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In this study, we present four cases of Human Bocavirus (HBoV) infection in children aged between 1 month and 4 years. Among these cases, two siblings were hospitalized with similar symptoms. Among the four pediatric cases of patients with HBoV infection, three were associated with acute respiratory failure and spontaneous pneumothorax, and two of these presented with subcutaneous emphysema. The presented patients were young children, aged between 1 month and 4 years, two of whom were siblings, suggesting a possible intrafamilial transmission of HBoV1 infection. These cases highlight the importance of considering HBoV as a differential diagnosis in pediatric patients with respiratory and gastrointestinal symptoms. Early recognition and appropriate medical care are important in treating HBoV infection in young children.

Goal: Analysis of the results of thrombectomy from the arteries of the lower extremities in patients with COVID-19 against the background of different severity of respiratory failure., Materials and Methods: This retrospective, cohort, comparative study for the period from 05/01/2022 to 20/07/2022 included 305 patients with acute thrombosis of the arteries of the lower extremities against the background of the course of COVID-19 (SARS-CoV-2 Omicron variant). Depending on the type of oxygen support, 3 groups of patients were formed: group 1 ( n = 168) - oxygen insufflation through nasal cannulas; group 2 ( n = 92) - non-invasive lung ventilation; and group 3 ( n = 45) - artificial lung ventilation., Results: Myocardial infarction and ischemic stroke were not detected in the total sample. The highest number of deaths (group 1: 5.3%, n = 9; group 2: 72.8%, n = 67; group 3: 100%, n = 45; p < 0.0001), rethrombosis (group 1 : 18.4%, n = 31; group 2: 69.5%, n = 64; group 3: 91.1%, n = 41; p < 0.0001), and limb amputations (group 1: 9.5%, n = 16; group 2: 56.5%, n = 52; group 3: 91.1%, n = 41; p < 0.0001) was recorded in group 3 (ventilated) patients., Conclusion: In patients infected with COVID-19 and on artificial lung ventilation, a more aggressive course of the disease is noted, expressed in an increase in laboratory parameters (C-reactive protein, ferritin, interleukin-6, and D-dimer) of the degree of pneumonia (CT-4 in overwhelming number) and localization of thrombosis of the arteries of the lower extremities, mainly in the tibial arteries., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

COVID-19 syndrome is characterized by acute lung injury, hypoxemic respiratory failure, and high mortality. Alveolar type 2 (AT2) cells are essential for gas exchange, repair, and regeneration of distal lung epithelium. We have shown that the causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and other members of the β-coronavirus genus induce an endoplasmic reticulum (ER) stress response in vitro; however, the consequences for host AT2 cell function in vivo are less understood. To study this, two murine models of coronavirus infection were used-mouse hepatitis virus-1 (MHV-1) in A/J mice and a mouse-adapted SARS-CoV-2 strain. MHV-1-infected mice exhibited dose-dependent weight loss with histological evidence of distal lung injury accompanied by elevated bronchoalveolar lavage fluid (BALF) cell counts and total protein. AT2 cells showed evidence of both viral infection and increased BIP/GRP78 expression, consistent with activation of the unfolded protein response (UPR). The AT2 UPR included increased inositol-requiring enzyme 1α (IRE1α) signaling and a biphasic response in PKR-like ER kinase (PERK) signaling accompanied by marked reductions in AT2 and BALF surfactant protein (SP-B and SP-C) content, increases in surfactant surface tension, and emergence of a reprogrammed epithelial cell population ( Krt8 + and Cldn4 + ). The loss of a homeostatic AT2 cell state was attenuated by treatment with the IRE1α inhibitor OPK-711. As a proof-of-concept, C57BL6 mice infected with mouse-adapted SARS-CoV-2 demonstrated similar lung injury and evidence of disrupted surfactant homeostasis. We conclude that lung injury from β-coronavirus infection results from an aberrant host response, activating multiple AT2 UPR stress pathways, altering surfactant metabolism/function, and changing AT2 cell state, offering a mechanistic link between SARS-CoV-2 infection, AT2 cell biology, and acute respiratory failure. NEW & NOTEWORTHY COVID-19 syndrome is characterized by hypoxemic respiratory failure and high mortality. In this report, we use two murine models to show that β-coronavirus infection produces acute lung injury, which results from an aberrant host response, activating multiple epithelial endoplasmic reticular stress pathways, disrupting pulmonary surfactant metabolism and function, and forcing emergence of an aberrant epithelial transition state. Our results offer a mechanistic link between SARS-CoV-2 infection, AT2 cell biology, and respiratory failure.

Cell-free DNA (cfDNA) is released from injured cells and aggravates inflammation. Patients with coronavirus disease (COVID-19) often develop pneumonia and respiratory failure, and require oxygen therapy (OT), including mechanical ventilation (MV). It remains unclear whether cfDNA predicts the risk of receiving OT or MV in COVID-19 patients. Therefore, we hypothesized that circulating cfDNA levels could reflect the severity of respiratory failure and determine a therapeutic approach for oxygenation in patients with COVID-19. We analyzed cfDNA levels in serum samples from 95 hospitalized patients with COVID-19 at Showa University Hospital (Tokyo, Japan). cfDNA levels were assessed by measuring the copy numbers of mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) using quantitative real-time PCR (qPCR). Both cf-nDNA and cf-mtDNA levels were negatively correlated with adjusted SpO 2 for FiO 2 (SpO 2 /FiO 2 ratio). Elevated cf-nDNA and cf-mtDNA levels were associated with the requirement for OT or MV during patient admission. Multivariate logistic regression analysis revealed that cf-nDNA and cf-mtDNA levels were independent risk factors for OT and MV. These results suggest that both serum cf-nDNA and cf-mtDNA could serve as useful early biomarkers to indicate the necessity of OT or MV in patients with COVID-19., (© 2024. The Author(s).)

Background: Respiratory syncytial virus (RSV) is widely recognized as a cause of acute respiratory failure in infants and immunocompromised patients. However, RSV can also contribute to acute respiratory failure in adults, particularly among the elderly population. The objective of this study was to analyze the clinical characteristics and outcomes of immunocompetent adults hospitalized for RSV infection., Methods: This retrospective study included all immunocompetent adult patients consecutively admitted to a tertiary care hospital with RSV-related acute respiratory failure over a seven-year period (2016-2023). Diagnosis of RSV infection was made through nasal swabs or pulmonary samples, with multiplex reverse transcription polymerase chain reaction (RT-PCR). Patients were eligible for inclusion if they required supplemental oxygen therapy for at least 48 h., Results: One hundred and four patients met the inclusion criteria. Median age [IQR] was 77 years [67-85]. Ninety-seven patients had at least one comorbidity (97/104, 93%). At the time of RSV diagnosis, 67 patients (67/104, 64%) experienced acute decompensation of a pre-existing chronic comorbidity. Antibiotics were started in 80% (77/104) of patients; however, only 16 patients had a confirmed diagnosis of bacterial superinfection. Twenty-six patients needed ventilatory support (26/104, 25%) and 21 were admitted to the intensive care unit (21/104, 20%). The median duration of oxygen therapy [IQR] was 6 days [3-9], while the median hospital length of stay [IQR] was 11 days [6-15]. The overall mortality rate within 1 month of hospital admission was 13% (14/104). The sole variables associated with one-month mortality were age and maximum oxygen flow during hospitalization., Conclusion: RSV-associated acute respiratory failure affected elderly individuals with multiple comorbidities and was associated with prolonged hospitalization and a high mortality rate., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. PL has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astrazeneca, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Moderna, Pfizer, Sanofi Pasteur and support for attending meetings and/or travel from Astrazeneca, Pfizer and Sanofi Pasteur. VB received support for attending meetings from LFB and worked with the advisory boards of Biotest, Novartis and Takeda., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The SARS CoV-2 pandemic has resulted in more than 1.1 million deaths in the USA alone. Therapeutic options for critically ill patients with COVID-19 are limited. Prior studies showed that post-infection treatment of influenza A virus-infected mice with the liponucleotide CDP-choline, which is an essential precursor for de novo phosphatidylcholine synthesis, improved gas exchange and reduced pulmonary inflammation without altering viral replication. In unpublished studies, we found that treatment of SARS CoV-2-infected K18-hACE2-transgenic mice with CDP-choline prevented development of hypoxemia. We hypothesize that administration of citicoline (the pharmaceutical form of CDP-choline) will be safe in hospitalized SARS CoV-2-infected patients with hypoxemic acute respiratory failure (HARF) and that we will obtain preliminary evidence of clinical benefit to support a larger Phase 3 trial using one or more citicoline doses., Methods: We will conduct a single-site, double-blinded, placebo-controlled, and randomized Phase 1/2 dose-ranging and safety study of Somazina® citicoline solution for injection in consented adults of any sex, gender, age, or ethnicity hospitalized for SARS CoV-2-associated HARF. The trial is named "SCARLET" (Supplemental Citicoline Administration to Reduce Lung injury Efficacy Trial). We hypothesize that SCARLET will show that i.v. citicoline is safe at one or more of three doses (0.5, 2.5, or 5 mg/kg, every 12 h for 5 days) in hospitalized SARS CoV-2-infected patients with HARF (20 per dose) and provide preliminary evidence that i.v. citicoline improves pulmonary outcomes in this population. The primary efficacy outcome will be the S p O 2 :F i O 2 ratio on study day 3. Exploratory outcomes include Sequential Organ Failure Assessment (SOFA) scores, dead space ventilation index, and lung compliance. Citicoline effects on a panel of COVID-relevant lung and blood biomarkers will also be determined., Discussion: Citicoline has many characteristics that would be advantageous to any candidate COVID-19 therapeutic, including safety, low-cost, favorable chemical characteristics, and potentially pathogen-agnostic efficacy. Successful demonstration that citicoline is beneficial in severely ill patients with SARS CoV-2-induced HARF could transform management of severely ill COVID patients., Trial Registration: The trial was registered at www., Clinicaltrials: gov on 5/31/2023 (NCT05881135)., Trial Status: Currently enrolling., (© 2024. The Author(s).)

The COVID-19 pandemic has undeniably changed the way intensivists manage acute hypoxaemic respiratory failure. Paradigms had evolved particularly in the way we support patients with respiratory failure, and the adjunctive therapies which can be used. Many questions have been answered, and many more generated, from the last few years. For example, is COVID-19 acute respiratory failure and acute respiratory distress syndrome similar to non-COVID-19? How can we personalize therapy in patients with COVID-19, and what are some new statistical tools that we can use to aid in this approach? Is intubation and invasive mechanical ventilation the only way to support patients with acute respiratory failure, or can we turn to other modalities of respiratory support? And what about patients with the most severe form of respiratory failure, how can we support them? In this chapter, we explore the lessons learnt, identifying gaps and advances in knowledge in terms of the pathophysiology of acute respiratory failure, its prognostic factors, oxygen supports, and other therapies. We also touch on how physicians treating patients can tap on international networks to create a "whole that is more than the sum of its parts", and impart clinical insights on the management of acute respiratory failure. Finally, we highlight the importance of a cautious skepticism in our approach to both clinical medicine and evidence-based medicine, highlighting how evidence in a pandemic can rapidly evolve both within an ICU, and longitudinally around the world., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

The coronavirus disease 2019 (COVID-19) pandemic has unquestionably transformed the field of intensive care medicine. Never have we witnessed millions of patients develop acute respiratory failure in such a short span of time. This led to extensive resource constraints and difficulty in treating patients. However, this also gave rise to several innovations that have spurred the development and progress of intensive care medicine as a specialty. In this chapter, we explore an overview of frailty, the impact of frailty in patients with severe COVID-19 respiratory failure, and the available supports, by summarising the current literature. This chapter also discusses the lessons learnt from each of the sections that can be applied to daily clinical practice. The chapter also proposes insights into future research., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Aiming to reduce mortality in COVID-19 with severe respiratory failure we administered a combined rescue treatment (COMBI) on top of standard-of-care (SOC: dexamethasone/heparin) consisted of inhaled DNase to dissolve thrombogenic neutrophil extracellular traps, plus agents against cytokine-mediated hyperinflammation, namely anti-IL-6-receptor tocilizumab and JAK1/2 inhibitor baricitinib. Patients with PaO2/FiO2 < 100 mmHg were analysed. COMBI group (n = 22) was compared with similar groups that had received SOC alone (n = 26) or SOC plus monotherapy with either IL-1-receptor antagonist anakinra (n = 19) or tocilizumab (n = 11). COMBI was significantly associated with lower in-hospital mortality and intubation rate, shorter duration of hospitalization, and prolonged overall survival after a median follow-up of 110 days. In vitro, COVID-19 plasma induced tissue factor/thrombin pathway in primary lung fibroblasts. This effect was inhibited by the immunomodulatory agents of COMBI providing a mechanistic explanation for the clinical observations. These results support the conduct of randomized trials using combined immunomodulation in COVID-19 to target multiple interconnected pathways of immunothrombosis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Severe hypoxic respiratory failure from COVID-19 pneumonia carries a high mortality risk. There is uncertainty surrounding which patients benefit from corticosteroids in combination with tocilizumab and the dosage and timing of these agents. The balance of controlling inflammation without increasing the risk of secondary infection is difficult. At present, dexamethasone 6 mg is the standard of care in COVID-19 hypoxia; whether this is the ideal choice of steroid or dosage remains to be proven., Objectives: The primary objective was to assess the impact on mortality of tocilizumab only, corticosteroids only, and combination therapy in patients with COVID-19 respiratory failure., Methods: A multihospital, retrospective study of adult patients with severe respiratory failure from COVID-19 who received supportive therapy, corticosteroids, tocilizumab, or combination therapy were assessed for 28-day mortality, biomarker improvement, and relative risk of infection. Propensity-matched analysis was performed between corticosteroid alone and combination therapies to further assess mortality benefit., Results: The steroid-only, tocilizumab-only, and combination groups showed hazard reduction in mortality at 28 days when compared with supportive therapy. In a propensity-matched analysis, the combination group (daily equivalent dexamethasone 10 mg and tocilizumab 400 mg) had an improved 28-day mortality compared with the steroid-only group (daily equivalent dexamethasone 10 mg; hazard ratio (95% CI) = 0.56 (0.38-0.84), P = 0.005] without increasing the risk of infection., Conclusion and Relevance: Combination of tocilizumab and corticosteroids was associated with improved 28-day survival when compared with corticosteroids alone. Modification of steroid dosing strategy as well as steroid type may further optimize therapeutic effect of the COVID-19 treatment.

Background: The role of type I interferons (IFNs) in the early phase of COVID-19 remains unclear., Objectives: To evaluate the relationship between IFN-I levels in patients with COVID-19 and clinical presentation, SARS-CoV-2 viral load, and other major pro-inflammatory cytokines., Methods: This prospective observational study recruited patients hospitalized with COVID-19. The levels of interferon-alpha (IFN-α), interferon-beta (IFN-β), interleukin-6 (IL-6), and C-X-C motif chemokine ligand (CXCL10) within 5 days after symptom onset were measured using an ELISA, in serum from blood collected within 5 days after the onset of symptoms. The SARS-CoV-2 viral load was determined via qPCR using nasal-swab specimens and serum., Results: The study enrolled 50 patients with COVID-19. IFN-α levels were significantly higher in patients who presented with pneumonia or developed hypoxemic respiratory failure (p < 0.001). Furthermore, IFN-α levels were associated with viral load in nasal-swab specimens and RNAemia (p < 0.05). In contrast, there was no significant association between IFN-β levels and the presence of pneumonia or RNAemia, despite showing a stronger association with nasal-swab viral load (p < 0.001). Correlation analysis showed that the serum levels of IFN-α significantly correlated with those of IFN-β, IL-6, and CXCL10, while the levels of IFN-β did not correlate with those of IL-6 or CXCL10., Conclusions: Serum IFN-I levels in the early phase of SARS-CoV-2 infection were higher in patients who developed hypoxemic respiratory failure. The association between IFN-α, IL-6, and CXCL10 may reflect the systemic immune response against SARS-CoV-2 invasion into pulmonary circulation, which might be an early predictor of respiratory failure due to COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nagaoka, Kawasuji, Murai, Kaneda, Ueno, Miyajima, Fukui, Morinaga and Yamamoto.)

Objectives/hypothesis: Prone positioning is frequently used in patients intubated for COVID-19-related lung injury to improve oxygenation. At our institution, we observed severe tongue edema develop in some of these patients. Hence, we sought to determine the incidence of tongue edema in this cohort and whether prone positioning was a risk factor associated with this complication., Study Design: Retrospective cohort study., Methods: A single-system retrospective cohort study of patients intubated for respiratory failure secondary to COVID-19 who subsequently developed clinically notable tongue edema from March 13 to July 5, 2020., Results: 260 patients were intubated for COVID-19-related respiratory failure during the study period. 158 patients (60.8%) underwent at least one episode of proning. Twelve patients in total (4.6%) developed clinically significant tongue edema. Eleven of the twelve patients (91.7%) who developed tongue edema underwent proning prior to the development of edema. Prone positioning was associated with an increased incidence of tongue edema (odds ratio [OR] 7.56, 95% confidence interval [CI] 0.96-59.46, P = .027). In all proned patients who developed edema, this complication was noted during proning or shortly after supination (range, 0-4 days). Tongue edema was primarily managed with conservative measures; one patient required tracheostomy for definitive management., Conclusions: Tongue edema appears to develop in a subset of patients with COVID-19 who are intubated. It appears to be associated with prone positioning but is likely multifactorial in nature. Further investigation into its incidence and pathophysiology is warranted., Level of Evidence: 4 Laryngoscope, 132:287-289, 2022., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: In patients with COVID-19-related acute respiratory failure (ARF), awake prone positioning (AW-PP) reduces the need for intubation in patients treated with high-flow nasal oxygen (HFNO). However, the effects of different exposure times on clinical outcomes remain unclear. We evaluated the effect of AW-PP on the risk of endotracheal intubation and in-hospital mortality in patients with COVID-19-related ARF treated with HFNO and analyzed the effects of different exposure times to AW-PP., Methods: This multicenter prospective cohort study in six ICUs of 6 centers in Argentine consecutively included patients > 18 years of age with confirmed COVID-19-related ARF requiring HFNO from June 2020 to January 2021. In the primary analysis, the main exposure was awake prone positioning for at least 6 h/day, compared to non-prone positioning (NON-PP). In the sensitivity analysis, exposure was based on the number of hours receiving AW-PP. Inverse probability weighting-propensity score (IPW-PS) was used to adjust the conditional probability of treatment assignment. The primary outcome was endotracheal intubation (ETI); and the secondary outcome was hospital mortality., Results: During the study period, 580 patients were screened and 335 were included; 187 (56%) tolerated AW-PP for [median (p25-75)] 12 (9-16) h/day and 148 (44%) served as controls. The IPW-propensity analysis showed standardized differences < 0.1 in all the variables assessed. After adjusting for other confounders, the OR (95% CI) for ETI in the AW-PP group was 0.36 (0.2-0.7), with a progressive reduction in OR as the exposure to AW-PP increased. The adjusted OR (95% CI) for hospital mortality in the AW-PP group ≥ 6 h/day was 0.47 (0.19-1.31). The exposure to prone positioning ≥ 8 h/d resulted in a further reduction in OR [0.37 (0.17-0.8)]., Conclusion: In the study population, AW-PP for ≥ 6 h/day reduced the risk of endotracheal intubation, and exposure ≥ 8 h/d reduced the risk of hospital mortality., (© 2022. The Author(s).)

Background: Most COVID-19 infections result in a viral syndrome characterized by fever, cough, shortness of breath, and myalgias. A small but significant proportion of patients develop severe COVID-19 resulting in respiratory failure. Many of these patients also develop multi-organ dysfunction as a byproduct of their critical illness. Although heart failure can be a part of this, there also appears to be a subset of patients who have primary cardiac collapse from COVID-19., Objective: Conduct a systematic review of COVID-19-associated myocarditis, including clinical presentation, risk factors, and prognosis., Discussion: Our review demonstrates two distinct etiologies of primary acute heart failure in surprisingly equal incidence in patients with COVID-19: viral myocarditis and Takotsubo cardiomyopathy. COVID myocarditis, Takotsubo cardiomyopathy, and severe COVID-19 can be clinically indistinguishable. All can present with dyspnea and evidence of cardiac injury, although in myocarditis and Takotsubo this is due to primary cardiac dysfunction as compared to respiratory failure in severe COVID-19., Conclusion: COVID-19-associated myocarditis differs from COVID-19 respiratory failure by an early shock state. However, not all heart failure from COVID-19 is from direct viral infection; some patient's develop takotsubo cardiomyopathy. Regardless of etiology, steroids may be a beneficial treatment, similar to other critically ill COVID-19 patients. Evidence of cardiac injury in the form of ECG changes or elevated troponin in patients with COVID-19 should prompt providers to consider concurrent myocarditis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Abstract: Although the number of deaths due to coronavirus disease 2019 (COVID-19) is higher in men than women, prior studies have provided limited sex-stratified clinical data.We evaluated sex-related differences in clinical outcomes among critically ill adults with COVID-19.Multicenter cohort study of adults with laboratory-confirmed COVID-19 admitted to intensive care units at 67 U.S. hospitals from March 4 to May 9, 2020. Multilevel logistic regression was used to evaluate 28-day in-hospital mortality, severe acute kidney injury (AKI requiring kidney replacement therapy), and respiratory failure occurring within 14 days of intensive care unit admission.A total of 4407 patients were included (median age, 62 years; 2793 [63.4%] men; 1159 [26.3%] non-Hispanic White; 1220 [27.7%] non-Hispanic Black; 994 [22.6%] Hispanic). Compared with women, men were younger (median age, 61 vs 64 years, less likely to be non-Hispanic Black (684 [24.5%] vs 536 [33.2%]), and more likely to smoke (877 [31.4%] vs 422 [26.2%]). During median follow-up of 14 days, 1072 men (38.4%) and 553 women (34.3%) died. Severe AKI occurred in 590 men (21.8%), and 239 women (15.5%), while respiratory failure occurred in 2255 men (80.7%) and 1234 women (76.5%). After adjusting for age, race/ethnicity and clinical variables, compared with women, men had a higher risk of death (OR, 1.50, 95% CI, 1.26-1.77), severe AKI (OR, 1.92; 95% CI 1.57-2.36), and respiratory failure (OR, 1.42; 95% CI, 1.11-1.80).In this multicenter cohort of critically ill adults with COVID-19, men were more likely to have adverse outcomes compared with women., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Hand, foot and mouth disease (HFMD) is a common infectious disease in western Asia area and the full range of the long-term sequelae of HFMD remains poorly described. We conducted a retrospective hospital-based cohort study of HFMD patients with central nervous system (CNS) complications caused by EV-A71 or CV-A16 between 2010 and 2016. Patients were classified into three groups, including CNS only, autonomic nervous system (ANS) dysregulation, and cardiorespiratory failure. Neurologic examination, neurodevelopmental assessments, Magnetic Resonance Imaging (MRI) and lung function, were performed at follow up. Of the 176 patients followed up, 24 suffered CNS only, 133 ANS dysregulation, and 19 cardiorespiratory failure. Median follow-up period was 4.3 years (range [1.4-8.3]). The rate of neurological abnormalities was 25% (43 of 171) at discharge and 10% (17 of 171) at follow-up. The rates of poor outcome were significantly different between the three groups of complications in motor (28%, 38%, 71%) domain (p=0.020), but not for cognitive (20%, 24%, 35%), language (25%, 36%, 41%) and adaptive (24%, 16%, 26%) domains ( p  = 0.537, p  = 0.551, p  = 0.403). For children with ventilated during hospitalization, 41% patients (14 of 34) had an obstructive ventilatory defect, and one patient with scoliosis had mixed ventilatory dysfunction. Persistent abnormalities on brain MRI were 0% (0 of 7), 9% (2 of 23) and 57% (4 of 7) in CNS, ANS and cardiorespiratory failure group separately. Patients with HFMD may have abnormalities in neurological, motor, language, cognition, adaptive behaviour and respiratory function. Long-term follow-up programmes for children's neurodevelopmental and respiratory function may be warranted.

Background: Infections with SARS-CoV-2 continue to cause significant morbidity and mortality. Interleukin (IL)-1 and IL-6 blockade have been proposed as therapeutic strategies in COVID-19, but study outcomes have been conflicting. We sought to study whether blockade of the IL-6 or IL-1 pathway shortened the time to clinical improvement in patients with COVID-19, hypoxic respiratory failure, and signs of systemic cytokine release syndrome., Methods: We did a prospective, multicentre, open-label, randomised, controlled trial, in hospitalised patients with COVID-19, hypoxia, and signs of a cytokine release syndrome across 16 hospitals in Belgium. Eligible patients had a proven diagnosis of COVID-19 with symptoms between 6 and 16 days, a ratio of the partial pressure of oxygen to the fraction of inspired oxygen (PaO 2 :FiO 2 ) of less than 350 mm Hg on room air or less than 280 mm Hg on supplemental oxygen, and signs of a cytokine release syndrome in their serum (either a single ferritin measurement of more than 2000 μg/L and immediately requiring high flow oxygen or mechanical ventilation, or a ferritin concentration of more than 1000 μg/L, which had been increasing over the previous 24 h, or lymphopenia below 800/mL with two of the following criteria: an increasing ferritin concentration of more than 700 μg/L, an increasing lactate dehydrogenase concentration of more than 300 international units per L, an increasing C-reactive protein concentration of more than 70 mg/L, or an increasing D-dimers concentration of more than 1000 ng/mL). The COV-AID trial has a 2 × 2 factorial design to evaluate IL-1 blockade versus no IL-1 blockade and IL-6 blockade versus no IL-6 blockade. Patients were randomly assigned by means of permuted block randomisation with varying block size and stratification by centre. In a first randomisation, patients were assigned to receive subcutaneous anakinra once daily (100 mg) for 28 days or until discharge, or to receive no IL-1 blockade (1:2). In a second randomisation step, patients were allocated to receive a single dose of siltuximab (11 mg/kg) intravenously, or a single dose of tocilizumab (8 mg/kg) intravenously, or to receive no IL-6 blockade (1:1:1). The primary outcome was the time to clinical improvement, defined as time from randomisation to an increase of at least two points on a 6-category ordinal scale or to discharge from hospital alive. The primary and supportive efficacy endpoints were assessed in the intention-to-treat population. Safety was assessed in the safety population. This study is registered online with ClinicalTrials.gov (NCT04330638) and EudraCT (2020-001500-41) and is complete., Findings: Between April 4, and Dec 6, 2020, 342 patients were randomly assigned to IL-1 blockade (n=112) or no IL-1 blockade (n=230) and simultaneously randomly assigned to IL-6 blockade (n=227; 114 for tocilizumab and 113 for siltuximab) or no IL-6 blockade (n=115). Most patients were male (265 [77%] of 342), median age was 65 years (IQR 54-73), and median Systematic Organ Failure Assessment (SOFA) score at randomisation was 3 (2-4). All 342 patients were included in the primary intention-to-treat analysis. The estimated median time to clinical improvement was 12 days (95% CI 10-16) in the IL-1 blockade group versus 12 days (10-15) in the no IL-1 blockade group (hazard ratio [HR] 0·94 [95% CI 0·73-1·21]). For the IL-6 blockade group, the estimated median time to clinical improvement was 11 days (95% CI 10-16) versus 12 days (11-16) in the no IL-6 blockade group (HR 1·00 [0·78-1·29]). 55 patients died during the study, but no evidence for differences in mortality between treatment groups was found. The incidence of serious adverse events and serious infections was similar across study groups., Interpretation: Drugs targeting IL-1 or IL-6 did not shorten the time to clinical improvement in this sample of patients with COVID-19, hypoxic respiratory failure, low SOFA score, and low baseline mortality risk., Funding: Belgian Health Care Knowledge Center and VIB Grand Challenges program., Competing Interests: Declaration of interests JD, KFAVD, BM, CB, VB, LH, LN, and EDL have received personal PhD training fellowships from FWO Flanders. SJT and LJMS have received personal postdoctoral fellowships from FWO Flanders and from the Ghent University BOF Fund. HA has received a postdoctoral personal training grant from VLAIO Flanders. US has received a grant from the European Respiratory Society. MH has received a grant from ULB Fonds Erasme on COVID-19 research, and an EU-Horizon DisCoVeRY trial grant and EU-Solid-Act trial grant on COVID-19 therapeutics; she received support for attending meetings from Pfizer and acts as the leader of the Sciensano committee, which produces the national guidelines on COVID-19 therapeutics. ND has received honoraria from Boehringer Ingelheim and support for attending meetings from Pfizer, Johnson & Johnson (J&J), and Merck Sharp & Dohme (MSD) and has served on a data and safety monitoring board (DSMB) for Roche. SA received research grants from Bristol-Myers Squibb (BMS)–Celgene and from European Hematology Association and consultancy fees from BMS–Celgene, J&J, Astellas, and Abbvie and honoraria from Pfizer and Astellas. JvdH received consultancy fess from Novartis and SOBI and honoraria from MSD, Sanofi, and J&J, and support for attending meetings from ViiV; he serves on DSMB boards for Novartis and SOBI. HS has received consultancy fees and support for attending meetings from Roche and Boehringer Ingelheim. CL has received consultancy fees from the sponsor Belgian Health Care Knowledge Center (KCE) to serve on the clinical trial board. MB owns stock of the International Drug Development Institute and Cluepoints. DS has received honoraria and support for attending meetings from AstraZeneca, Chiesi, GSK, Roche, and Merck. FB has received support from the Ghent University Hospital Clinical Research Fund. FHa has received a VIB Grand Challenge research grant, a Ghent University Special Research Fund (BOF) research grant, and a Ghent University Hospital Innovation Research Grant as well as lecture honoraria from CSL Behring. LV has received grants from University Hospital Ghent Innovation Fund, Research Foundation—Flanders–Strategic Basic Research (FWO-SBO) and FWO to do COVID-19 related research; he received consultancy fees and honoraria from Gilead and ViiV Healthcare. EvB received a grant from Ghent University Special Research Fund (BOF) and a research grant from ExeVir to do COVID-19 related research. She received honoraria from Gilead and is a member of the Sciensano committee, which produces the national guidelines on COVID-19 therapeutics. SR has received honoraria and meeting attendance support from BMS, MSD, Pfizer, Bayer, J&J, Astellas, Roche, and Ipsen; she serves on DSMBs organised by Pfizer, J&J, BMS, and MSD. IP has received research grants from FWO and honoraria from UCB Pharma and Galapagos. She serves on advisory boards from Abbvie, Amgen, Argenx, AstraZeneca, BMS, Galapagos, and Novartis. FHu is an employee of KCE The Belgian Healthcare Knowledge center, a public federal agency. BNL received an European Research Council Advanced Grant (ERC-2017-ADG-789384) and several FWO grants, as well as a University of Ghent Methusalem Grant. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Interleukin-6 receptor antagonists (IL-6RAs) and steroids are emerging immunomodulatory therapies for severe and critical coronavirus disease (COVID-19). In this preliminary report, we aim to describe the epidemiology, clinical characteristics, and outcomes of adult critically ill COVID-19 patients, requiring invasive mechanical ventilation (iMV), and receiving IL-6RA and steroids therapy over the last 11 months., Materials and Methods: International, multicenter, cohort study derived from Viral Infection and Respiratory Illness University Study registry and conducted through Discovery Network, Society of Critical Care Medicine. Data were collected between March 01, 2020, and January 10, 2021., Results: Of 860 patients who met eligibility criteria, 589 received steroids, 170 IL-6RAs, and 101 combinations. Patients who received IL-6RAs were younger (median age of 57.5 years vs. 61.1 and 61.8 years in the steroids and combination groups, respectively). The median C-reactive protein level was > 75 mg/L, indicating a hyperinflammatory phenotype. The median daily steroid dose was 7.5 mg dexamethasone or equivalent (interquartile range: 6-14 mg); 80.8% and 19.2% received low-dose and high-dose steroids, respectively. Of the patients who received IL-6RAs, the majority received one dose of tocilizumab and sarilumab (dose range of 600-800 mg for tocilizumab and 200-400 mg for sarilumab). Regarding the timing of administration, we observed that steroid and IL-6RA administration on day 0 of ICU admission was only 55.6% and 39.5%, respectively. By day 28, when compared with steroid use alone, IL-6RA use was associated with an adjusted incidence rate ratio (aIRR) of 1.12 (95% confidence interval [CI] 0.88, 1.4) for ventilator-free days, while combination therapy was associated with an aIRR of 0.83 (95% CI 0.6, 1.14). IL-6RA use was associated with an adjusted odds ratio (aOR) of 0.68 (95% CI 0.44, 1.07) for the 28-day mortality rate, while combination therapy was associated with an aOR of 1.07 (95% CI 0.67, 1.70). Liver dysfunction was higher in IL-6RA group (p = 0.04), while the bacteremia rate did not differ among groups., Conclusions: Discordance was observed between the registry utilization patterns (i.e., timing of steroids and IL-6RA administration) and new evidence from the recent randomized controlled trials and guideline recommendations. These data will help us to identify areas of improvement in prescribing patterns and enhance our understanding of IL-6RA safety with different steroid regimens. Further studies are needed to evaluate the drivers of hospital-level variation and their impact on clinical outcomes. Trial registration ClinicalTrials.gov: NCT04486521. Registered on July 2020., (© 2021. The Author(s).)

The recent renascence of phenotypic drug discovery (PDD) is catalyzed by its ability to identify first-in-class drugs and deliver results when the exact molecular mechanism is partially obscure. Acute respiratory distress syndrome (ARDS) is a severe, life-threatening condition with a high mortality rate that has increased in frequency due to the COVID-19 pandemic. Despite decades of laboratory and clinical study, no efficient pharmacological therapy for ARDS has been found. An increase in endothelial permeability is the primary event in ARDS onset, causing the development of pulmonary edema that leads to respiratory failure. Currently, the detailed molecular mechanisms regulating endothelial permeability are poorly understood. Therefore, the use of the PDD approach in the search for efficient ARDS treatment can be more productive than classic target-based drug discovery (TDD), but its use requires a new cell-based assay compatible with high-throughput (HTS) and high-content (HCS) screening. Here we report the development of a new plate-based image cytometry method to measure endothelial barrier function. The incorporation of image cytometry in combination with digital image analysis substantially decreases assay variability and increases the signal window. This new method simultaneously allows for rapid measurement of cell monolayer permeability and cytological analysis. The time-course of permeability increase in human pulmonary artery endothelial cells (HPAECs) in response to the thrombin and tumor necrosis factor α treatment correlates with previously published data obtained by transendothelial resistance (TER) measurements. Furthermore, the proposed image cytometry method can be easily adapted for HTS/HCS applications.

Introduction: In COVID-19 associated hypoxemic acute respiratory failure (ARF) without mandatory indication for urgent endotracheal intubation, a trial of CPAP may be considered. We aimed to evaluate HACOR (heart rate, acidosis, consciousness, oxygenation, respiratory rate) score performance in these patients as predictor of CPAP failure., Methods: Prospective observational multicentric study (three centers in different countries), including adult patients with SARS-CoV-2 pneumonia admitted to a respiratory intermediate care unit, presenting PaO 2 /FiO 2  < 300 and PaCO 2  < 45 mmHg, who received CPAP. One hour after starting CPAP, HACOR was calculated., Results: We enrolled 128 patients, mean age 61,7 years. Mean HACOR at 1 h after starting CPAP was 3,27 ± 3,84 and mean PaO 2 /FiO 2 was 203,30 ± 92,21 mmHg; 35 patients (27,3 %) presented CPAP failure: 29 underwent oro-tracheal intubation and 6 died due to COVID-19 (all having a do-not-intubate order). HACOR accuracy for predicting CPAP failure was 82,03 %, while PaO 2 /FiO2 accuracy was 81,25 %., Conclusion: Although HACOR score had a good diagnostic performance in predicting CPAP failure in COVID-19-related ARF, PaO 2 /FiO 2 has also shown to be a good predictor of failure., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Context: About 19% of COVID-19-patients undergo hypoxic breathing problems, approximately 14% require intensive oxygen therapy, and 5% require mechanical ventilation and ICU admission. These patients can deteriorate rapidly, so nurses must closely watch them., Objective: The study intended to examine the role of emergency nurses as care providers in intensive care units (ICUs)., Design: The research team performed a narrative review by searching the Mendeley, Medline, Google Scholar, ScienceDirect, Springer, and PubMed databases. The search used the keywords COVID-19 infection, epidemiology of respiratory failure pathology in COVID-19 infection, involvement of viral spike protein S of SARSCoV-2, SARS CoV2 transmission, pathophysiology of SARSCoV-2 attack-mediated ARDS, transmission of viral particles of SARSCoV-2 in lungs, mechanism of cytokines in lungs, immunomodulatory response changes in lung physiology, and involvement of nursing officer in nursing patient care management in ICU respiratory failure., Setting: This study were conducted at The First Affiliated Hospital of Nanchang University, China., Results: Nurses are necessarily not only responsible for adequate oxygen management but also for other critical health services to benefit patients, such as control of oxygen saturation and vital signs, to reduce respiratory failure in the ICU., Conclusions: The diagnosis of the root cause of respiratory failure and its treatment are complex because a variety of pulmonary and extrapulmonary conditions can cause respiratory failure. Methods of treating acute respiratory failure and other respiratory illness require a multidisciplinary, collaborative approach. Nurses are in the best position to determine patients' risks for respiratory distress, observe them during hospitalizations, and evaluate their treatments.

We report 2 cases of bilateral lung transplantation for nonresolving coronavirus disease 2019 associated respiratory failure. In the first patient, the severe acute respiratory syndrome coronavirus 2 infection caused acute respiratory distress syndrome requiring prolonged extracorporeal membrane oxygenation support; in the second patient, coronavirus disease 2019 resulted in irreversible pulmonary fibrosis requiring only ventilatory support. The 2 cases represent the 2 ends of the spectrum showing significant differences in preoperative and postoperative courses., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We present results from clinical, radiologic, gas exchange, lung mechanics, and fibre-optic bronchoscopy-guided transbronchial biopsies in a case of acute respiratory failure due to SARS-CoV-2 (Covid-19). This report highlights the pulmonary, immunological, and inflammatory changes found during acute diffuse alveolar damage and the later organizing phase. An early diffuse alveolar damage pattern with predominant epithelial involvement with active recruitment of T cells and monocytes was observed followed by a late organizing pattern with pneumocyte hyperplasia, inflammatory infiltration, prominent endotheliitis, and secondary germinal centers. The patient's deterioration paralleling the late immuno-pathological findings based the decision to administer intravenous corticosteroids, resulting in clinical, gasometric, and radiologic improvement. We believe that real-time clinicopathological correlation, along with the description of the immunological processes at play, will contribute to the full clinical picture of Covid-19 and might lead to a more rational approach in the precise timing of anti-inflammatory, anti-cytokine, or steroid therapies., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Coronavirus Disease-2019 (COVID-19) may impair outcomes of patients with ST-segment elevation myocardial infarction (STEMI). The extent of this phenomenon and its mechanisms are unclear., Methods and results: This study prospectively included 50 consecutive STEMI patients admitted to our center for primary percutaneous coronary intervention (PCI) at the peak of the Italian COVID-19 outbreak. At admission, a COVID-19 test was positive in 24 patients (48%), negative in 26 (52%). The primary endpoint was in-hospital all-cause mortality. Upon admission, COVID-19 subjects had lower PO2/FiO2 (169 [100-425] vs. 390 [302-477], P<0.01), more need for oxygen support (62.5% vs. 26.9%, P=0.02) and a higher rate of myocardial dysfunction (ejection fraction <30% in 45.8% vs. 19.2%, P=0.04). All patients underwent emergency angiography. In 12.5% of COVID-19 patients, no culprit lesions were detected, thus PCI was performed in 87.5% and 100% of COVID-19 positive and negative patients, respectively (P=0.10). Despite a higher rate of obstinate thrombosis in the COVID-19 group (47.6% vs. 11.5%, P<0.01), the PCI result was similar (TIMI 2-3 in 90.5% vs. 100%, P=0.19). In-hospital mortality was 41.7% and 3.8% in COVID-19 positive and negative patients, respectively (P<0.01). Respiratory failure was the leading cause of death (80%) in the COVID-19 group, frequently associated with severe myocardial dysfunction., Conclusions: In-hospital mortality of COVID-19 patients with STEMI remains high despite successful PCI, mainly due to coexisting severe respiratory failure. This may be a critical factor in patient management and treatment selection.

Background: New treatment modalities are urgently needed for patients with COVID-19. The World Health Organization (WHO) Solidarity trial showed no effect of remdesivir or hydroxychloroquine (HCQ) on mortality, but the antiviral effects of these drugs are not known., Objective: To evaluate the effects of remdesivir and HCQ on all-cause, in-hospital mortality; the degree of respiratory failure and inflammation; and viral clearance in the oropharynx., Design: NOR-Solidarity is an independent, add-on, randomized controlled trial to the WHO Solidarity trial that included biobanking and 3 months of clinical follow-up (ClinicalTrials.gov: NCT04321616)., Setting: 23 hospitals in Norway., Patients: Eligible patients were adults hospitalized with confirmed SARS-CoV-2 infection., Intervention: Between 28 March and 4 October 2020, a total of 185 patients were randomly assigned and 181 were included in the full analysis set. Patients received remdesivir ( n  = 42), HCQ ( n  = 52), or standard of care (SoC) ( n  = 87)., Measurements: In addition to the primary end point of WHO Solidarity, study-specific outcomes were viral clearance in oropharyngeal specimens, the degree of respiratory failure, and inflammatory variables., Results: No significant differences were seen between treatment groups in mortality during hospitalization. There was a marked decrease in SARS-CoV-2 load in the oropharynx during the first week overall, with similar decreases and 10-day viral loads among the remdesivir, HCQ, and SoC groups. Remdesivir and HCQ did not affect the degree of respiratory failure or inflammatory variables in plasma or serum. The lack of antiviral effect was not associated with symptom duration, level of viral load, degree of inflammation, or presence of antibodies against SARS-CoV-2 at hospital admittance., Limitation: The trial had no placebo group., Conclusion: Neither remdesivir nor HCQ affected viral clearance in hospitalized patients with COVID-19., Primary Funding Source: National Clinical Therapy Research in the Specialist Health Services, Norway.

Importance: Use of non-invasive respiratory modalities in COVID-19 has the potential to reduce rates of intubation and mortality in severe disease however data regarding the use of high-flow nasal cannula (HFNC) in this population is limited., Objective: To interrogate clinical and laboratory features of SARS-CoV-2 infection associated with high-flow failure., Design: We conducted a retrospective cohort study to evaluate characteristics of high-flow therapy use early in the pandemic and interrogate factors associated with respiratory therapy failure., Setting: Multisite single centre hospital system within the metropolitan Detroit region., Participants: Patients from within the Detroit Medical Center (n=104, 89% African American) who received HFNC therapy during a COVID-19 admission between March and May of 2020., Primary Outcome: HFNC failure is defined as death or intubation while on therapy., Results: Therapy failure occurred in 57% of the patient population, factors significantly associated with failure centred around markers of multiorgan failure including hepatic dysfunction/transaminitis (OR=6.1, 95% CI 1.9 to 19.4, p<0.01), kidney injury (OR=7.0, 95% CI 2.7 to 17.8, p<0.01) and coagulation dysfunction (OR=4.5, 95% CI 1.2 to 17.1, p=0.03). Conversely, comorbidities, admission characteristics, early oxygen requirements and evaluation just prior to HFNC therapy initiation were not significantly associated with success or failure of therapy., Conclusions: In a population disproportionately affected by COVID-19, we present key indicators of likely HFNC failure and highlight a patient population in which aggressive monitoring and intervention are warranted., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Although COVID-19 has greatly affected many low-income and middle-income countries, detailed information about patients admitted to the intensive care unit (ICU) is still scarce. Our aim was to examine ventilation characteristics and outcomes in invasively ventilated patients with COVID-19 in Argentina, an upper middle-income country., Methods: In this prospective, multicentre cohort study (SATICOVID), we enrolled patients aged 18 years or older with RT-PCR-confirmed COVID-19 who were on invasive mechanical ventilation and admitted to one of 63 ICUs in Argentina. Patient demographics and clinical, laboratory, and general management variables were collected on day 1 (ICU admission); physiological respiratory and ventilation variables were collected on days 1, 3, and 7. The primary outcome was all-cause in-hospital mortality. All patients were followed until death in hospital or hospital discharge, whichever occurred first. Secondary outcomes were ICU mortality, identification of independent predictors of mortality, duration of invasive mechanical ventilation, and patterns of change in physiological respiratory and mechanical ventilation variables. The study is registered with ClinicalTrials.gov, NCT04611269, and is complete., Findings: Between March 20, 2020, and Oct 31, 2020, we enrolled 1909 invasively ventilated patients with COVID-19, with a median age of 62 years [IQR 52-70]. 1294 (67·8%) were men, hypertension and obesity were the main comorbidities, and 939 (49·2%) patients required vasopressors. Lung-protective ventilation was widely used and median duration of ventilation was 13 days (IQR 7-22). Median tidal volume was 6·1 mL/kg predicted bodyweight (IQR 6·0-7·0) on day 1, and the value increased significantly up to day 7; positive end-expiratory pressure was 10 cm H 2 O (8-12) on day 1, with a slight but significant decrease to day 7. Ratio of partial pressure of arterial oxygen (PaO 2 ) to fractional inspired oxygen (FiO 2 ) was 160 (IQR 111-218), respiratory system compliance 36 mL/cm H 2 O (29-44), driving pressure 12 cm H 2 O (10-14), and FiO 2 0·60 (0·45-0·80) on day 1. Acute respiratory distress syndrome developed in 1672 (87·6%) of patients; 1176 (61·6%) received prone positioning. In-hospital mortality was 57·7% (1101/1909 patients) and ICU mortality was 57·0% (1088/1909 patients); 462 (43·8%) patients died of refractory hypoxaemia, frequently overlapping with septic shock (n=174). Cox regression identified age (hazard ratio 1·02 [95% CI 1·01-1·03]), Charlson score (1·16 [1·11-1·23]), endotracheal intubation outside of the ICU (ie, before ICU admission; 1·37 [1·10-1·71]), vasopressor use on day 1 (1·29 [1·07-1·55]), D-dimer concentration (1·02 [1·01-1·03]), PaO 2 /FiO 2 on day 1 (0·998 [0·997-0·999]), arterial pH on day 1 (1·01 [1·00-1·01]), driving pressure on day 1 (1·05 [1·03-1·08]), acute kidney injury (1·66 [1·36-2·03]), and month of admission (1·10 [1·03-1·18]) as independent predictors of mortality., Interpretation: In patients with COVID-19 who required invasive mechanical ventilation, lung-protective ventilation was widely used but mortality was high. Predictors of mortality in our study broadly agreed with those identified in studies of invasively ventilated patients in high-income countries. The sustained burden of COVID-19 on scarce health-care personnel might have contributed to high mortality over the course of our study in Argentina. These data might help to identify points for improvement in the management of patients in middle-income countries and elsewhere., Funding: None., Translation: For the Spanish translation of the Summary see Supplementary Materials section., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: There are limited data on the long-term outcomes of COVID-19 from different parts of the world., Aims: To determine risk factors of 90-day mortality in critically ill patients in Turkish intensive care units (ICUs), with respiratory failure., Study Design: Retrospective, observational cohort., Methods: Patients with laboratory-confirmed COVID-19 and who had been followed up in the ICUs with respiratory failure for more than 24 hours were included in the study. Their demographics, clinical characteristics, laboratory variables, treatment protocols, and survival data were recorded., Results: A total of 421 patients were included. The median age was 67 (IQR: 57-76) years, and 251 patients (59.6%) were men. The 90-day mortality rate was 55.1%. The factors independently associated with 90-day mortality were invasive mechanical ventilation (IMV) (HR 4.09 [95% CI: [2.20-7.63], P < .001), lactate level >2 mmol/L (2.78 [1.93-4.01], P < .001), age ≥60 years (2.45 [1.48-4.06)], P < .001), cardiac arrhythmia during ICU stay (2.01 [1.27-3.20], P = .003), vasopressor treatment (1.94 [1.32-2.84], P = .001), positive fluid balance of ≥600 mL/day (1.68 [1.21-2.34], P = .002), PaO2/FiO2 ratio of ≤150 mmHg (1.66 [1.18-2.32], P = .003), and ECOG score ≥1 (1.42 [1.00-2.02], P = .050)., Conclusion: Long-term mortality was high in critically ill patients with COVID-19 hospitalized in intensive care units in Turkey. Invasive mechanical ventilation, lactate level, age, cardiac arrhythmia, vasopressor therapy, positive fluid balance, severe hypoxemia and ECOG score were the independent risk factors for 90-day mortality.

This case series describes three patients affected by severe acute respiratory syndrome coronavirus 2, who developed polyradiculoneuritis as a probable neurological complication of coronavirus disease 2019 (COVID-19). A diagnosis of Guillain Barré syndrome was made on the basis of clinical symptoms, cerebrospinal fluid analysis, and electroneurography. In all of them, the therapeutic approach included the administration of intravenous immunoglobulin (0.4 gr/kg for 5 days), which resulted in the improvement of neurological symptoms. Clinical neurophysiology revealed the presence of conduction block, absence of F waves, and in two cases, a significant decrease in amplitude of compound motor action potential cMAP. Due to the potential role of inflammation on symptoms development and prognosis, interleukin-6 (IL-6) and IL-8 levels were measured in serum and cerebrospinal fluid during the acute phase, while only serum was tested after recovery. Both IL-6 and IL-8 were found increased during the acute phase, both in the serum and cerebrospinal fluid, whereas 4 months after admission (at complete recovery), only IL-8 remained elevated in the serum. These results confirm the inflammatory response that might be linked to peripheral nervous system complications and encourage the use of IL-6 and IL-8 as prognostic biomarkers in COVID-19., (© 2021 The Authors. Journal of Medical Virology Published by Wiley Periodicals LLC.)

Background: There are limited data on management strategies and outcomes among lung transplant (LT) patients with Coronavirus disease 2019 (COVID-19). We implemented management protocols based on the best available evidence and consensus among multidisciplinary teams. The current study reports our experience and outcomes using this protocol-based management strategy., Methods: We included single or bilateral LT patients who tested positive for SARS-CoV-2 on nasopharyngeal swab between March 1, 2020, to December 15, 2020 (n = 25; median age: 60, range 20-73 years; M: F 17:8). A group of patients with Respiratory Syncytial Virus (RSV) infection during 2016-18 were included to serve as a comparator group (n = 36)., Results: As compared to RSV, patients with COVID-19 were more likely to present with constitutional symptoms, spirometric decline, pulmonary opacities, new or worsening respiratory failure, and need for ventilator support. Patients with SARS-CoV-2 infection were less likely to receive a multimodality treatment strategy, and they experienced worse post-infection lung function loss, functional decline, and three-month survival. A significant proportion of patients with COVID-19 needed readmission for worsening allograft function (36.4%), and chronic kidney disease at initial presentation was associated with this complication. Lower pre-morbid FEV 1 appeared to increase the risk of new or worsening respiratory failure, which was associated with worse outcomes. Overall hospital survival was 88% (n = 22). Follow-up data was available for all discharged patients (median: 43.5 days, range 15-287 days). A majority had persistent radiological opacities (19/22, 86.4%), with nearly half of the patients with available post-COVID-19 spirometry showing > 10% loss in lung function (6/13, median loss: 14.5%, range 10%-31%)., Conclusions: Despite similar demographic characteristics and predispositions, LT patients with COVID-19 are sicker and experience worse outcomes as compared to RSV. Despite the availability of newer therapeutic agents, COVID-19 continues to be associated with significant morbidity and mortality., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak., Methods: This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged ≥18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1-9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020-001236-10)., Findings: Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56-73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0·95 [95% CI 0·76-1·20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0·51 [0·27-0·95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0·52 (95% CI 0·26-1·05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1·07 (0·63-1·80; p=0·81). The median duration of invasive mechanical ventilation was 7 days (IQR 3-13) in the imatinib group compared with 12 days (6-20) in the placebo group (p=0·0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events., Interpretation: The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings., Funding: Amsterdam Medical Center Foundation, Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ZonMW, and the European Union Innovative Medicines Initiative 2., Competing Interests: Declaration of interests JA and AVN are inventors on a patent (WO2012150857A1; 2011) covering protection against endothelial barrier dysfunction through inhibition of the tyrosine kinase abl-related gene (arg). JA reports serving as a non-compensated scientific advisor for Exvastat. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Plasma levels of C-reactive protein (CRP), induced by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) triggering COVID-19, can rise surprisingly high. The increase of the CRP concentration as well as a certain threshold concentration of CRP are indicative of clinical deterioration to artificial ventilation. In COVID-19, virus-induced lung injury and the subsequent massive onset of inflammation often drives pulmonary fibrosis. Fibrosis of the lung usually proceeds as sequela to a severe course of COVID-19 and its consequences only show months later. CRP-mediated complement- and macrophage activation is suspected to be the main driver of pulmonary fibrosis and subsequent organ failure in COVID-19. Recently, CRP apheresis was introduced to selectively remove CRP from human blood plasma., Case Report: A 53-year-old, SARS-CoV-2 positive, male patient with the risk factor diabetes type 2 was referred with dyspnea, fever and fulminant increase of CRP. The patient's lungs already showed a pattern enhancement as an early sign of incipient pneumonia. The oxygen saturation of the blood was ≤ 89%. CRP apheresis using the selective CRP adsorber (PentraSorb ® CRP) was started immediately. CRP apheresis was performed via peripheral venous access on 4 successive days. CRP concentrations before CRP apheresis ranged from 47 to 133 mg/l. The removal of CRP was very effective with up to 79% depletion within one apheresis session and 1.2 to 2.14 plasma volumes were processed in each session. No apheresis-associated side effects were observed. It was at no point necessary to transfer the patient to the Intensive Care Unit or to intubate him due to respiratory failure. 10 days after the first positive SARS-CoV-2 test, CRP levels stayed below 20 mg/l and the patient no longer exhibited fever. Fourteen days after the first positive SARS-CoV-2 test, the lungs showed no sign of pneumonia on X-ray., Conclusion: This is the first report on CRP apheresis in an early COVID-19 patient with fulminant CRP increase. Despite a poor prognosis due to his diabetes and biomarker profile, the patient was not ventilated, and the onset of pneumonia was reverted., Competing Interests: AS is Founder and Shareholder of Pentracor GmbH. CB and AR are employees of Pentracor GmbH. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ringel, Ramlow, Bock and Sheriff.)

Rationale: The feasibility and safety of awake prone positioning and its impact on outcomes in non-intubated patients with acute respiratory distress syndrome secondary to COVID-19 is unknown. Results of the observational studies published during this pandemic have been conflicting. In this context, we conducted a multi-center, parallel group, randomized controlled feasibility study on awake prone positioning in non-intubated patients with COVID-19 pneumonia requiring supplemental oxygen., Methods: 60 patients with acute hypoxic respiratory failure secondary to COVID-19 pneumonia requiring 4 or more liters of oxygen to maintain a saturation of ≥92% were recruited in this study. Thirty patients each were randomized to either standard care or awake prone group. Patients randomized to the prone group were encouraged to self-prone for at least 6 hours a day. The primary outcome was the proportion of patients adhering to the protocol in each group., Results: In the prone group, 43% (13 out of 30) of patients were able to self-prone for 6 or more hours a day. In the supine group, 47% (14 out of 30) were completely supine and 53% spent some hours in the prone position, but none exceeded 6 hours. There was no significant difference in any of the secondary outcomes between the 2 groups and there were no adverse events., Conclusions: Awake prone positioning in non-intubated patients with acute hypoxic respiratory failure is feasible and safe under clinical trial conditions. The results of our feasibility study will potentially help in the design of larger definitive trials to address this key knowledge gap.

COVID-19, the disease caused by the SARS-CoV-2 virus, can progress to multisystem organ failure and viral sepsis characterized by respiratory failure, arrhythmias, thromboembolic complications, and shock with high mortality. Autopsy and preclinical evidence implicate aberrant complement activation in endothelial injury and organ failure. Erythrocytes express complement receptors and are capable of binding immune complexes; therefore, we investigated complement activation in patients with COVID-19 using erythrocytes as a tool to diagnose complement activation. We discovered enhanced C3b and C4d deposition on erythrocytes in COVID-19 sepsis patients and non-COVID sepsis patients compared with healthy controls, supporting the role of complement in sepsis-associated organ injury. Our data suggest that erythrocytes may contribute to a precision medicine approach to sepsis and have diagnostic value in monitoring complement dysregulation in COVID-19-sepsis and non-COVID sepsis and identifying patients who may benefit from complement targeted therapies.

Background: The COVID-19 pandemic has led to a surge in critically unwell patients with type 1 respiratory failure. In an attempt to reduce the number of patients requiring mechanical ventilation, prone positioning (PP) of non-intubated patients has been added to many hospital guidelines around the world. We set out to conduct a systematic review of the evidence relating to PP in the non-intubated patient with type 1 respiratory failure secondary to COVID-19 and other causes., Methods: The review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. A literature search of major databases and grey sources was conducted. Studies were assessed for inclusion by two authors according to prespecified criteria. Data collection processes, analysis and risk of bias assessment were planned., Results: 31 studies were included for analysis. These consisted of prospective and retrospective case series, cohort studies and case reports. None of the studies included a comparison group. No statistical analysis was performed. Descriptive data of included studies and narrative synthesis are presented., Conclusions: No high-quality randomised controlled trials were found and thus evidence in relation to PP as a treatment for non-intubated patients with type 1 respiratory failure is lacking., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Right ventricular (RV) dysfunction is common and associated with worse outcomes in patients with coronavirus disease 2019 (COVID-19). In non-COVID-19 acute respiratory distress syndrome, RV dysfunction develops due to pulmonary hypoxic vasoconstriction, inflammation, and alveolar overdistension or atelectasis. Although similar pathogenic mechanisms may induce RV dysfunction in COVID-19, other COVID-19-specific pathology, such as pulmonary endothelialitis, thrombosis, or myocarditis, may also affect RV function. We quantified RV dysfunction by echocardiographic strain analysis and investigated its correlation with disease severity, ventilatory parameters, biomarkers, and imaging findings in critically ill COVID-19 patients., Methods: We determined RV free wall longitudinal strain (FWLS) in 32 patients receiving mechanical ventilation for COVID-19-associated respiratory failure. Demographics, comorbid conditions, ventilatory parameters, medications, and laboratory findings were extracted from the medical record. Chest imaging was assessed to determine the severity of lung disease and the presence of pulmonary embolism., Results: Abnormal FWLS was present in 66% of mechanically ventilated COVID-19 patients and was associated with higher lung compliance (39.6 vs 29.4 mL/cmH 2 O, P = 0.016), lower airway plateau pressures (21 vs 24 cmH 2 O, P = 0.043), lower tidal volume ventilation (5.74 vs 6.17 cc/kg, P = 0.031), and reduced left ventricular function. FWLS correlated negatively with age (r = -0.414, P = 0.018) and with serum troponin (r = 0.402, P = 0.034). Patients with abnormal RV strain did not exhibit decreased oxygenation or increased disease severity based on inflammatory markers, vasopressor requirements, or chest imaging findings., Conclusions: RV dysfunction is common among critically ill COVID-19 patients and is not related to abnormal lung mechanics or ventilatory pressures. Instead, patients with abnormal FWLS had more favorable lung compliance. RV dysfunction may be secondary to diffuse intravascular micro- and macro-thrombosis or direct myocardial damage., Trial Registration: National Institutes of Health #NCT04306393. Registered 10 March 2020, https://clinicaltrials.gov/ct2/show/NCT04306393.

Objective: The aim of this study was to assess the outcomes of tracheostomy in patients with COVID-19 respiratory failure., Summary Background Data: Tracheostomy has an essential role in managing COVID-19 patients with respiratory failure who require prolonged mechanical ventilation. However, limited data are available on how tracheostomy affects COVID-19 outcomes, and uncertainty surrounding risk of infectious transmission has led to divergent recommendations and practices., Methods: It is a multicenter, retrospective study; data were collected on all tracheostomies performed in COVID-19 patients at 7 hospitals in 5 tertiary academic medical systems from February 1, 2020 to September 4, 2020., Result: Tracheotomy was performed in 118 patients with median time from intubation to tracheostomy of 22 days (Q1-Q3: 18-25). All tracheostomies were performed employing measures to minimize aerosol generation, 78.0% by percutaneous technique, and 95.8% at bedside in negative pressure rooms. Seventy-eight (66.1%) patients were weaned from the ventilator and 18 (15.3%) patients died from causes unrelated to tracheostomy. No major procedural complications occurred. Early tracheostomy (≤14 days) was associated with decreased ventilator days; median ventilator days (Q1-Q3) among patients weaned from the ventilator in the early, middle and late groups were 21 (21-31), 34 (26.5-42), and 37 (32-41) days, respectively with P = 0.030. Compared to surgical tracheostomy, percutaneous technique was associated with faster weaning for patients weaned off the ventilator [median (Q1-Q3): 34 (29-39) vs 39 (34-51) days, P = 0.038]; decreased ventilator-associated pneumonia (58.7% vs 80.8%, P = 0.039); and among patients who were discharged, shorter intensive care unit duration [median (Q1-Q3): 33 (27-42) vs 47 (33-64) days, P = 0.009]; and shorter hospital length of stay [median (Q1-Q3): 46 (33-59) vs 59.5 (48-80) days, P = 0.001]., Conclusion: Early, percutaneous tracheostomy was associated with improved outcomes compared to surgical tracheostomy in a multi-institutional series of ventilated patients with COVID-19., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Non-invasive ventilation (NIV) has been widely used in hypoxemic acute respiratory failure (ARF) due to influenza pneumonia in the emergency department (ED). However, NIV used in influenza-associated acute respiratory failure had a variable rate of failure. Previous studies have reported that prolonged use of NIV was associated with increased mortality. Our study aimed to identify risk factors for NIV failure in influenza infection with acute respiratory failure in ED., Method: We performed a retrospective cohort observational study. Enrolled patients were older than 18 years who used NIV due to influenza infection with ARF between 1 January 2017 to 31 December 2018 in Ramathibodi Emergency Department. Patients characteristics, comorbidity, clinical, laboratory outcome, chest imaging, initial NIV setting, and parameters were collected in ED setting. Sequential organ failure assessment (SOFA) score and PaO2/FiO2 (PF) ratio were calculated from the first arterial blood gas in ED. We followed the outcome success or failure of the NIV used., Results: A total of 162 patients were enrolled and 72 (44%) suffered NIV failure in influenza infection with ARF. We used univariate and multivariate logistic analyses to assess risk factors for NIV failure. The ability of risk factor to predict NIV failure was analyzed using the area under the receiver operating characteristic (AUROC). Risk factors of NIV failure included SOFA score (P = 0.001), PF ratio (P = 0.001) and quadrant infiltrations in chest x-rays (CXR) (P = 0.001). SOFA score, PF ratio, and number quadrant infiltrations in chest radiography have good ability to predict NIV failure, AUROC 0.894 (95%CI 0.839-0.948), 0.828 (95%CI 0.764-0.892), and 0.792 (95%CI 0.721-0.863), respectively and no significant difference in the ability to predict NIV failure among three parameters. The use of PF ratio plus number quadrant infiltrations in chest radiography demonstrated a higher predictive ability for NIV failure in influenza infection with ARF., Conclusions: SOFA score, PF ratio, and quadrant infiltrations in chest radiography were good predictors of NIV failure in influenza infection with ARF., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The viral infection caused by SARS-CoV-2 has increased the mortality rate and engaged several adverse effects on the affected individuals. Currently available antiviral drugs have found to be unsuccessful in the treatment of COVID-19 patients. The demand for efficient antiviral drugs has created a huge burden on physicians and health workers. Plasma therapy seems to be less accomplishable due to insufficient donors to donate plasma and low recovery rate from viral infection. Repurposing of antivirals has been evolved as a suitable strategy in the current treatment and preventive measures. The concept of drug repurposing represents new experimental approaches for effective therapeutic benefits. Besides, SARS-CoV-2 exhibits several complications such as lung damage, blood clot formation, respiratory illness and organ failures in most of the patients. Based on the accumulation of data, sulfated marine polysaccharides have exerted successful inhibition of virus entry, attachment and replication with known or unknown possible mechanisms against deadly animal and human viruses so far. Since the virus entry into the host cells is the key process, the prevention of such entry mechanism makes any antiviral strategy effective. Enveloped viruses are more sensitive to polyanions than non-enveloped viruses. Besides, the viral infection caused by RNA virus types embarks severe oxidative stress in the human body that leads to malfunction of tissues and organs. In this context, polysaccharides play a very significant role in providing shielding effect against the virus due to their polyanionic rich features and a molecular weight that hinders their reactive surface glycoproteins. Significantly the functional groups especially sulfate, sulfate pattern and addition, uronic acids, monosaccharides, glycosidic linkage and high molecular weight have greater influence in the antiviral activity. Moreover, they are very good antioxidants that can reduce the free radical generation and provokes intracellular antioxidant enzymes. Additionally, polysaccharides enable a host-virus immune response, activate phagocytosis and stimulate interferon systems. Therefore, polysaccharides can be used as candidate drugs, adjuvants in vaccines or combination with other antivirals, antioxidants and immune-activating nutritional supplements and antiviral materials in healthcare products to prevent SARS-CoV-2 infection., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

This protocol aids both new and experienced researchers in designing retrospective clinical and translational studies of acute respiratory decline in hospitalized patients. This protocol addresses (1) the basics of respiratory failure and electronic health record research, (2) defining patient cohorts as "mild, progressive, or severe" instead of "ICU versus non-ICU", (3) adapting physiological indices, and (4) using biomarker trends. We apply these approaches to inflammatory biomarkers in COVID-19, but this protocol can be applied to any progressive respiratory failure study. For complete details on the use and execution of this protocol, please refer to Mueller et al. (2020)., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

The aim of our study was to elucidate if SARS-CoV-2 viral load on admission, measured by real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) cycle threshold (Ct) value on nasopharyngeal samples, was a marker of disease severity. All hospitalized adult patients with a diagnosis of SARS-CoV-2 infection by rRT-PCR performed on a nasopharingeal sample from March 1 to March 18 in our institution were included. The study population was divided according to the Ct value obtained upon admission in patients with high viral load (Ct < 25), intermediate viral load (Ct: 25-30) and low viral load (Ct > 30). Demographic, clinical and laboratory variables of the different groups were analyzed to assess the influence of viral load on the development of respiratory failure during admission. Overall, 455 sequential patients were included. The median Ct value was 28 (IQR: 24-32). One hundred and thirty patients (28.6%) had a high viral load, 175 (38.5%) an intermediate viral load and 150 (33%) a low viral load. Advanced age, male sex, presence of cardiovascular disease and laboratory markers such as lactate dehydrogenase, lymphocyte count and C-reactive protein, as well as a high viral load on admission, were predictive of respiratory failure. A Ct value < 25 was associated with a higher risk of respiratory failure during admission (OR: 2.99, 95%IC: 1.57-5.69). SARS-CoV-2 viral load, measured through the Ct value on admission, is a valuable tool to predict the development of respiratory failure in COVID-19 inpatients.

Background: While emergency physicians are familiar with the management of hypoxemic respiratory failure, management of mechanical ventilation and advanced therapies for oxygenation in the emergency department have become essential during the coronavirus disease 2019 (COVID-19) pandemic., Objective: We review the current evidence on hypoxemia in COVID-19 and place it in the context of known evidence-based management of hypoxemic respiratory failure in the emergency department., Discussion: COVID-19 causes mortality primarily through the development of acute respiratory distress syndrome (ARDS), with hypoxemia arising from shunt, a mismatch of ventilation and perfusion. Management of patients developing ARDS should focus on mitigating derecruitment and avoiding volutrauma or barotrauma., Conclusions: High flow nasal cannula and noninvasive positive pressure ventilation have a more limited role in COVID-19 because of the risk of aerosolization and minimal benefit in severe cases, but can be considered. Stable patients who can tolerate repositioning should be placed in a prone position while awake. Once intubated, patients should be managed with ventilation strategies appropriate for ARDS, including targeting lung-protective volumes and low pressures. Increasing positive end-expiratory pressure can be beneficial. Inhaled pulmonary vasodilators do not decrease mortality but may be given to improve refractory hypoxemia. Prone positioning of intubated patients is associated with a mortality reduction in ARDS and can be considered for patients with persistent hypoxemia. Neuromuscular blockade should also be administered in patients who remain dyssynchronous with the ventilator despite adequate sedation. Finally, patients with refractory severe hypoxemic respiratory failure in COVID-19 should be considered for venovenous extracorporeal membrane oxygenation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: It has been suggested that COVID-19-associated severe respiratory failure (CARDS) might differ from usual acute respiratory distress syndrome (ARDS) due to failing autoregulation of pulmonary vessels and higher shunt. We sought to investigate pulmonary hemodynamics and ventilation properties in patients with CARDS compared to patients with ARDS of pulmonary origin., Methods: This was a retrospective analysis of prospectively collected data from consecutive adults with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 patients treated in our ICU in 04/2020 and a comparison of the data to matched controls with ARDS due to respiratory infections treated in our ICU from 01/2014 to 08/2019 for whom pulmonary artery catheter data were available., Results: CARDS patients (n = 10) had ventilation characteristics similar to those of ARDS (n = 10) patients. Nevertheless, mechanical power applied by ventilation was significantly higher in CARDS patients (23.4 ± 8.9 J/min) than in ARDS (15.9 ± 4.3 J/min; P < 0.05). COVID-19 patients had similar pulmonary artery pressure but significantly lower pulmonary vascular resistance, as cardiac output was higher in CARDS vs. ARDS patients ( P < 0.05). Shunt fraction and dead space were similar in CARDS compared to ARDS ( P > 0.05) and were correlated with hypoxemia in both groups. The arteriovenous pCO 2 difference (▵pCO 2 ) was elevated (CARDS 5.5 ± 2.8 mmHg vs. ARDS 4.7 ± 1.1 mmHg; P > 0.05), as was the P (v-a) CO 2 /C (a-v) O 2 ratio (CARDS mean 2.2 ± 1.5 vs. ARDS 1.7 ± 0.8; P > 0.05)., Conclusions: Respiratory failure in COVID-19 patients seems to differ only slightly from ARDS regarding ventilation characteristics and pulmonary hemodynamics. Our data indicate microcirculatory dysfunction. More data need to be collected to assure these findings and gain more pathophysiological insights into COVID-19 and respiratory failure.

COVID-19 has affected every aspect of life over the last year. This article reviews some of the effects that the pandemic had on cardiac surgery including volumes, ethical concerns with resource-intense procedures like dissection and transplant, and ECMO for COVID-19-derived refractory respiratory failure.

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pneumopathy is characterized by a complex clinical picture and heterogeneous pathological lesions, both involving alveolar and vascular components. The severity and distribution of morphological lesions associated with SARS-CoV-2 and how they relate to clinical, laboratory, and radiological data have not yet been studied systematically. The main goals of the present study were to objectively identify pathological phenotypes and factors that, in addition to SARS-CoV-2, may influence their occurrence. Lungs from 26 patients who died from SARS-CoV-2 acute respiratory failure were comprehensively analysed. Robust machine learning techniques were implemented to obtain a global pathological score to distinguish phenotypes with prevalent vascular or alveolar injury. The score was then analysed to assess its possible correlation with clinical, laboratory, radiological, and tissue viral data. Furthermore, an exploratory random forest algorithm was developed to identify the most discriminative clinical characteristics at hospital admission that might predict pathological phenotypes of SARS-CoV-2. Vascular injury phenotype was observed in most cases being consistently present as pure form or in combination with alveolar injury. Phenotypes with more severe alveolar injury showed significantly more frequent tracheal intubation; longer invasive mechanical ventilation, illness duration, intensive care unit or hospital ward stay; and lower tissue viral quantity (p < 0.001). Furthermore, in this phenotype, superimposed infections, tumours, and aspiration pneumonia were also more frequent (p < 0.001). Random forest algorithm identified some clinical features at admission (body mass index, white blood cells, D-dimer, lymphocyte and platelet counts, fever, respiratory rate, and PaCO 2 ) to stratify patients into different clinical clusters and potential pathological phenotypes (a web-app for score assessment has also been developed; https://r-ubesp.dctv.unipd.it/shiny/AVI-Score/). In SARS-CoV-2 positive patients, alveolar injury is often associated with other factors in addition to viral infection. Identifying phenotypical patterns at admission may enable a better stratification of patients, ultimately favouring the most appropriate management. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has resulted in >72 million cases and 1.6 million deaths. End-stage lung disease from COVID-19 is a new and growing entity that may benefit from lung transplant; however, there are limited data on the patient selection, perioperative management, and expected outcomes of transplantation for this indication., Methods: A systematic review of the literature was performed with searches of MEDLINE and Web of Science databases as well as the gray literature. All manuscripts, editorials, commentaries, and gray literature reports of lung transplantation for COVID-related respiratory failure were included. A case from the University of Virginia is described and included in the review., Results: A total of 27 studies were included: 11 manuscripts, 5 commentaries, and 11 gray literature reports. The total number of transplantations for COVID-related lung disease was 21. The mean age was 55±12 years, 16 (76%) were male individuals, and the acuity was high, with 85% on extracorporeal membrane oxygenation preoperatively. There was a 95% early survival rate, with 1 additional late death. There is growing histopathologic evidence for permanent structural damage with no replicating virus at the time of transplantation., Conclusions: Bilateral lung transplantation is an effective treatment option with reasonable short-term outcomes for patients with end-stage lung failure secondary to COVID-19. However, specific considerations in this new population require a multidisciplinary approach. As we move into the second wave of the COVID-19 global pandemic, lung transplantation will likely have a growing role in management of these complex patients., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)