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Extracorporeal membrane oxygenation (ECMO) is a cardiac or pulmonary function support system that is used in cases of refractory organ failure in addition to conventional treatment. Currently, Level I evidence is not yet available, which reflects improved outcomes with ECMO in pregnant women, the use in pregnancy should be indicated in selected cases and only in specialized centers. We searched articles in the most important scientific databases from 2009 until 31 December 2023 consulting also the site ClinicalTrials.com to find out about studies that have been recently conducted or are currently ongoing. We matched the combination of the following keywords: "ECMO and pregnancy", "H1N1 and pregnancy", "COVID-19 and pregnancy", "ARDS and pregnancy", "ECMO and pregnancy AND (cardiac arrest)". We selected the following number of articles for each keyword combination: "ECMO and pregnancy" (665 articles); "ECMO and influenza H1N1" (384 articles); "pregnancy and influenza H1N1" (1006 articles); "pregnancy and ARDS" (2930 articles); "ECMO and pregnancy and ARDS and influenza H1N1" (24 articles); and "[ECMO and pregnancy AND (cardiac arrest)]" (74 articles). After careful inspection, only 43 papers fitted our scope. There are two types of ECMO: venous-venous (VV-ECMO) and venous-arterial (VA-ECMO). The first-one is necessary to cope with severe hypoxia: oxygen-depleted blood is taken from the venous circulation, oxygenated, and carbon dioxide removed from the extracorporeal circuit and returned to the same venous system. The VA-ECMO is a type of mechanical assistance to the circulatory system that allows to put the failing organ at rest by ensuring adequate oxygenation and systemic de-oxygenation, avoiding multi-organ failure. The main indications for ECMO support in pregnant women are cardiogenic shock, acute respiratory distress syndrome (ARDS), pulmonary embolism, and eclampsia. There are also fetal indications for ECMO, and they are fetal distress, hypoxic-ischemic encephalopathy (HIE), and twin-to-twin transfusion syndrome (TTTS). Until now, based on the outcomes of the numerous clinical studies conducted, ECMO has been shown to be a successful therapeutic strategy in cases where medical treatment has been unsuccessful. In well-selected pregnant patients, it appears to be safe and associated with a low risk of maternal and fetal complications. The aim of this review is to report the main properties of ECMO (VV and VA) and the indications for its use in pregnant women. [ABSTRACT FROM AUTHOR]

Rationale: Acute respiratory distress syndrome (ARDS) is a major global health concern with a significant unmet need. EXO-CD24 is delivered via inhalation-reduced cytokines and chemokine secretion and lung injury in ARDS and improved survival in mice models of ARDS, influenza, and sepsis. Objectives: This clinical paper aims to evaluate the potential of EXO-CD24, a novel immunomodulatory treatment, in the compassionate care of critically ill, intubated patients with post-infection-induced acute respiratory distress syndrome (ARDS). Methods: Eleven critically ill patients diagnosed with post-infection ARDS (10 with COVID-19 and one with an adenovirus-associated infection) were administered EXO-CD24 in four medical centers across Israel. The patients had multiple co-morbidities, including cancer, hypertension, diabetes, and ischemic heart disease, and met the criteria for severe ARDS according to the Berlin classification. EXO-CD24 was administered via inhalation, and adverse events related to its use were carefully monitored. Measurements and Main Results: The administration of EXO-CD24 did not result in any recorded adverse events. The median hospitalization duration was 11.5 days, and the overall mortality rate was 36%. Notably, patients treated at the Tel Aviv Medical Center (TASMC) showed a lower mortality rate of 12.5%. The WBC and CRP levels decreased in comparison to baseline levels at hospitalization, and rapid responses occurred even in patients with kidney transplants who were off the ventilator within a few days and discharged shortly thereafter. The production of cytokines and chemokines was significantly suppressed in all patients, including those who died. Among the patients at TASMC, four had kidney transplants and were on immunosuppressive drugs, and all of them fully recovered and were discharged from the hospital. Conclusions: EXO-CD24 holds promise as a potential therapeutic agent for all stages of ARDS, even in severe intubated cases. Importantly, EXO-CD24 demonstrated a favorable safety profile without any apparent side effects with promising efficacy. Furthermore, the potential of EXO-CD24 as a platform for addressing hyper-inflammatory states warrants exploration. Further research and larger-scale clinical trials are warranted to validate these preliminary findings. [ABSTRACT FROM AUTHOR]

Acute Respiratory Distress Syndrome (ARDS) is a condition that endangers the lives of many Intensive Care Unit patients through gradual reduction of lung function. Due to its heterogeneity, this condition has been difficult to diagnose and treat, although it has been the subject of continuous research, leading to the development of several tools for modeling disease progression on the one hand, and guidelines for diagnosis on the other, mainly the "Berlin Definition". This paper describes the development of a deep learning-based surrogate model of one such tool for modeling ARDS onset in a virtual patient: the Nottingham Physiology Simulator. The model-development process takes advantage of current machine learning and data-analysis techniques, as well as efficient hyperparameter-tuning methods, within a high-performance computing-enabled data science platform. The lightweight models developed through this process present comparable accuracy to the original simulator (per-parameter R2 > 0.90). The experimental process described herein serves as a proof of concept for the rapid development and dissemination of specialised diagnosis support systems based on pre-existing generalised mechanistic models, making use of supercomputing infrastructure for the development and testing processes and supported by open-source software for streamlined implementation in clinical routines. [ABSTRACT FROM AUTHOR]

Simple Summary: In the modern era, characterized by parenchymal-sparing procedures, in some cases pneumonectomy remains the only therapeutic approach to achieving oncological radicality. One of the most feared complications is undoubtedly respiratory failure and ARDS. Its cause after pneumonectomy is still unclear, and the study of risk factors is a subject of debate. In this paper, we evaluate the main risk factors for ARDS of a large cohort of patients and we classify them in four classes of growing risk in order to quantify their postoperative risk of ARDS and facilitate their global management. (1) Background: The cause of ARDS after pneumonectomy is still unclear, and the study of risk factors is a subject of debate. (2) Methods: We reviewed a large panel of pre-, peri- and postoperative data of 211 patients who underwent pneumonectomy during the period 2014–2021. Univariable and multivariable logistic regression was used to quantify the association between preoperative parameters and the risk of developing ARDS, in addition to odds ratios and their respective 95% confidence intervals. A backward stepwise selection approach was used to limit the number of variables in the final multivariable model to significant independent predictors of ARDS. A nomogram was constructed based on the results of the final multivariable model, making it possible to estimate the probability of developing ARDS. Statistical significance was defined by a two-tailed p-value < 0.05. (3) Results: Out of 211 patients (13.3%), 28 developed ARDS. In the univariate analysis, increasing age, Charlson Comorbidity Index and ASA scores, DLCO < 75% predicted, preoperative C-reactive protein (CRP), lung perfusion and duration of surgery were associated with ARDS; a significant increase in ARDS was also observed with decreasing VO2max level. Multivariable analysis confirmed the role of ASA score, DLCO < 75% predicted, preoperative C-reactive protein and lung perfusion. Using the nomogram, we classified patients into four classes with rates of ARDS ranking from 2.0% to 34.0%. (4) Conclusions: Classification in four classes of growing risk allows a correct preoperative stratification of these patients in order to quantify the postoperative risk of ARDS and facilitate their global management. [ABSTRACT FROM AUTHOR]

Simple Summary: The world has been stricken mentally, physically, and economically by the COVID-19 virus. However, while SARS-CoV-2 viral infection results in mild flu-like symptoms in most patients, a number of those infected develop severe illness. These patients require hospitalization and intensive care. The severe disease can spiral downwards with eventual severe damage to the lungs and failure of multiple organs, leading to the individual's demise. It is necessary to identify those who are developing a severe form of illness to provide early management. Therefore, it is crucial to learn about the mechanisms and chemical mediators that lead to critical conditions in SARS-CoV-2 infection. This paper reviews studies regarding the individual chemical mediators, pathways, and means that contribute to worsening health conditions in SARS-CoV-2 infection. A significant part of the world population has been affected by the devastating SARS-CoV-2 infection. It has deleterious effects on mental and physical health and global economic conditions. Evidence suggests that the pathogenesis of SARS-CoV-2 infection may result in immunopathology such as neutrophilia, lymphopenia, decreased response of type I interferon, monocyte, and macrophage dysregulation. Even though most individuals infected with the SARS-CoV-2 virus suffer mild symptoms similar to flu, severe illness develops in some cases, including dysfunction of multiple organs. Excessive production of different inflammatory cytokines leads to a cytokine storm in COVID-19 infection. The large quantities of inflammatory cytokines trigger several inflammation pathways through tissue cell and immune cell receptors. Such mechanisms eventually lead to complications such as acute respiratory distress syndrome, intravascular coagulation, capillary leak syndrome, failure of multiple organs, and, in severe cases, death. Thus, to devise an effective management plan for SARS-CoV-2 infection, it is necessary to comprehend the start and pathways of signaling for the SARS-CoV-2 infection-induced cytokine storm. This article discusses the current findings of SARS-CoV-2 related to immunopathology, the different paths of signaling and other cytokines that result in a cytokine storm, and biomarkers that can act as early signs of warning for severe illness. A detailed understanding of the cytokine storm may aid in the development of effective means for controlling the disease's immunopathology. In addition, noting the biomarkers and pathophysiology of severe SARS-CoV-2 infection as early warning signs can help prevent severe complications. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to evaluate the efficacy of sivelestat sodium on mortality, oxygenation index, and serum markers in patients with acute respiratory distress syndrome (ARDS) associated with Coronavirus Disease 2019 (COVID-19). Methods: A retrospective analysis was conducted on adult inpatients admitted to the Intensive Care Unit (ICU). The study compared clinical characteristics, laboratory indices, and mortality rates between patients treated with and without sivelestat sodium. Cox regression analysis was employed to assess the effect of sivelestat sodium on the risk of death, oxygenation index, and improvement of serum markers in patients with COVID-19-associated ARDS. Results: A total of 110 patients with COVID-19-associated ARDS were included, with 45 patients in the sivelestat group and 65 patients in the control group. The overall patient mortality rate was 69.1%, with 62.2% in the sivelestat group and 73.8% in the control group. After five days of treatment, the median change from baseline in the oxygenation index was 21 mmHg in the medicated group and −31 mmHg in the control group (p < 0.05). Analysis of the oxygenation index as a clinical endpoint event showed a significantly higher rate of improvement in the sivelestat group compared to the control group (57.8% vs. 38.5%, p < 0.05), and the odds of raising the oxygenation index after treatment were 2.05 times higher in the sivelestat group than in the control group (HR = 2.05, 95%CI: 1.02–4.15, p < 0.05). Among patients with a baseline oxygenation index < 200 mmHg, patients in the sivelestat group had an 86% lower risk of death compared to the control group (HR = 0.14, 95%CI: 0.02–0.81, p < 0.05). Conclusions: Sivelestat sodium demonstrated a significant improvement in the oxygenation index of patients with COVID-19-associated ARDS and was found to considerably reduce the risk of death in patients with a baseline oxygenation index of <200 mmHg. [ABSTRACT FROM AUTHOR]

Ustekinumab is a monoclonal antibody targeting the p40 subunit of IL-12 and IL-23, approved for treating psoriasis, psoriatic arthritis, and inflammatory bowel disease. Despite a remarkable success in treating chronic inflammatory conditions and a generally favorable safety profile, its role in inducing rare adverse events, such as interstitial pneumonia and acute respiratory distress syndrome (ARDS), remains largely uncharted. We report a case of a 66-year-old male patient treated with Ustekinumab for severe psoriasis who, after almost two years of treatment, developed dyspnea, asthenia, and fever progressing to non-infectious pneumonia and ARDS leading to ICU admission. Moreover, we conducted a literature review on Ustekinumab-associated pulmonary complications. Our case underscores the importance of appropriate and long-term clinical monitoring in patients on Ustekinumab treatment, particularly considering the potential lung complications. The possibility of non-infectious pneumonitis should be considered alongside infectious causes, facilitating prompt management in the case of negative infectious screening. Additionally, the severity of ARDS underscores the importance of timely recognition and proper management. Further investigations are recommended to investigate the immunological basis of Ustekinumab-induced ARDS for designing appropriate monitoring strategies. [ABSTRACT FROM AUTHOR]

Acute Respiratory Distress Syndrome (ARDS) is characterized by lung inflammation and increased membrane permeability, which represents the leading cause of mortality in ICUs. Mechanical ventilation strategies are at the forefront of supportive approaches for ARDS. Recently, an increasing understanding of RNA biology, function, and regulation, as well as the success of RNA vaccines, has spurred enthusiasm for the emergence of novel RNA-based therapeutics. The most common types of RNA seen in development are silencing (si)RNAs, antisense oligonucleotide therapy (ASO), and messenger (m)RNAs that collectively account for 80% of the RNA therapeutics pipeline. These three RNA platforms are the most mature, with approved products and demonstrated commercial success. Most recently, miRNAs have emerged as pivotal regulators of gene expression. Their dysregulation in various clinical conditions offers insights into ARDS pathogenesis and offers the innovative possibility of using microRNAs as targeted therapy. This review synthesizes the current state of the literature to contextualize the therapeutic potential of miRNA modulation. It considers the potential for miR-based therapeutics as a nuanced approach that incorporates the complexity of ARDS pathophysiology and the multifaceted nature of miRNA interactions. [ABSTRACT FROM AUTHOR]

Artificial intelligence (AI) can make intelligent decisions in a manner akin to that of the human mind. AI has the potential to improve clinical workflow, diagnosis, and prognosis, especially in radiology. Acute respiratory distress syndrome (ARDS) is a very diverse illness that is characterized by interstitial opacities, mostly in the dependent areas, decreased lung aeration with alveolar collapse, and inflammatory lung edema resulting in elevated lung weight. As a result, lung imaging is a crucial tool for evaluating the mechanical and morphological traits of ARDS patients. Compared to traditional chest radiography, sensitivity and specificity of lung computed tomography (CT) and ultrasound are higher. The state of the art in the application of AI is summarized in this narrative review which focuses on CT and ultrasound techniques in patients with ARDS. A total of eighteen items were retrieved. The primary goals of using AI for lung imaging were to evaluate the risk of developing ARDS, the measurement of alveolar recruitment, potential alternative diagnoses, and outcome. While the physician must still be present to guarantee a high standard of examination, AI could help the clinical team provide the best care possible. [ABSTRACT FROM AUTHOR]

Lung ultrasound is gaining popularity as a quick, easy, and accurate method for the detection of pneumothorax. The typical sonographic features of pneumothorax are the absence of lung sliding, the presence of a lung point, the absence of a lung pulse, and the absence of B-lines. However, we found that in some cases, each of these elements might be misleading. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is a life-threatening event that occurs in patients suffering from bacterial, fungal, or viral sepsis. Research performed over the last five decades showed that ARDS is a consequence of severe unrestrained systemic inflammation, which leads to injury of the lung's microvasculature and alveolar epithelium. ARDS leads to acute hypoxic/hypercapnic respiratory failure and death in a significant number of patients hospitalized in intensive care units worldwide. Basic and clinical research performed during the time since ARDS was first described has been unable to construct a pharmacological agent that will combat the inflammatory fire leading to ARDS. In-depth studies of the molecular pharmacology of vitamin C indicate that it can serve as a potent anti-inflammatory agent capable of attenuating the pathobiological events that lead to acute injury of the lungs and other body organs. This analysis of vitamin C's role in the treatment of ARDS includes a focused systematic review of the literature relevant to the molecular physiology of vitamin C and to the past performance of clinical trials using the agent. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) has no specific and effective treatment, and there is an urgent need to understand its pathogenesis. Therefore, based on the hypothesis that molecules whose expression is upregulated in injured pulmonary vascular endothelial cells (VECs) are involved in the pathogenesis of ARDS, we conducted a study to elucidate the molecular mechanisms and identify target factors for treatment. Primary human lung microvascular endothelial cells (HMVEC-Ls) were stimulated with lipopolysaccharide (LPS) or poly (I:C) and analyzed via a microarray to identify target genes for ARDS. We found that a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) was induced in murine lung VECs in an LPS-mediated ARDS model. Elevated ADAMTS4 was also observed by the immunostaining of lung samples from ARDS patients. The suppression of ADAMTS4 by siRNA in VECs ameliorated LPS-stimulated vascular permeability. The impairment of the cell surface expression of syndecan-1, a marker of the glycocalyx that is an extracellular matrix involved in vascular permeability, was dramatically inhibited by ADAMTS4 suppression. In addition, the suppression of ADAMTS4 protected against LPS-induced reductions in syndecan-1 and the adherens junction protein vascular endothelial cadherin. These results suggest that ADAMTS4 regulates VEC permeability in ARDS and may be a predictive marker and therapeutic target for ARDS. [ABSTRACT FROM AUTHOR]

Current studies agree on the impact of sleep and circadian rest–activity rhythm alterations in acute respiratory distress syndrome (ARDS) survivors. However, research on the duration of this impact is scarce. In this study, we evaluate the impact of ARDS on the sleep and circadian rest–activity rhythm of COVID-19 survivors twelve months after hospital discharge. This is a prospective study including COVID-19 survivors with and without ARDS during hospitalization. Data was collected four and twelve months after hospital discharge. The interventions included one-week wrist actigraphy and a home sleep apnea test (HSAT), and evaluations were conducted according to the Pittsburgh sleep quality index (PSQI), Epworth sleepiness scale (ESS), and insomnia severity index (ISI). Fifty-two patients were evaluated (ARDS = 31 and non-ARDS = 21); they had a median age of 49.0 [39.0;57.2] years and 53.8% were male. After twelve months, 91.3% presented poor sleep quality, 58.7% presented insomnia, 50% presented daytime somnolence, and 37% presented comorbid insomnia and obstructive sleep apnea (COMISA). No significant improvement was observed in relation to sleep or the circadian rest–activity rhythm between four and twelve months. A tendency of poor sleep quality, insomnia, daytime somnolence, and COMISA was observed. Finally, there was no significant impact on the circadian rest–activity rhythm between four and twelve months or between the groups. [ABSTRACT FROM AUTHOR]

Sepsis is a life-threatening condition caused by the body's overwhelming response to an infection, such as pneumonia or urinary tract infection. It occurs when the immune system releases cytokines into the bloodstream, triggering widespread inflammation. If not treated, it can lead to organ failure and death. Unfortunately, sepsis has a high mortality rate, with studies reporting rates ranging from 20% to over 50%, depending on the severity and promptness of treatment. According to the World Health Organization (WHO), the annual death toll in the world is about 11 million. One of the main toxins responsible for inflammation induction are lipopolysaccharides (LPS, endotoxin) from Gram-negative bacteria, which rank among the most potent immunostimulants found in nature. Antibiotics are consistently prescribed as a part of anti-sepsis-therapy. However, antibiotic therapy (i) is increasingly ineffective due to resistance development and (ii) most antibiotics are unable to bind and neutralize LPS, a prerequisite to inhibit the interaction of endotoxin with its cellular receptor complex, namely Toll-like receptor 4 (TLR4)/MD-2, responsible for the intracellular cascade leading to pro-inflammatory cytokine secretion. The pandemic virus SARS-CoV-2 has infected hundreds of millions of humans worldwide since its emergence in 2019. The COVID-19 (Coronavirus disease-19) caused by this virus is associated with high lethality, particularly for elderly and immunocompromised people. As of August 2023, nearly 7 million deaths were reported worldwide due to this disease. According to some reported studies, upregulation of TLR4 and the subsequent inflammatory signaling detected in COVID-19 patients "mimics bacterial sepsis". Furthermore, the immune response to SARS-CoV-2 was described by others as "mirror image of sepsis". Similarly, the cytokine profile in sera from severe COVID-19 patients was very similar to those suffering from the acute respiratory distress syndrome (ARDS) and sepsis. Finally, the severe COVID-19 infection is frequently accompanied by bacterial co-infections, as well as by the presence of significant LPS concentrations. In the present review, we will analyze similarities and differences between COVID-19 and sepsis at the pathophysiological, epidemiological, and molecular levels. [ABSTRACT FROM AUTHOR]

Background: A few prospective trials and case series have suggested that hyperbaric oxygen therapy (HBOT) may be efficacious for the treatment of severe COVID-19, but safety is a concern for critically ill patients. We present an interim analysis of the safety of HBOT via a randomized controlled trial (COVID-19-HBO). Methods: A randomized controlled, open-label, clinical trial was conducted in compliance with good clinical practice to explore the safety and efficacy of HBOT for severe COVID-19 in critically ill patients with moderate acute respiratory distress syndrome (ARDS). Between 3 June 2020, and 17 May 2021, 31 patients with severe COVID-19 and moderate-to-severe ARDS, a ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) < 26.7 kPa (200 mmHg), and at least two defined risk factors for intensive care unit (ICU) admission and/or mortality were enrolled in the trial and randomized 1:1 to best practice, or HBOT in addition to best practice. The subjects allocated to HBOT received a maximum of five treatments at 2.4 atmospheres absolute (ATA) for 80 min over seven days. The subjects were followed up for 30 days. The safety endpoints were analyzed. Results: Adverse events (AEs) were common. Hypoxia was the most common adverse event reported. There was no statistically significant difference between the groups. Numerically, serious adverse events (SAEs) and barotrauma were more frequent in the control group, and the differences between groups were in favor of the HBOT in PaO2/FiO2 (PFI) and the national early warning score (NEWS); statistically, however, the differences were not significant at day 7, and no difference was observed for the total oxygen burden and cumulative pulmonary oxygen toxicity dose (CPTD). Conclusion: HBOT appears to be safe as an intervention for critically ill patients with moderate-to-severe ARDS induced by COVID-19. Clinical trial registration: NCT04327505 (31 March 2020) and EudraCT 2020-001349-37 (24 April 2020). [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is associated with a heterogeneous pattern of injury throughout the lung parenchyma that alters regional alveolar opening and collapse time constants. Such heterogeneity leads to atelectasis and repetitive alveolar collapse and expansion (RACE). The net effect is a progressive loss of lung volume with secondary ventilator-induced lung injury (VILI). Previous concepts of ARDS pathophysiology envisioned a two-compartment system: a small amount of normally aerated lung tissue in the non-dependent regions (termed "baby lung"); and a collapsed and edematous tissue in dependent regions. Based on such compartmentalization, two protective ventilation strategies have been developed: (1) a "protective lung approach" (PLA), designed to reduce overdistension in the remaining aerated compartment using a low tidal volume; and (2) an "open lung approach" (OLA), which first attempts to open the collapsed lung tissue over a short time frame (seconds or minutes) with an initial recruitment maneuver, and then stabilize newly recruited tissue using titrated positive end-expiratory pressure (PEEP). A more recent understanding of ARDS pathophysiology identifies regional alveolar instability and collapse (i.e., hidden micro-atelectasis) in both lung compartments as a primary VILI mechanism. Based on this understanding, we propose an alternative strategy to ventilating the injured lung, which we term a "stabilize lung approach" (SLA). The SLA is designed to immediately stabilize the lung and reduce RACE while gradually reopening collapsed tissue over hours or days. At the core of SLA is time-controlled adaptive ventilation (TCAV), a method to adjust the parameters of the airway pressure release ventilation (APRV) modality. Since the acutely injured lung at any given airway pressure requires more time for alveolar recruitment and less time for alveolar collapse, SLA adjusts inspiratory and expiratory durations and inflation pressure levels. The TCAV method SLA reverses the open first and stabilize second OLA method by: (i) immediately stabilizing lung tissue using a very brief exhalation time (≤0.5 s), so that alveoli simply do not have sufficient time to collapse. The exhalation duration is personalized and adaptive to individual respiratory mechanical properties (i.e., elastic recoil); and (ii) gradually recruiting collapsed lung tissue using an inflate and brake ratchet combined with an extended inspiratory duration (4–6 s) method. Translational animal studies, clinical statistical analysis, and case reports support the use of TCAV as an efficacious lung protective strategy. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is one of the most severe complications of the COVID-19 disease. The role of IL-33 and calpain 1 was previously described in lung infections and lung tissue damage. Our study examined the association between serum calpain 1 activity and IL-33 concentration in patients with COVID-19 ARDS. In the research, we included 80 subjects who had COVID-19 pneumonia and divided them into 2 groups: 40 subjects with ARDS and 40 subjects without ARDS. The basis of the research was the collection of subjects' data and the sampling of peripheral venous blood. The concentration of IL-33 was determined by the ELISA method and the activity of calpain 1 by the fluorometry method. Our research showed elevated calpain 1 activity and IL-33 concentration in the serum of COVID-19 patients who developed ARDS compared to those who did not develop ARDS and a positive correlation between them was established. Further, a positive correlation was established between the examined parameters and the severity of the disease, proinflammatory markers, and the use of mechanical ventilation. These results indicate a possible association and role of calpain 1 and IL-33 with the development of ARDS in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is a severe complication of lung injuries, commonly associated with bacterial, fungal and viral infections, including SARS-CoV-2 viral infections. ARDS is strongly correlated with patient mortality and its clinical management is very complex, with no effective treatment presently available. ARDS involves severe respiratory failure, fibrin deposition in both airways and lung parenchyma, with the development of an obstructing hyaline membrane drastically limiting gas exchange. Moreover, hypercoagulation is related to deep lung inflammation, and a pharmacological action toward both aspects is expected to be beneficial. Plasminogen (PLG) is a main component of the fibrinolytic system playing key roles in various inflammation regulatory processes. The inhalation of PLG has been proposed in the form of the off-label administration of an eyedrop solution, namely, a plasminogen-based orphan medicinal product (PLG-OMP), by means of jet nebulisation. Being a protein, PLG is susceptible to partial inactivation under jet nebulisation. The aim of the present work is to demonstrate the efficacy of the mesh nebulisation of PLG-OMP in an in vitro simulation of clinical off-label administration, considering both the enzymatic and immunomodulating activities of PLG. Biopharmaceutical aspects are also investigated to corroborate the feasibility of PLG-OMP administration by inhalation. The nebulisation of the solution was performed using an Aerogen® SoloTM vibrating-mesh nebuliser. Aerosolised PLG showed an optimal in vitro deposition profile, with 90% of the active ingredient impacting the lower portions of a glass impinger. The nebulised PLG remained in its monomeric form, with no alteration of glycoform composition and 94% of enzymatic activity maintenance. Activity loss was observed only when PLG-OMP nebulisation was performed under simulated clinical oxygen administration. In vitro investigations evidenced good penetration of aerosolised PLG through artificial airway mucus, as well as poor permeation across an Air–Liquid Interface model of pulmonary epithelium. The results suggest a good safety profile of inhalable PLG, excluding high systemic absorption but with good mucus diffusion. Most importantly, the aerosolised PLG was capable of reversing the effects of an LPS-activated macrophage RAW 264.7 cell line, demonstrating the immunomodulating activity of PLG in an already induced inflammatory state. All physical, biochemical and biopharmaceutical assessments of mesh aerosolised PLG-OMP provided evidence for its potential off-label administration as a treatment for ARDS patients. [ABSTRACT FROM AUTHOR]

Background: Acute respiratory distress syndrome (ARDS) is a severe lung condition that can be caused by a variety of underlying illnesses. Due to SARS-CoV-2, the number of cases with ARDS has increased worldwide, making it essential to compare this form of acute respiratory failure with classical causes of ARDS. While there have been several studies investigating the differences between COVID-19 and non-COVID-19 ARDS in early stages of the pandemic, little is known about the differences in later phases, especially in Germany. Aim: The aim of this study is to characterize and compare the comorbidities, treatments, adverse events, and outcomes of COVID-19-associated ARDS and non-COVID-19 ARDS using a representative sample of German health claims data from the years 2019 and 2021. Methods: We compare percentages and median values of the quantities of interest from the COVID-19 and non-COVID-19 ARDS group, with p-values calculated after conducting Pearson's chi-squared test or the Wilcoxon rank sum test. We also run logistic regressions to access the effect of comorbidities on mortality for COVID-19 ARDS and non-COVID-19 ARDS. Results: Despite many similarities, we find that that there are some remarkable differences between COVID-19 and non-COVID-19 ARDS cases in Germany. Most importantly, COVID-19 ARDS cases display fewer comorbidities and adverse events, and are more often treated with non-invasive ventilation and nasal high-flow therapy. Conclusions: This study highlights the importance of comprehending the contrasting epidemiological features and clinical outcomes of COVID-19 and non-COVID-19 ARDS. This understanding can aid in clinical decision making and guide future research initiatives aimed at enhancing the management of patients afflicted with this severe condition. [ABSTRACT FROM AUTHOR]

The clinical manifestations of SARS-CoV-2 infection vary widely, from asymptomatic infection to the development of acute respiratory distress syndrome (ARDS) and death. The host response elicited by SARS-CoV-2 plays a key role in determining the clinical outcome. We hypothesized that determining the dynamic whole blood transcriptomic profile of hospitalized adult COVID-19 patients and characterizing the subgroup that develops severe disease and ARDS would broaden our understanding of the heterogeneity in clinical outcomes. We recruited 60 hospitalized patients with RT-PCR-confirmed SARS-CoV-2 infection, among whom 19 developed ARDS. Peripheral blood was collected using PAXGene RNA tubes within 24 h of admission and on day 7. There were 2572 differently expressed genes in patients with ARDS at baseline and 1149 at day 7. We found a dysregulated inflammatory response in COVID-19 ARDS patients, with an increased expression of genes related to pro-inflammatory molecules and neutrophil and macrophage activation at admission, in addition to an immune regulation loss. This led, in turn, to a higher expression of genes related to reactive oxygen species, protein polyubiquitination, and metalloproteinases in the latter stages. Some of the most significant differences in gene expression found between patients with and without ARDS corresponded to long non-coding RNA involved in epigenetic control. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is intricately linked with SARS-CoV-2-associated disease severity and mortality, especially in patients with co-morbidities. Lung tissue injury caused as a consequence of ARDS leads to fluid build-up in the alveolar sacs, which in turn affects oxygen supply from the capillaries. ARDS is a result of a hyperinflammatory, non-specific local immune response (cytokine storm), which is aggravated as the virus evades and meddles with protective anti-viral innate immune responses. Treatment and management of ARDS remain a major challenge, first, because the condition develops as the virus keeps replicating and, therefore, immunomodulatory drugs are required to be used with caution. Second, the hyperinflammatory responses observed during ARDS are quite heterogeneous and dependent on the stage of the disease and the clinical history of the patients. In this review, we present different anti-rheumatic drugs, natural compounds, monoclonal antibodies, and RNA therapeutics and discuss their application in the management of ARDS. We also discuss on the suitability of each of these drug classes at different stages of the disease. In the last section, we discuss the potential applications of advanced computational approaches in identifying reliable drug targets and in screening out credible lead compounds against ARDS. [ABSTRACT FROM AUTHOR]

Simple Summary: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the pandemic coronavirus disease-2019 (COVID-19), which can lead to severe pneumonia and acute respiratory distress syndrome (ARDS). The immune system plays a key role in the defense against COVID-19. Nonetheless, if dysregulated and hyperactivated, the immune response can trigger the deleterious "cytokine storm". Multiple studies are aimed at finding potential immunomodulators to rebalance the immune response against the virus, thus limiting its dangerous effects. Moreover, the development of vaccines against SARS-CoV-2 has represented a global challenge. The aim of this narrative review is to describe the state-of-the-art knowledge on the immune system response in COVID-19 and to underline the main therapeutic strategies and the key role of vaccines. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen of coronavirus disease 19 (COVID-19). COVID-19 can manifest with a heterogenous spectrum of disease severity, from mild upper airways infection to severe interstitial pneumonia and devastating acute respiratory distress syndrome (ARDS). SARS-CoV-2 infection may induce an over activation of the immune system and the release of high concentrations of pro-inflammatory cytokines, leading to a "cytokine storm", a recognized pathogenetic mechanism in the genesis of SARS-CoV-2-induced lung disease. This overproduction of inflammatory cytokines has been recognized as a poor prognostic factor, since it can lead to disease progression, organ failure, ARDS and death. Moreover, the immune system shows dysregulated activity, particularly through activated macrophages and T-helper cells and in the co-occurrent exhaustion of lymphocytes. We carried out a non-systematic literature review aimed at providing an overview of the current knowledge on the pathologic mechanisms played by the immune system and the inflammation in the genesis of SARS-CoV-2-induced lung disease. An overview on potential treatments for this harmful condition and for contrasting the "cytokine storm" has also been presented. Finally, a look at the experimented experimental vaccines against SARS-CoV-2 has been included. [ABSTRACT FROM AUTHOR]

The effects of a moderately elevated intra-abdominal pressure (IAP) on lung mechanics in acute respiratory distress syndrome (ARDS) have still not been fully analyzed. Moreover, the optimal positive end-expiratory pressure (PEEP) in elevated IAP and ARDS is unclear. In this paper, 18 pigs under general anesthesia received a double hit lung injury. After saline lung lavage and 2 h of injurious mechanical ventilation to induce an acute lung injury (ALI), an intra-abdominal balloon was filled until an IAP of 10 mmHg was generated. Animals were randomly assigned to one of three groups (group A = PEEP 5, B = PEEP 10 and C = PEEP 15 cmH2O) and ventilated for 6 h. We measured end-expiratory lung volume (EELV) per kg bodyweight, driving pressure (ΔP), transpulmonary pressure (ΔPL), static lung compliance (Cstat), oxygenation (P/F ratio) and cardiac index (CI). In group A, we found increases in ΔP (22 ± 1 vs. 28 ± 2 cmH2O; p = 0.006) and ΔPL (16 ± 1 vs. 22 ± 2 cmH2O; p = 0.007), with no change in EELV/kg (15 ± 1 vs. 14 ± 1 mL/kg) when comparing hours 0 and 6. In group B, there was no change in ΔP (26 ± 2 vs. 25 ± 2 cmH2O), ΔPL (19 ± 2 vs. 18 ± 2 cmH2O), Cstat (21 ± 3 vs. 21 ± 2 cmH2O/mL) or EELV/kg (12 ± 2 vs. 13 ± 3 mL/kg). ΔP and ΔPL were significantly lower after 6 h when comparing between group C and A (21 ± 1 vs. 28 ± 2 cmH2O; p = 0.020) and (14 ± 1 vs. 22 ± 2 cmH2O; p = 0.013)). The EELV/kg increased over time in group C (13 ± 1 vs. 19 ± 2 mL/kg; p = 0.034). The P/F ratio increased in all groups over time. CI decreased in groups B and C. The global lung injury score did not significantly differ between groups (A: 0.25 ± 0.05, B: 0.21 ± 0.02, C: 0.22 ± 0.03). In this model of ALI, elevated IAP, ΔP and ΔPL increased further over time in the group with a PEEP of 5 cmH2O applied over 6 h. This was not the case in the groups with a PEEP of 10 and 15 cmH2O. Although ΔP and ΔPL were significantly lower after 6 hours in group C compared to group A, we could not show significant differences in histological lung injury score. [ABSTRACT FROM AUTHOR]

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), might be complicated by Acute Respiratory Distress Syndrome (ARDS) caused by severe lung damage. It is relevant to find treatments for COVID-19-related ARDS. Currently, DHA and EPA n-3 PUFAs, known for their immunomodulatory activities, have been proposed for COVID-19 management, and clinical trials are ongoing. Here, examining COVID-19-related ARDS immunopathology, we reference in vitro and in vivo studies, indicating n-3 PUFA immunomodulation on lung microenvironment (bronchial and alveolar epithelial cells, macrophages, infiltrating immune cells) and ARDS, potentially affecting immune responses in COVID-19-related ARDS. Concerning in vitro studies, evidence exists of the potential anti-inflammatory activity of DHA on airway epithelial cells and monocytes/macrophages; however, it is necessary to analyze n-3 PUFA immunomodulation using viral experimental models relevant to SARS-CoV-2 infection. Then, although pre-clinical investigations in experimental acute lung injury/ARDS revealed beneficial immunomodulation by n-3 PUFAs when extracellular pathogen infections were used as lung inflammatory models, contradictory results were reported using intracellular viral infections. Finally, clinical trials investigating n-3 PUFA immunomodulation in ARDS are limited, with small samples and contradictory results. In conclusion, further in vitro and in vivo investigations are needed to establish whether n-3 PUFAs may have some therapeutic potential in COVID-19-related ARDS. [ABSTRACT FROM AUTHOR]

Acute Respiratory Distress Syndrome (ARDS) caused by COVID-19 is substantially different from ARDS caused by other diseases and its treatment is dissimilar and challenging. As many studies showed conflicting results regarding the use of Non-invasive ventilation in COVID-19-associated ARDS, no unquestionable indications by operational guidelines were reported. The aim of this study was to estimate the use and success rate of Helmet (h) Continuous Positive Airway Pressure (CPAP) in COVID-19-associated ARDS in medical regular wards patients and describe the predictive risk factors for its use and failure. In our monocentric retrospective observational study, we included patients admitted for COVID-19 in medical regular wards. hCPAP was delivered when supplemental conventional or high-flow nasal oxygen failed to achieve respiratory targets. The primary outcomes were hCPAP use and failure rate (including the need to use Bilevel (BL) PAP or oro-tracheal intubation (OTI) and death during ventilation). The secondary outcome was the rate of in-hospital death and OTI. We computed a score derived from the factors independently associated with hCPAP failure. Out of 701 patients admitted with COVID-19 symptoms, 295 were diagnosed with ARDS caused by COVID-19 and treated with hCPAP. Factors associated with the need for hCPAP use were the PaO2/FiO2 ratio < 270, IL-6 serum levels over 46 pg/mL, AST > 33 U/L, and LDH > 570 U/L; age > 78 years and neuropsychiatric conditions were associated with lower use of hCPAP. Failure of hCPAP occurred in 125 patients and was associated with male sex, polypharmacotherapy (at least three medications), platelet count < 180 × 109/L, and PaO2/FiO2 ratio < 240. The computed hCPAP-f Score, ranging from 0 to 11.5 points, had an AUC of 0.74 in predicting hCPAP failure (significantly superior to Call Score), and 0.73 for the secondary outcome (non-inferior to IL-6 serum levels). In conclusion, hCPAP was widely used in patients with COVID-19 symptoms admitted to medical regular wards and developing ARDS, with a low OTI rate. A score computed combining male sex, multi-pharmacotherapy, low platelet count, and low PaO2/FiO2 was able to predict hCPAP failure in hospitalized patients with ARDS caused by COVID-19. [ABSTRACT FROM AUTHOR]

Background: Acute Respiratory Distress Syndrome (ARDS) is caused by non-cardiogenic pulmonary edema and occurs in critically ill patients. It is one of the fatal complications observed among severe COVID-19 cases managed in intensive care units (ICU). Supportive lung-protective ventilation and prone positioning remain the mainstay interventions. Purpose: We describe the severity of ARDS, clinical outcomes, and management of ICU patients with laboratory-confirmed COVID-19 infection in multiple Saudi hospitals. Methods: A multicenter retrospective cohort study was conducted of critically ill patients who were admitted to the ICU with COVID-19 and developed ARDS. Results: During our study, 1154 patients experienced ARDS: 591 (51.2%) with severe, 415 (36.0%) with moderate, and 148 (12.8%) with mild ARDS. The mean sequential organ failure assessment (SOFA) score was significantly higher in severe ARDS with COVID-19 (6 ± 5, p = 0.006). Kaplan–Meier survival analysis showed COVID-19 patients with mild ARDS had a significantly higher survival rate compared to COVID-19 patients who experienced severe ARDS (p = 0.023). Conclusion: ARDS is a challenging condition complicating COVID-19 infection. It carries significant morbidity and results in elevated mortality. ARDS requires protective mechanical ventilation and other critical care supportive measures. The severity of ARDS is associated significantly with the rate of death among the patients. [ABSTRACT FROM AUTHOR]

Prone positioning is frequently used for non-intubated hypoxemic patients with COVID-19, although conclusive evidence is still lacking. The aim of the present study was to investigate whether baseline CT-scans could predict the improvement in oxygenation in COVID-19 related Acute respira-tory syndrome (ARDS) patients when pronated. Methods: A retrospective study of COVID-19 patients who underwent non-invasive ventilation (NIV) and prone positioning was conducted. Results: Forty-five patients were included. On average, 50% of the overall lung volume was affected by the disease, as observed in the CT-scans, with ground glass opacities (GGOs) and consolidations accounting for 44% and 4%, respectively. The abnormalities were mainly posterior, as demonstrated by posterior/anterior distribution ratios of 1.5 and 4.4 for GGO and consolidation, respectively. The median PaO2/FiO2 ratio during NIV in a supine position (SP1) was 140 [IQR 108–169], which improved by 67% (+98) during prone positioning, on average. Once supine positioning was resumed (SP2), the improvement in oxygenation was maintained in 28 patients (62% of the overall population, categorized as "responders"). We found no significant differences between responders and non-responders in terms of the extent (p = 0.92) and the distribution of parenchymal abnormalities seen in the baseline CT (p = 0.526). Conclusion: Despite the lack of a priori estimation of the sample size, considering the absence of any trends in the differences and correlations, we can reasonably conclude that the baseline chest CT-scan does not predict a gas-exchange response in awake prone-positioned patients with COVID-19 related ARDS. Physicians dealing with this category of patients should not rely on the imaging at presentation when evaluating whether to pronate patients. [ABSTRACT FROM AUTHOR]

The trajectory from moderate and severe COVID-19 into acute respiratory distress syndrome (ARDS) necessitating mechanical ventilation (MV) is a field of active research. We determined serum levels within 24 h of presentation of 20 different sets of mediators (calprotectin, pro- and anti-inflammatory cytokines, interferons) of patients with COVID-19 at different stages of severity (asymptomatic, moderate, severe and ARDS/MV). The primary endpoint was to define associations with critical illness, and the secondary endpoint was to identify the pathways associated with mortality. Results were validated in serial measurements of mediators among participants of the SAVE-MORE trial. Levels of the proinflammatory interleukin (IL)-8, IL-18, matrix metalloproteinase-9, platelet-derived growth factor (PDGF)-B and calprotectin (S100A8/A9) were significantly higher in patients with ARDS and MV. Levels of the anti-inflammatory IL-1ra and IL-33r were also increased; IL-38 was increased only in asymptomatic patients but significantly decreased in the more severe cases. Multivariate ordinal regression showed that pathways of IL-6, IL-33 and calprotectin were associated with significant probability for worse outcome. Calprotectin was serially increased from baseline among patients who progressed to ARDS and MV. Further research is needed to decipher the significance of these findings compared to other acute-phase reactants, such as C-reactive protein (CRP) or ferritin, for the prognosis and development of effective treatments. [ABSTRACT FROM AUTHOR]

A significant proportion of patients with COVID-19 pneumonia could develop acute respiratory distress syndrome (ARDS), thus requiring mechanical ventilation, and resulting in a high rate of intensive care unit (ICU) admission. Several complications can arise during an ICU stay, from both COVID-19 infection and the respiratory supporting system, including barotraumas (pneumothorax and pneumomediastinum), superimposed pneumonia, coagulation disorders (pulmonary embolism, venous thromboembolism, hemorrhages and acute ischemic stroke), abdominal involvement (acute mesenteric ischemia, pancreatitis and acute kidney injury) and sarcopenia. Imaging plays a pivotal role in the detection and monitoring of ICU complications and is expanding even to prognosis prediction. The present pictorial review describes the clinicopathological and radiological findings of COVID-19 ARDS in ICU patients and discusses the imaging features of complications related to invasive ventilation support, as well as those of COVID-19 itself in this particularly fragile population. Radiologists need to be familiar with COVID-19's possible extra-pulmonary complications and, through reliable and constant monitoring, guide therapeutic decisions. Moreover, as more research is pursued and the pathophysiology of COVID-19 is increasingly understood, the role of imaging must evolve accordingly, expanding from the diagnosis and subsequent management of patients to prognosis prediction. [ABSTRACT FROM AUTHOR]

Background: The interest in protective ventilation strategies and individualized approaches for patients with severe illness on veno venous extracorporeal support has increased in recent years. Wide heterogeneity exists among patients with COVID-19 related acute respiratory distress syndrome (C-ARDS) and ARDS from other etiologies (NC-ARDS). EIT is a useful tool for the accurate analysis of regional lung volume distribution and allows for a tailored ventilatory setting. The aim of this work is to retrospectively describe the results of EIT assessments performed in patients C-ARDS and NC-ARDS undergoing V-V ECMO support. Methods: A clinical EIT-guided decremental PEEP trail was conducted for all patients included in the study and mechanically ventilated. Results: 12 patients with C-ARDS and 12 patients with NC-ARDS were included in the study for a total of 13 and 18 EIT evaluations, respectively. No significant differences in arterial blood gas, respiratory parameters, and regional ventilation before and after the EIT exam were recorded. The subset of patients with NC-ARDS whose EIT exam led to PEEP modification was characterized by a lower baseline compliance compared with the C-ARDS group: 18 (16–28) vs. 27 (24–30) (p = 0.04). Overdistension significantly increased at higher steps only for the NC-ARDS group. A higher percentage of overdistension was described in patients with NC-ARDS when compared with patients with C-ARDS. Conclusions: EIT is feasible in patients with COVID-19-associated ARDS on veno-venous extracorporeal support and may help in tailoring the PEEP setting. Overall, severe COVID-19-related ARDS presents respiratory characteristics similar to severe "classical" NC-ARDS. However, C-ARDS is associated with a lower risk of overdistension at a higher PEEP level compared with NC-ARDS. [ABSTRACT FROM AUTHOR]

Background: Ground-level ozone has been gaining notoriety with increasing evidence of its nefarious effects on health, especially respiratory diseases. Where do we stand on the solidity of this data and is there room for improvement? Objectives: Evaluate this evidence for incongruities or heterogeneity in this field of research. How is the exposure assessment conducted, where does Portugal stand in this field, and what can be improved? Health deterioration concerning asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS) are analysed. Methods: A review of 1735 studies was conducted through PubMed and Google Scholar engines for the past two decades. We identified 59 eligible studies and included an array of variables, including O 3 measurements, number of air-quality monitoring stations used, relative risks, odds ratios, hazard ratios, number of hospital admissions, visits, or mortality, and size of population dataset used. Results: Approximately 83% of data in this review presents significant correlations of ozone with asthma, COPD, and ARDS. Studies that report negative or not significant associations mention a lack of data or topographic differences as the main issue with these divergent results. Studies consistently report summer as a period of particular concern. Portuguese data in this field is lacking. Conclusions: This research field is growing in interest and there is evidence that ozone plays a non-negligible role in health deterioration. The few Portuguese studies in this field seem aligned with the literature reviewed but more research is needed. Suggested improvements are more and better data through denser air-quality networks to accurately depict personal exposure to ozone. Homogenization of the exposure assessment concerning averaging times of ozone to daily maximum 8 h averages whenever possible. Risk increments based on 10 ppb instead of interquartile ranges. Lastly, contrary to some studies in this review, the topographic effect on concentrations and health deterioration should not be underestimated and seasonality should always be checked. [ABSTRACT FROM AUTHOR]

Background: Presently, a number of specific observations have been performed on microcirculatory function in a coronavirus disease-19 (COVID-19) setting. We hypothesized that, in the critically ill, endothelial dysfunction secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the subsequent inflammation and coagulopathy may lead to microcirculatory alterations, further exacerbated by the hypoxemic state. A dysfunctional microcirculation may represent the hidden motor underlying the development of COVID-19's clinical manifestations. Methods: A single center, prospective, observational study. We analyzed bedside sublingual microcirculation in twenty-four consecutive COVID-19-associated acute respiratory distress syndrome (ARDS) patients mechanically ventilated in an Intensive Care Unit (ICU), together with macro-hemodynamics, clinical parameters, echocardiography, and laboratory data at a single time-point after ICU admission. All participants were recruited between March and May 2020. Results: The microcirculatory pattern was characterized by increased values of total vessel density and perfused vessel density, a reduced value of proportion of perfused vessels and microvascular flow index, and high values of heterogeneity index. The duration of mechanical ventilation before microcirculation assessment was inversely associated with the proportion of perfused vessels (p = 0.023). Within the macro-hemodynamic parameters, the right ventricle end-diastolic diameter was inversely associated with proportion of perfused vessels and microvascular flow index (p = 0.039 and 0.014, respectively) and directly associated with the heterogeneity index (p = 0.033). Conclusions: In COVID-19-associated ARDS patients, the microcirculation showed impaired quality of flow parameters coupled with a high vessel density. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is a serious complication of COVID-19. This study aimed to evaluate the prevalence of ARDS among patients hospitalized with COVID-19 in Poland as well as to characterize clinical outcomes in patients hospitalized with COVID-19-associated ARDS. This is a retrospective, secondary analysis of epidemiological data from 116,539 discharge reports on patients hospitalized with COVID-19 in Poland between March and December 2020. The overall prevalence of ARDS was 3.6%, respectively 2.9% among females, and 4.4% among males (p < 0.001). Of the 4237 patients hospitalized with COVID-19-associated ARDS, 3764 deaths were reported (88.8%). Participants aged 60 years and over had more than three times higher odds of COVID-19-associated ARDS. Men had higher odds of COVID-19-associated ARDS than women (OR = 1.55; 95% CI: 1.45–1.65; p < 0.001). Patients with COVID-19 and diabetes had higher odds of COVID-19-associated ARDS (OR = 1.16; 95% CI: 1.03–1.30; p = 0.01). Among patients with COVID-19-associated ARDS, older age, male sex (OR = 1.27; 95% CI: 1.03–1.56; p = 0.02), and presence of cardiovascular diseases (OR = 1.26; 95% CI: 1.00–1.59; p = 0.048) were significantly associated with the risk of in-hospital death. Among patients hospitalized with COVID-19 in Poland, the prevalence of ARDS was relatively low, but the in-hospital mortality rate in patients with COVID-19-associated ARDS was higher compared to other EU countries. [ABSTRACT FROM AUTHOR]

Background: Impaired liver function and cholestasis are frequent findings in critically ill patients and are associated with poor outcomes. We tested the hypothesis that hypoxic liver injury and hypoxic cholangiocyte injury are detectable very early in patients with ARDS, may depend on the severity of hypoxemia, and may be aggravated by the use of rescue therapies (high PEEP level and prone positioning) but could be attenuated by extracorporeal membrane oxygenation (ECMO). Methods: In 70 patients with ARDS, aspartate-aminotransferase (AST), alanin-aminotransferase (ALT) and gamma glutamyltransferase (GGT) were measured on the day of the diagnosis of ARDS and three more consecutive days (day 3, day 5, day 10), total bile acids were measured on day 0, 3, and 5. Results: AST levels increased on day 0 and remained constant until day 5, then dropped to normal on day 10 (day 0: 66.5 U/l; day 3: 60.5 U/l; day 5: 63.5 U/l, day 10: 32.1 U/l), ALT levels showed the exact opposite kinetic. GGT was already elevated on day 0 (91.5 U/l) and increased further throughout (day 3: 163.5 U/l, day 5: 213 U/l, day 10: 307 U/l), total bile acids levels increased significantly from day 0 to day 3 (p = 0.019) and day 0 to day 5 (p < 0.001), but not between day 3 and day 5 (p = 0.217). Total bile acids levels were significantly correlated to GGT on day 0 (p < 0.001), day 3 (p = 0.02), and in a trend on day 5 (p = 0.055). PEEP levels were significantly correlated with plasma levels of AST (day 3), ALT (day 5) and GGT (day 10). Biomarker levels were not associated with the use of ECMO, prone position, the cause of ARDS, and paO2. Conclusions: We found no evidence of hypoxic liver injury or hypoxic damage to cholangiocytes being caused by the severity of hypoxemia in ARDS patients during the very early phase of the disease. Additionally, mean PEEP level, prone positioning, and ECMO treatment did not have an impact in this regard. Nevertheless, GGT levels were elevated from day zero and rising, this increase was not related to paO2, prone position, ECMO treatment, or mean PEEP, but correlated to total bile acid levels. [ABSTRACT FROM AUTHOR]

The outburst of inflammatory response and hypercoagulability are among the factors contributing to increased mortality in severe COVID-19 cases. Pentoxifylline (PTX), a xanthine-derived drug registered for the treatment of vascular claudication, has been reported to display broad-spectrum anti-inflammatory and immunomodulatory properties via adenosine A2A receptor (A2AR)-related mechanisms, in parallel to its rheological actions. Prior studies have indicated the efficacy of PTX in the treatment of various pulmonary diseases, including the management of acute respiratory distress syndrome of infectious causes. Therefore, PTX has been proposed to have potential benefits in the treatment of SARS-CoV-2 symptoms, as well as its complications. The aim of this review is to discuss available knowledge regarding the role of PTX as a complementary therapeutic in SARS-CoV-2. [ABSTRACT FROM AUTHOR]

(1) Background: Extracorporeal membrane oxygenation (ECMO) is increasingly used for acute respiratory failure with few absolute but many relative contraindications. The provider in charge often has a difficult time weighing indications and contraindications to anticipate if the patient will benefit from this treatment, a decision that often decides life and death for the patient. To assist in this process in coming to a good evidence-based decision, we reviewed the available literature. (2) Methods: We performed a systematic review through a literature search of the MEDLINE database of former and current absolute and relative contraindications to the initiation of ECMO treatment. (3) Results: The following relative and absolute contraindications were identified in the literature: absolute—refusal of the use of extracorporeal techniques by the patient, advanced stage of cancer, fatal intracerebral hemorrhage/cerebral herniation/intractable intracranial hypertension, irreversible destruction of the lung parenchyma without the possibility of transplantation, and contraindications to lung transplantation; relative—advanced age, immunosuppressed patients/pharmacological immunosuppression, injurious ventilator settings > 7 days, right-heart failure, hematologic malignancies, especially bone marrow transplantation and graft-versus-host disease, SAPS II score ≥ 60 points, SOFA score > 12 points, PRESERVE score ≥ 5 points, RESP score ≤ −2 points, PRESET score ≥ 6 points, and "do not attempt resuscitation" order (DN(A)R status). (4) Conclusions: We provide a simple-to-follow algorithm that incorporates absolute and relative contraindications to the initiation of ECMO treatment. This algorithm attempts to weigh pros and cons regarding the benefit for an individual patient and hopefully assists caregivers to make better, informed decisions. [ABSTRACT FROM AUTHOR]

The use of extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS) has increased in the last decade. However, mortality remains high, and the complexity of ECMO requires individualized treatment. There are some biomarkers to monitor progression and predict clinical outcomes of ARDS. This project aims to advance the management of ARDS patients treated with ECMO by exploring miRNA expression in whole blood. The analysis was conducted on two groups with different length of ECMO: Group A (longer runs) and group B (shorter runs). We analyzed miRNAs before ECMO cannulation, and at 7 and 14 days of ECMO support. Our results showed that in the group B patients, 11 deregulated miRNAs were identified, and showed an opposite trend of expression compared to the group A patients. In silico analysis revealed that these 11 miRNAs were related to processes involved in the pathogenesis and evolution of ARDS. This scenario could represent homeostatic mechanisms by which, in ECMO responsive patients, pathways activated during ARDS progression are switched-off. Circulating miRNAs could represent promising biomarkers to monitor the evolution of ARDS under ECMO support. Further studies may shed light on this topic to improve a personalized approach in such a complex setting of patients. [ABSTRACT FROM AUTHOR]

Infection with the novel severe acute respiratory coronavirus-2 (SARS-CoV2) results in COVID-19, a disease primarily affecting the respiratory system to provoke a spectrum of clinical manifestations, the most severe being acute respiratory distress syndrome (ARDS). A significant proportion of COVID-19 patients also develop various cardiac complications, among which dysfunction of the right ventricle (RV) appears particularly common, especially in severe forms of the disease, and which is associated with a dismal prognosis. Echocardiographic studies indeed reveal right ventricular dysfunction in up to 40% of patients, a proportion even greater when the RV is explored with strain imaging echocardiography. The pathophysiological mechanisms of RV dysfunction in COVID-19 include processes increasing the pulmonary vascular hydraulic load and others reducing RV contractility, which precipitate the acute uncoupling of the RV with the pulmonary circulation. Understanding these mechanisms provides the fundamental basis for the adequate therapeutic management of RV dysfunction, which incorporates protective mechanical ventilation, the prevention and treatment of pulmonary vasoconstriction and thrombotic complications, as well as the appropriate management of RV preload and contractility. This comprehensive review provides a detailed update of the evidence of RV dysfunction in COVID-19, its pathophysiological mechanisms, and its therapy. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible RNA virus that is the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic. Patients with severe COVID-19 may develop acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) and require mechanical ventilation. Key features of SARS-CoV-2 induced pulmonary complications include an overexpression of pro-inflammatory chemokines and cytokines that contribute to a 'cytokine storm.' In the current study an inflammatory state in Calu-3 human lung epithelial cells was characterized in which significantly elevated transcripts of the immunostimulatory chemokines CXCL9, CXCL10, and CXCL11 were present. Additionally, an increase in gene expression of the cytokines IL-6, TNFα, and IFN-γ was observed. The transcription of CXCL9, CXCL10, IL-6, and IFN-γ was also induced in the lungs of human transgenic angiotensin converting enzyme 2 (ACE2) mice infected with SARS-CoV-2. To elucidate cell signaling pathways responsible for chemokine upregulation in SARS-CoV-2 infected cells, small molecule inhibitors targeting key signaling kinases were used. The induction of CXCL9, CXCL10, and CXCL11 gene expression in response to SARS-CoV-2 infection was markedly reduced by treatment with the AKT inhibitor GSK690693. Samples from COVID-19 positive individuals also displayed marked increases in CXCL9, CXCL10, and CXCL11 transcripts as well as transcripts in the AKT pathway. The current study elucidates potential pathway specific targets for reducing the induction of chemokines that may be contributing to SARS-CoV-2 pathogenesis via hyperinflammation. [ABSTRACT FROM AUTHOR]

(1) Background: To evaluate time-dependent right ventricular (RV) performance in patients with COVID-19-associated acute respiratory distress syndrome (ARDS) undergoing intensive care (ICU) treatment. (2) Methods: This prospective observational study included 21 ICU patients with COVID-19-associated ARDS in a university hospital in 2020 (first wave). Patients were evaluated by transthoracic echocardiography at an early (EE) and late (LE) stage of disease. Echocardiographic parameters describing RV size and function as well as RV size in correlation to PaO2/FiO2 ratio were assessed in survivors and nonsurvivors. (3) Results: Echocardiographic RV parameters were within normal range and not significantly different between EE and LE. Comparing survivors and nonsurvivors revealed no differences in RV performance at EE. Linear regression analysis did not show a correlation between RV size and PaO2/FiO2 ratio over all measurements. Analysing EE and LE separately showed a significant increase in RV size correlated to a lower PaO2/FiO2 ratio at a later stage of COVID-19 ARDS. (4) Conclusion: The present study reveals neither a severe RV dilatation nor an impairment of systolic RV function during the initial course of COVID-19-associated ARDS. A trend towards an increase in RV size in correlation with ARDS severity in the second week after ICU admission was observed. [ABSTRACT FROM AUTHOR]

The high mortality of pediatric acute respiratory distress syndrome (PARDS) is partly related to fluid overload. Extracorporeal membrane oxygenation (ECMO) is used to treat pediatric patients with severe PARDS, but can result in acute kidney injury (AKI) and worsening fluid overload. The objective of this study was to determine whether the addition of CRRT to ECMO in patients with PARDS is associated with increased mortality. Methods: We conducted a retrospective 7-year study of patients with PARDS requiring ECMO and divided them into those requiring CRRT and those not requiring CRRT. We calculated severity of illness scores, the amount of blood products administered to both groups, and determined the impact of CRRT on mortality and morbidity. Results: We found no significant difference in severity of illness scores except the vasoactive inotropic score (VIS, 45 ± 71 vs. 139 ± 251, p = 0.042), which was significantly elevated during the initiation and the first three days of ECMO. CRRT was associated with an increase in the use of blood products and noradrenaline (p < 0.01) without changing ECMO duration, length of PICU stay or mortality. Conclusion: The addition of CRRT to ECMO is associated with a greater consumption of blood products but no increase in mortality. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) patients can develop interstitial pneumonia, which, in turn, can evolve into acute respiratory distress syndrome (ARDS). This is accompanied by an inflammatory cytokine storm. severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has proteins capable of promoting the cytokine storm, especially in patients with comorbidities, including obesity. Since currently no resolutive therapy for ARDS has been found and given the scientific literature regarding the use of adenosine, its application has been hypothesized. Through its receptors, adenosine is able to inhibit the acute inflammatory process, increase the protection capacity of the epithelial barrier, and reduce the damage due to an overactivation of the immune system, such as that occurring in cytokine storms. These features are known in ischemia/reperfusion models and could also be exploited in acute lung injury with hypoxia. Considering these hypotheses, a COVID-19 patient with unresponsive respiratory failure was treated with adenosine for compassionate use. The results showed a rapid improvement of clinical conditions, with negativity of SARS-CoV2 detection. [ABSTRACT FROM AUTHOR]

Hypothesizing that pulmonary artery diameter is a marker of subclinical pulmonary hypertension, we assessed its impact on postoperative outcome in patients requiring pneumonectomy. Morphometric, clinical, and laboratory data were retrospectively retrieved from files of 294 consecutive patients treated by pneumonectomy for malignancy (289 NSCLC). Pulmonary artery was measured at bifurcation level on CT scan and normalized by body surface area. Median normalized pulmonary artery diameter (cut-off for analyses) was 14 mm/m2. Postoperatively, 46 patients required re-do intubation and 30 had acute respiratory distress syndrome (ARDS). Multivariate analysis showed that Charlson Comorbidity Index >5 (p = 0.0009, OR 3.8 [1.76–8.22]), right side of pneumonectomy (p = 0.013, OR 2.37 [1.20–4.71]), and higher normalized pulmonary artery diameter (p = 0.029, OR 2.16 [1.08–4.33]) were independent predictors of re-do intubation, while Charlson Comorbidity Index >5 (p = 0.018, OR 2.55 [1.17–5.59]) and higher normalized pulmonary artery diameter (p = 0.028, OR = 2.52 [1.10–5.77]) were independently associated with occurrence of ARDS. Post-operative mortality was 8.5%. Higher normalized pulmonary artery diameter, (p = 0.026, OR 3.39 [1.15–9.95]), right side of pneumonectomy (p = 0.0074, OR 4.11 [1.46–11.56]), and Charlson Comorbidity Index >5 (p = 0.0011, OR 5.56 [1.99–15.54]) were independent predictors of postoperative death. We conclude that pre-operative normalized pulmonary artery diameter predicts the risk of re-do intubation, ARDS and mortality in patients undergoing pneumonectomy for cancer. [ABSTRACT FROM AUTHOR]

Hypoxia, or lack of oxygen, can occur in both physiological (high altitude) and pathological conditions (respiratory diseases). In this narrative review, we introduce high altitude pulmonary edema (HAPE), acute respiratory distress syndrome (ARDS), Chronic Obstructive Pulmonary Disease (COPD), and Cystic Fibrosis (CF) as examples of maladaptation to hypoxia, and highlight some of the potential mechanisms influencing the prognosis of the affected patients. Among the specific pathways modulated in response to hypoxia, iron metabolism has been widely explored in recent years. Recent evidence emphasizes hepcidin as highly involved in the compensatory response to hypoxia in healthy subjects. A less investigated field in the adaptation to hypoxia is the sphingolipid (SPL) metabolism, especially through Ceramide and sphingosine 1 phosphate. Both individually and in concert, iron and SPL are active players of the (mal)adaptation to physiological hypoxia, which can result in the pathological HAPE. Our aim is to identify some pathways and/or markers involved in the physiological adaptation to low atmospheric pressures (high altitudes) that could be involved in pathological adaptation to hypoxia as it occurs in pulmonary inflammatory diseases. Hepcidin, Cer, S1P, and their interplay in hypoxia are raising growing interest both as prognostic factors and therapeutical targets. [ABSTRACT FROM AUTHOR]

Influenza virus infection is responsible for significant morbidity and mortality in the pediatric and pregnant women populations, with deaths frequently caused by severe influenza-associated lower respiratory tract infection and acute respiratory distress syndrome (ARDS). An appropriate immune response requires controlling the viral infection through activation of antiviral defenses, which involves cells of the lung and immune system. High levels of viral infection or high levels of inflammation in the lower airways can contribute to ARDS. Pregnant women and young children, especially those born prematurely, may develop serious complications if infected with influenza virus. Vaccination against influenza virus will lead to lower infection rates and fewer complications, even if the vaccine is poorly matched to circulating viral strains. Maternal vaccination offers infants protection via antibody transmission through the placenta and breast milk. Despite the health benefits of the influenza vaccine, vaccination rates around the world remain well below targets. Trust in the use of vaccines among the public must be restored in order to increase vaccination rates and decrease the public health burden of influenza. [ABSTRACT FROM AUTHOR]

Modern ventilatory strategies are based on the assumption that lung terminal airspaces act as isotropic balloons that progressively accommodate gas. Phase contrast synchrotron radiation computed tomography (PCSRCT) has recently challenged this concept, showing that in healthy lungs, deflation mechanisms are based on the sequential de-recruitment of airspaces. Using PCSRCT scans in an animal model of acute respiratory distress syndrome (ARDS), this study examined whether the numerosity (ASnum) and dimension (ASdim) of lung airspaces change during a deflation maneuver at decreasing levels of positive end-expiratory pressure (PEEP) at 12, 9, 6, 3, and 0 cmH2O. Deflation was associated with significant reduction of ASdim both in the whole lung section (passing from from 13.1 ± 2.0 at PEEP 12 to 7.6 ± 4.2 voxels at PEEP 0) and in single concentric regions of interest (ROIs). However, the regression between applied PEEP and ASnum was significant in the whole slice (ranging from 188 ± 52 at PEEP 12 to 146.4 ± 96.7 at PEEP 0) but not in the single ROIs. This mechanism of deflation in which reduction of ASdim is predominant, differs from the one observed in healthy conditions, suggesting that the peculiar alveolar micromechanics of ARDS might play a role in the deflation process. [ABSTRACT FROM AUTHOR]