2/FiO2, alveolar-arterial gradient (Aa-O2), respiratory rate and PaCO2 could predict the need for intubation. As secondary objective, we assessed the effects of aPP on the same parameters for all the sessions considered together. METHODS: Retrospective analysis of consecutive SARS-CoV-2 pneumonia patients suffering from acute respiratory failure with moderate to severe hypoxaemia for whom aPP was performed for at least 45 minutes based on the prescription of the clinician in charge according to predefined criteria. Respiratory rate, blood gases and oxygenation parameters (PaO2/FiO2 and Aa-O2), before and after the first aPP were compared between patients who were subsequently intubated or not. Effects of all the aPP sessions together were also analysed. RESULTS: One hundred and sixty-six patients were admitted for SARS-CoV-2 pneumonia during the study period. Among them, 50 received aPP lasting at least 45 minutes. Because 17 denied consent for data analysis and 2 were excluded because of a "do not intubate order", 31 patients (for a total of 116 aPP sessions without any severe adverse events reported) were included. Among them, 10 (32.3%) were intubated. Mean age ± standard deviation (SD) was 60 ± 12 years. At ICU admission, respiratory rate was 26 ± 7/minute, median PaO2/FiO2 94 (interquartile range [IQR] 74-116) mm Hg and median Aa-O2 412 (IQR 286-427) mm Hg (markedly increased). Baseline characteristics did not statistically differ between patients who subsequently needed intubation or not. During the first aPP, PaO2/FiO2 increased and Aa-O2 decreased. When comparing patients who later where intubated or not, we observed, in the non intubated group only, a clinically significant decrease in median Aa-O2, from 294 (280-414) to 204 (107-281) mm Hg, corresponding to a 40% (26-56%) reduction, and a PaO2/FiO2 increase, from 103 (84-116) to 162 (138-195), corresponding to an increase of 48% (11-93%). The p value is <0.005 for both. When all the aPP sessions (n = 80) were considered together, aPP was associated with a significant increase in PaO2/FiO2 from 112 (80-132) to 156 (86-183) mm Hg (p <0.001) and Aa-O2 decrease from 304 (244-418) to 224 (148-361) mm Hg (p = 0.001). CONCLUSIONS: Awake pronation in spontaneously breathing patients is feasible, and improves PaO2/FiO2 and Aa-O2. Response to the first session seems to be associated with lower intubation rate.

Autopsy Case Report of Severe COVID-19 Pneumonia at a General Municipal Hospital.

We present the autopsy procedure and findings of severe coronavirus disease 2019 (COVID-19) pneumonia in an 85-year-old man. The patient required intubation immediately after admission for severe COVID-19 pneumonia. He had severe hypoxia that did not improve despite treatment with remdesivir, corticosteroids, and appropriate mechanical ventilation. On day 13, the patient developed sudden hypercapnia. His renal dysfunction subsequently worsened and became associated with hyperkalemia, and he passed away on day 15. An autopsy was performed to clarify the cause of the hypercapnic hypoxia. None of the medical personnel involved in the autopsy developed symptoms of COVID-19. Histologic examination showed various stages of diffuse alveolar damage throughout the lungs, with intra-alveolar hemorrhage in the upper zones. Microscopic examination of the kidneys revealed acute tubular necrosis. There was no significant systemic thrombosis. The autopsy findings were consistent with those typical of COVID-19.

SARS-CoV-2 mitochondriopathy in COVID-19 pneumonia exacerbates hypoxemia.

RATIONALE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 pneumonia. We hypothesize that SARS-CoV-2 causes alveolar injury and hypoxemia by damaging mitochondria in airway epithelial cells (AEC) and pulmonary artery smooth muscle cells (PASMC), triggering apoptosis and bioenergetic impairment, and impairing hypoxic pulmonary vasoconstriction (HPV), respectively. OBJECTIVES: We examined the effects of: A) human betacoronaviruses, SARS-CoV-2 and HCoV-OC43, and individual SARS-CoV-2 proteins on apoptosis, mitochondrial fission, and bioenergetics in AEC; and B) SARS-CoV-2 proteins and mouse hepatitis virus (MHV-1) infection on HPV. METHODS: We used transcriptomic data to identify temporal changes in mitochondrial-relevant gene ontology (GO) pathways post-SARS-CoV-2 infection. We also transduced AECs with SARS-CoV-2 proteins (M, Nsp7 or Nsp9) and determined effects on mitochondrial permeability transition pore (mPTP) activity, relative membrane potential, apoptosis, mitochondrial fission, and oxygen consumption rates (OCR). In human PASMC, we assessed the effects of SARS-CoV-2 proteins on hypoxic increases in cytosolic calcium, an HPV proxy. In MHV-1 pneumonia, we assessed HPV via cardiac catheterization and apoptosis using the TUNEL assay. RESULTS: SARS-CoV-2 regulated mitochondrial apoptosis, mitochondrial membrane permeabilization and electron transport chain (ETC) GO pathways within 2 hours of infection. SARS-CoV-2 downregulated ETC Complex I and ATP synthase genes, and upregulated apoptosis-inducing genes. SARS-CoV-2 and HCoV-OC43 upregulated and activated dynamin-related protein 1 (Drp1) and increased mitochondrial fission. SARS-CoV-2 and transduced SARS-CoV-2 proteins increased apoptosis inducing factor (AIF) expression and activated caspase 7, resulting in apoptosis. Coronaviruses also reduced OCR, decreased ETC Complex I activity and lowered ATP levels in AEC. M protein transduction also increased mPTP opening. In human PASMC, M and Nsp9 proteins inhibited HPV. In MHV-1 pneumonia, infected AEC displayed apoptosis and HPV was suppressed. BAY K8644, a calcium channel agonist, increased HPV and improved SpO2. CONCLUSIONS: Coronaviruses, including SARS-CoV-2, cause AEC apoptosis, mitochondrial fission, and bioenergetic impairment. SARS-CoV-2 also suppresses HPV by targeting mitochondria. This mitochondriopathy is replicated by transduction with SARS-CoV-2 proteins, indicating a mechanistic role for viral-host mitochondrial protein interactions. Mitochondriopathy is a conserved feature of coronaviral pneumonia that may exacerbate hypoxemia and constitutes a therapeutic target.

Noninvasive Ventilation in Treatment of Respiratory Failure-Related COVID-19 Infection: Review of the Literature.

The recently diagnosed coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in December 2019 commonly affects the respiratory system. The incidence of acute hypoxic respiratory failure varied among epidemiological studies with high percentage of patients requiring mechanical ventilation with a high mortality. Noninvasive ventilation is an alternative tool for ventilatory support instead of invasive mechanical ventilation, especially with scarce resources and intensive care beds. Initially, there were concerns by the national societies regarding utilization of noninvasive ventilation in acute respiratory failure. Recent publications reflect the gained experience with the safe utilization of noninvasive mechanical ventilation. Noninvasive ventilation has beneficiary role in treatment of acute hypoxic respiratory failure with proper indications, setting, monitoring, and timely escalation of therapy. Patients should be monitored frequently for signs of improvement or deterioration in the clinical status. Awareness of indications, contraindications, and parameters reflecting either success or failure of noninvasive ventilation in the management of acute respiratory failure secondary to COVID-19 is essential for improvement of outcomes.

Risks of Severe COVID-19 Outcomes Among Patients With Diabetic Polyneuropathy in the United States.

CONTEXT: Diabetic neuropathy (DN) affects more than 50% of diabetic patients who are also likely to have compromised immune system and respiratory function, both of which can make them susceptible to the SARS-CoV-2 virus. OBJECTIVE: To assess the risk of severe COVID-19 illness among adults with DN, compared with those with no DN and those with no diabetes. SETTING: The analysis utilized electronic health records from 55 US health care organizations in the TriNetX research database. DESIGN: A retrospective cohort study. PARTICIPANTS: The analysis included 882 650 adults diagnosed with COVID-19 in January 2020 to June 2021, including 16 641 with DN, 81 329 with diabetes with no neuropathy, and 784 680 with no diabetes. OUTCOME MEASURES: The presence of health care utilization (admissions to emergency department, hospital, intensive care unit), 30-day mortality, clinical presentation (cough, fever, hypoxemia, dyspnea, or acute respiratory distress syndrome), and diagnostic test results after being infected affected by COVID-19. RESULTS: The DN cohort was 1.19 to 2.47 times more likely than the non-DN cohorts to utilize care resources, receive critical care, and have higher 30-day mortality rates. Patients with DN also showed increased risk (1.13-2.18 times) of severe symptoms, such as hypoxemia, dyspnea, and acute respiratory distress syndrome. CONCLUSIONS: Patients with DN had a significantly greater risk of developing severe COVID-19-related complications than those with no DN. It is critical for the public health community to continue preventive measures, such as social distancing, wearing masks, and vaccination, to reduce infection rates, particularly in higher risk groups, such as those with DN.

Serum concentration of extracellular cold-inducible RNA-binding protein is associated with respiratory failure in COVID-19.

Uncontrolled release of damage-associated molecular patterns (DAMPs) is suggested to be a major trigger for the dysregulated host immune response that leads to severe COVID-19. Cold-inducible RNA-binding protein (CIRP), is a newly identified DAMP that aggravates inflammation and tissue injury, and induces respiratory failure in sepsis. Whether CIRP contributes to the pathogenesis of respiratory failure in COVID-19 has not yet been explored. Aim: To investigate if the concentration of extracellular CIRP (eCIRP) in serum associates with respiratory failure and lung involvement by chest computed tomography (CT) in COVID-19. Methods: Herein we report a prospective observational study of patients with COVID-19 included at two University Hospitals in Sweden between April 2020 and May 2021. Serum from hospitalized patients in Örebro (N=97) were used to assess the association between eCIRP and the level of respiratory support and its correlation with pulmonary involvement on chest CT and inflammatory biomarkers. A cohort of hospitalized and non-hospitalized patients from Umeå (N=78) was used as an external validation cohort. The severity of disease was defined according to the highest degree of respiratory support; mild disease (no oxygen), non-severe hypoxemia (conventional oxygen or high-flow nasal oxygen, HFNO <50% FiO2), and severe hypoxemia (HFNO ≥50% FiO2, mechanical ventilation). Unadjusted and adjusted linear regression was used to evaluate peak eCIRP day 0-4 in respect to severity, age, sex, Charlson comorbidity score, symptom duration, and BMI. Results: Peak eCIRP concentrations were higher in patients with severe hypoxemia and were independently associated with the degree of respiratory support in both cohorts (Örebro; p=0.01, Umeå; p<0.01). The degree of pulmonary involvement measured by CT correlated with eCIRP, rs=0.30, p<0.01 (n=97). Conclusion: High serum levels of eCIRP are associated with acute respiratory failure in COVID-19. Experimental studies are needed to determine if treatments targeting eCIRP reduces the risk of acute respiratory failure in COVID-19.

Desidustat: First Approval.

Desidustat (Oxemia™) is an orally bioavailable, small molecule, hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor developed by Zydus Cadila for the treatment of anaemia associated with chronic kidney disease (CKD), COVID-2019 infections and chemotherapy induced anaemia. Desidustat inhibits prolyl hydroxylase domain enzymes, resulting in the stabilisation of hypoxia-inducible factor which stimulates erythropoietin production and erythropoiesis. In March 2022, desidustat received its first approval in India for the treatment of anaemia in adults with CKD who are either on dialysis or not on dialysis. Desidustat is in clinical development in China for the treatment of anaemia in patients with CKD, in Mexico for the management of COVID-2019 infections and in the USA for the treatment of chemotherapy induced anaemia. This article summarizes the milestones in the development of desidustat leading to this first approval for anaemia associated with CKD.

Pulse oximetry and oxygen services for the care of children with pneumonia attending frontline health facilities in Lagos, Nigeria (INSPIRING-Lagos): study protocol for a mixed-methods evaluation.

INTRODUCTION: The aim of this evaluation is to understand whether introducing stabilisation rooms equipped with pulse oximetry and oxygen systems to frontline health facilities in Ikorodu, Lagos State, alongside healthcare worker (HCW) training improves the quality of care for children with pneumonia aged 0-59 months. We will explore to what extent, how, for whom and in what contexts the intervention works. METHODS AND ANALYSIS: Quasi-experimental time-series impact evaluation with embedded mixed-methods process and economic evaluation. SETTING: seven government primary care facilities, seven private health facilities, two government secondary care facilities. TARGET POPULATION: children aged 0-59 months with clinically diagnosed pneumonia and/or suspected or confirmed COVID-19. INTERVENTION: 'stabilisation rooms' within participating primary care facilities in Ikorodu local government area, designed to allow for short-term oxygen delivery for children with hypoxaemia prior to transfer to hospital, alongside HCW training on integrated management of childhood illness, pulse oximetry and oxygen therapy, immunisation and nutrition. Secondary facilities will also receive training and equipment for oxygen and pulse oximetry to ensure minimum standard of care is available for referred children. PRIMARY OUTCOME: correct management of hypoxaemic pneumonia including administration of oxygen therapy, referral and presentation to hospital. SECONDARY OUTCOME: 14-day pneumonia case fatality rate. Evaluation period: August 2020 to September 2022. ETHICS AND DISSEMINATION: Ethical approval from University of Ibadan, Lagos State and University College London. Ongoing engagement with government and other key stakeholders during the project. Local dissemination events will be held with the State Ministry of Health at the end of the project (December 2022). We will publish the main impact results, process evaluation and economic evaluation results as open-access academic publications in international journals. TRIAL REGISTRATION NUMBER: ACTRN12621001071819; Registered on the Australian and New Zealand Clinical Trials Registry.

Severe acute reentry high altitude pulmonary edema in pediatric patients: report of three cases and literature review.

BACKGROUND: High Altitude Pulmonary Edema (HAPE) is a fatal form of severe high-altitude illness. It is a form of noncardiogenic, noninfectious pulmonary edema secondary to alveolar hypoxia. The exact incidence of HAPE in children is unknown; however, most literature reports an incidence between 0.5-15%. There are three proposed HAPE types including classic HAPE, reentry HAPE, and high-altitude resident pulmonary edema (HARPE). CASE: We present three pediatric patients who were diagnosed with re-entry high altitude pulmonary edema and did not have any underlying cardiac abnormalities. All patients reside in areas of high altitude with a history of travelling to places of lower altitude. They had respiratory infections prior to the manifestation of HAPE. CONCLUSIONS: These are the first reported cases of children with reentry HAPE in Saudi Arabia. Reentry HAPE can occur in otherwise healthy children. Rapid ascent to high altitude and recent respiratory infections are the most commonly reported triggers. Prognosis is very favorable with a very rapid response to oxygen therapy. Education about HAPE is mandatory for families and health care workers working in high altitude areas.

Effect of extracorporeal carbon dioxide removal on respiratory quotient measured by indirect calorimetry: Unravelling the mystery.

NEW FINDINGS: What is the main observation in this case? Several studies have reported progressive hypoxaemia once extracorporeal carbon dioxide removal is started in patients with hypercapnic respiratory failure, possibly attributable to an altered respiratory quotient. What insights does it reveal? In this quality control report, we show that the respiratory quotient exhibits only minimal alteration when extracorporeal carbon dioxide removal is started and assume that the progressive hypoxaemia is attributable to an increase in intrapulmonary shunt. ABSTRACT: The use of extracorporeal carbon dioxide removal (ECCO2 R) has been proposed in patients with acute respiratory distress syndrome to achieve lung-protective ventilation and in patients with selective hypercapnic respiratory failure. However, several studies have reported progressive hypoxaemia, as expressed by a need to increase the inspired oxygen fraction (Fi O2 ) to maintain adequate oxygenation or by a decrease in the ratio of arterial oxygen tension (Pa O2 ) to Fi O2 once ECCO2 R is started. We present the case of a patient who was admitted to the intensive care unit for a coronavirus disease 2019 pneumonia and who was intubated because of hypercapnic respiratory insufficiency. Extracorporeal carbon dioxide removal was started, and the patient subsequently developed progressive hypoxaemia. To test whether the hypoxaemia was attributable to the ECCO2 R, blood samples were taken in different settings: (1) 'no ECCO2 R', blood flow 150 ml/min with a ECCO2 R gas flow of 0 L/min; and (2) 'with ECCO2 R', blood flow 400 ml/min with gas flow 12 L/min. We measured Pa O2 , alveolar oxygen tension, Pa O2 /Fi O2 , alveolar-arterial oxygen tension difference, arterial carbon dioxide tension and the respiratory quotient (RQ) by indirect calorimetry in each setting. The RQ was 0.60 without ECCO2 R and 0.57 with ECCO2 R. The alveolar oxygen tension was 220.4 mmHg without ECCO2 R and increased to 240.3 mmHg with ECCO2 R, whereas Pa O2 /Fi O2 decreased from 177 to 171. Our study showed only a minimal change in RQ when ECCO2 R was started. We were the first to measure the RQ directly, before and after the initiation of ECCO2 R, in a patient with hypercapnic respiratory failure.

Role of helmet ventilation during the 2019 coronavirus disease pandemic.

Coronavirus disease 2019 (COVID-19) has been declared a pandemic by the World Health Organization; it has affected millions of people and caused hundreds of thousands of deaths. Patients with COVID-19 pneumonia may develop acute hypoxia respiratory failure and require noninvasive respiratory support or invasive respiratory management. Healthcare workers have a high risk of contracting COVID-19 while fitting respiratory devices. Recently, European experts have suggested that the use of helmet continuous positive airway pressure should be the first choice for acute hypoxia respiratory failure caused by COVID-19 because it reduces the spread of the virus in the ambient air. By contrast, in the United States, helmets were restricted for respiratory care before the COVID-19 pandemic until the Food and Drug Administration provided the 'Umbrella Emergency Use Authorization for Ventilators and Ventilator Accessories'. This narrative review provides an evidence-based overview of the use of helmet ventilation for patients with respiratory failure.

Long-term cognitive impairments following COVID-19: a possible impact of hypoxia.

BACKGROUND: Cognitive and emotional disorders frequently persist after recovery from the acute symptoms of COVID-19; possible explanations include pneumonia-induced hypoxia, infection of the central nervous system, and microstrokes. The objective of the present study was to characterize the impact of hypoxia on the cognitive and psychological profile following COVID-19. METHODS: Sixty-two patients with COVID-19 were enrolled in a cross-sectional study and divided into two groups based on disease severity: outpatients with no pulmonary complications vs. inpatients with hypoxemic pneumonia having received oxygen therapy. All the participants underwent a comprehensive neuropsychological evaluation that included depression, anxiety, fatigue, sleepiness, attentional, memory and executive processes, and social cognition. For the inpatients, we also collected laboratory data (blood gas, blood glucose, fibrin, fibrinogen, D-dimer, and C-reactive protein). RESULTS: Cognitive disorders was found in patients with COVID-19: at least 18% had an impairment of memory and 11% had attentional dysfunctions. A high level of fatigue (90% of the patients), anxiety (52%), and depression (50%) was also observed. The impairments in attentional (p < 0.001 for omission and commission in CPT 3) and memory (p < 0.003 for Index Cue Efficiency from free and cue selected reminding test) functions were greater in COVID-19 inpatients that in COVID-19 outpatients. In contrast, levels of fatigue, depression, and anxiety were similarly high in both groups. CONCLUSIONS: These findings might help to improve the management of COVID-19 patients as a function of the disease severity in particular for patients with hypoxia.

The Role of Na+/K+-ATPase in the Development of Hyponatrenemia under Conditions of Hypoxic Stress in Patients with SARS-CoV-2 Infection.

We studied laboratory parameters of patients with COVID-19 against the background of chronic pathologies (cardiovascular pathologies, obesity, type 2 diabetes melitus, and cardiovascular pathologies with allergy to statins). A decrease in pH and a shift in the electrolyte balance of blood plasma were revealed in all studied groups and were most pronounced in patients with cardiovascular pathologies with allergy to statin. It was found that low pH promotes destruction of lipid components of the erythrocyte membranes in patients with chronic pathologies, which was seen from a decrease in Na+/K+-ATPase activity and significant hyponatrenemia. In patients with cardiovascular pathologies and allergy to statins, erythrocyte membranes were most sensitive to a decrease in pH, while erythrocyte membranes of obese patients showed the greatest resistance to low pH and oxidative stress.

Admission criteria in critically ill COVID-19 patients: A physiology-based approach.

INTRODUCTION: The COVID-19 pandemic required careful management of intensive care unit (ICU) admissions, to reduce ICU overload while facing limitations in resources. We implemented a standardized, physiology-based, ICU admission criteria and analyzed the mortality rate of patients refused from the ICU. MATERIALS AND METHODS: In this retrospective observational study, COVID-19 patients proposed for ICU admission were consecutively analyzed; Do-Not-Resuscitate patients were excluded. Patients presenting an oxygen peripheral saturation (SpO2) lower than 85% and/or dyspnea and/or mental confusion resulted eligible for ICU admission; patients not presenting these criteria remained in the ward with an intensive monitoring protocol. Primary outcome was both groups' survival rate. Secondary outcome was a sub analysis correlating SpO2 cutoff with ICU admission. RESULTS: From March 2020 to January 2021, 1623 patients were admitted to our Center; 208 DNR patients were excluded; 97 patients were evaluated. The ICU-admitted group (n = 63) mortality rate resulted 15.9% at 28 days and 27% at 40 days; the ICU-refused group (n = 34) mortality rate resulted 0% at both intervals (p < 0.001). With a SpO2 cut-off of 85%, a significant correlation was found (p = 0.009), but with a 92% a cut-off there was no correlation with ICU admission (p = 0.26). A similar correlation was also found with dyspnea (p = 0.0002). CONCLUSION: In COVID-19 patients, standardized ICU admission criteria appeared to safely reduce ICU overload. In the absence of dyspnea and/or confusion, a SpO2 cutoff up to 85% for ICU admission was not burdened by negative outcomes. In a pandemic context, the SpO2 cutoff of 92%, as a threshold for ICU admission, needs critical re-evaluation.

Enhanced platelet inhibition treatment improves hypoxemia in patients with severe Covid-19 and hypercoagulability. A case control, proof of concept study.

Patients affected by severe coronavirus induced disease-2019 (Covid-19) often experience hypoxemia due to alveolar involvement and endothelial dysfunction, which leads to the formation of micro thrombi in the pulmonary capillary vessels. Both hypoxemia and a prothrombotic diathesis have been associated with more severe disease and increased risk of death. To date, specific indications to treat this condition are lacking. This was a single center, investigator initiated, compassionate use, proof of concept, case control, phase IIb study (NCT04368377) conducted in the Intermediate Respiratory Care Unit of L. Sacco University Hospital in Milano, Italy. Our objective was to explore the effects of the administration of anti-platelet therapy on arterial oxygenation and clinical outcomes in patients with severe Covid-19 with hypercoagulability. We enrolled five consecutive patients with laboratory confirmed SARS-CoV-2 infection, severe respiratory failure requiring helmet continuous positive airway pressure (CPAP), bilateral pulmonary infiltrates and a pro-thrombotic state identified as a D-dimer > 3 times the upper limit of normal. Five patients matched for age, D-dimer value and SOFA score formed the control group. Beyond standard of care, treated patients received 25 µg/Kg/body weight tirofiban as bolus infusion, followed by a continuous infusion of 0.15 µg/Kg/body weight per minute for 48 hours. Before tirofiban, patients received acetylsalicylic acid 250 mg infusion and oral clopidogrel 300 mg; both were continued at a dose of 75 mg daily for 30 days. Fondaparinux2.5 mg/day sub-cutaneous was given for the duration of the hospital stay. All controls were receiving prophylactic or therapeutic dose heparin, according to local standard operating procedures. Treated patients consistently experienced a mean (SD) reduction in A-a O2 gradient of -32.6 mmHg (61.9, P = 0.154), -52.4 mmHg (59.4, P = 0.016) and -151.1 mmHg (56.6, P = 0.011; P = 0.047 vs. controls) at 24, 48 hours and 7 days after treatment. PaO2/FiO2 ratio increased by 52 mmHg (50, P = 0.172), 64 mmHg (47, P = 0.040) and 112 mmHg (51, P = 0.036) after 24, 48 hours and 7 days, respectively. All patients but one were successfully weaned from CPAP after 3 days. This was not true for the control group. No major adverse events were observed. Antiplatelet therapy might be effective in improving the ventilation/perfusion ratio in Covid-19 patients with severe respiratory failure. The effects might be sustained by the prevention and interference on forming clots in lung capillary vessels and by modulating megakaryocytes' function and platelet adhesion. Randomized clinical trials are urgently needed to confirm these results.

Characteristics and predictors for silent hypoxemia in a cohort of hospitalized COVID-19 patients.

BACKGROUND: An intriguing feature recently unveiled in some COVID-19 patients is the "silent hypoxemia" phenomenon, which refers to the discrepancy of subjective well-being sensation while suffering hypoxia, manifested as the absence of dyspnea. OBJECTIVE: To describe the clinical characteristics and predictors of silent hypoxemia in hospitalized COVID-19 patients. METHODS: We conducted a prospective cohort study including consecutive hospitalized adult (≥ 18 years) patients with confirmed COVID-19 presenting to the emergency department with oxygen saturation (SpO2) ≤ 80% on room air from March 15 to June 30, 2020. We analyzed the characteristics, disease severity, and in-hospital outcomes of patients presenting with dyspnea and those without dyspnea (silent hypoxemia). RESULTS: We studied 470 cases (64.4% men; median age 55 years, interquartile range 46-64). There were 447 (95.1%) patients with dyspnea and 23 (4.9%) with silent hypoxemia. The demographic and clinical characteristics, comorbidities, laboratory and imaging findings, disease severity, and outcomes were similar between groups. Higher breathing and heart rates correlated significantly with lower SpO2 in patients with dyspnea but not in those with silent hypoxemia. Independent predictors of silent hypoxemia were the presence of new-onset headache (OR 2.919, 95% CI 1.101-7.742; P = 0.031) and presenting to the emergency department within the first eight days after symptoms onset (OR 3.183, 95% CI 1.024-9.89; P = 0.045). CONCLUSIONS: Patients with silent hypoxemia sought medical attention earlier and had new-onset headache more often. They were also likely to display lower hemodynamic compensatory responses to hypoxemia, which may underestimate the disease severity.

Syncope and silent hypoxemia in COVID-19: Implications for the autonomic field.

Coronavirus-19 (COVID-19), the infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has wreaked havoc across the globe since its emergence in December 2019. Reports of patients presenting with syncope and pre-syncope, as well as hypoxemia without symptoms of dyspnea ("silent hypoxemia"), have led researchers to speculate whether SARS-CoV-2 can alter autonomic nervous system function. As viral infections are commonly reported triggers of altered autonomic control, we must consider whether SARS-CoV-2 can also interfere with autonomic activity, at least in some patients. As we are still in the early stages of understanding COVID-19, we still do not know whether syncope and silent hypoxemia are more strongly associated with COVID-19 compared to any other viral infections that severely compromise gas exchange. Therefore, in this perspective we discuss these two intriguing clinical presentations, as they relate to autonomic nervous system function. In our discussion, we will explore COVID-specific, as well as non-COVID specific mechanisms that may affect autonomic activity and potential therapeutic targets. As we move forward in our understanding of COVID-19, well-designed prospective studies with appropriate control and comparator groups will be necessary to identify potential unique effects of COVID-19 on autonomic function.

Identification of VEGFA-centric temporal hypoxia-responsive dynamic cardiopulmonary network biomarkers.

AIMS: Hypoxia, a pathophysiological condition, is profound in several cardiopulmonary diseases (CPD). Every individual's lethality to a hypoxia state differs in terms of hypoxia exposure time, dosage units and dependent on the individual's genetic makeup. Most of the proposed markers for CPD were generally aim to distinguish disease samples from normal samples. Although, as per the 2018 GOLD guidelines, clinically useful biomarkers for several cardio pulmonary disease patients in stable condition have yet to be identified. We attempt to address these key issues through the identification of Dynamic Network Biomarkers (DNB) to detect hypoxia induced early warning signals of CPD before the catastrophic deterioration. MATERIALS AND METHODS: The human microvascular endothelial tissues microarray datasets (GSE11341) of lung and cardiac expose to hypoxia (1% O2) for 3, 24 and 48 h were retrieved from the public repository. The time dependent differentially expressed genes were subjected to tissue specificity and promoter analysis to filtrate the noise levels in the networks and to dissect the tissue specific hypoxia induced genes. These filtered out genes were used to construct the dynamic segmentation networks. The hypoxia induced dynamic differentially expressed genes were validated in the lung and heart tissues of male rats. These rats were exposed to hypobaric hypoxia (simulated altitude of 25,000 or PO2 - 282 mm of Hg) progressively for 3, 24 and 48 h. KEY FINDINGS: To identify the temporal key genes regulated in hypoxia, we ranked the dominant genes based on their consolidated topological features from tissue specific networks, time dependent networks and dynamic networks. Overall topological ranking described VEGFA as a single node dynamic hub and strongly communicated with tissue specific genes to carry forward their tissue specific information. We named this type of VEGFAcentric dynamic networks as "V-DNBs". As a proof of principle, our methodology helped us to identify the V-DNBs specific for lung and cardiac tissues namely V-DNBL and V-DNBC respectively. SIGNIFICANCE: Our experimental studies identified VEGFA, SLC2A3, ADM and ENO2 as the minimum and sufficient candidates of V-DNBL. The dynamic expression patterns could be readily exploited to capture the pre disease state of hypoxia induced pulmonary vascular remodelling. Whereas in V-DNBC the minimum and sufficient candidates are VEGFA, SCL2A3, ADM, NDRG1, ENO2 and BHLHE40. The time dependent single node expansion indicates V-DNBC could also be the pre disease state pathological hallmark for hypoxia-associated cardiovascular remodelling. The network cross-talk and expression pattern between V-DNBL and V-DNBC are completely distinct. On the other hand, the great clinical advantage of V-DNBs for pre disease predictions, a set of samples during the healthy condition should suffice. Future clinical studies might further shed light on the predictive power of V-DNBs as prognostic and diagnostic biomarkers for CPD.

Clinical Characteristics of COVID-19 Related Deaths in Ethiopia.

BACKGROUND: Since the occurrence of COVID-19 in the world, it has claimed nearly 1.39 million human lives in the world and more than 1500 lives in Ethiopia. The number of deaths is increasing with variable distribution in the world. Despite its increasing fatality, the clinical characteristics of the deceased patients are not yet fully known. Analyzing the clinical characteristics of deceased patients will help to improve the outcome of infected patients. Hence, this study aimed to determine the clinical characteristics of patients who died due to COVID-19 in Ethiopia. METHODS: Hospital based multi-center cross-sectional study was conducted using chart review of deceased patients. Since the number of COVID-19 related deaths was limited, all consecutive COVID-19 related hospital deaths were analyzed. The data was entered into and analyzed using SPSS version 25.0. Descriptive statistics was used to explain the data collected from the survey. RESULT: A total of 92 deceased patient charts were analyzed. Of these patients, 65(71%) were males. Age ranged from 17 to 92 years (mean age being 59 years). On arrival vital signs, 60.5% of them had hypoxia, 49% had tachycardia and only 32% of patients had fever. Three fourth of the patients 64/85 had at least one comorbidity. Diabetes mellitus (DM) was the commonest comorbidity accounting for 445.9%, followed by hypertension, 23/85(27%), and HIV/ AIDS, 15/85 (17.5%). CONCLUSION: The results of this study showed that COVID-19 deceased patients presented with respiratory failure and hypoxia. However, less than a third of these patients had fever. In addition, the presence of comorbid illnesses and non-COVID-19 diseases like AIDS defining illness in significant amount needs further study to identify their level of contribution to the increasing burden of COVID-19 deaths in Ethiopia.