Pulmonary Abnormalities in Liver Disease: Relevance to Transplantation and Outcome.

Pulmonary disease in liver cirrhosis and portal hypertension (PH) constitutes a challenging clinical scenario and may have important implications with regard to prognosis, liver transplantation (LT) candidacy, and post-LT outcome. Pre-LT evaluation should include adequate screening for pulmonary diseases that may occur concomitantly with liver disease as well as for those that may arise as a complication of end-stage liver disease and PH, given that either may jeopardize safe LT and successful outcome. It is key to discriminate those patients who would benefit from LT, especially pulmonary disorders that have been reported to resolve post-LT and are considered "pulmonary indications" for transplant, from those who are at increased mortality risk and in whom LT is contraindicated. In conclusion, in this article, we review the impact of several pulmonary disorders, including cystic fibrosis, alpha 1-antitrypsin deficiency, hereditary hemorrhagic telangiectasia, sarcoidosis, coronavirus disease 2019, asthma, chronic obstructive pulmonary disease, pulmonary nodules, interstitial lung disease, hepatic hydrothorax, hepatopulmonary syndrome, and portopulmonary hypertension, on post-LT survival, as well as the reciprocal impact of LT on the evolution of lung function.

Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-a new coronavirus that has led to a worldwide pandemic1-has a furin cleavage site (PRRAR) in its spike protein that is absent in other group-2B coronaviruses2. To explore whether the furin cleavage site contributes to infection and pathogenesis in this virus, we generated a mutant SARS-CoV-2 that lacks the furin cleavage site (ΔPRRA). Here we report that replicates of ΔPRRA SARS-CoV-2 had faster kinetics, improved fitness in Vero E6 cells and reduced spike protein processing, as compared to parental SARS-CoV-2. However, the ΔPRRA mutant had reduced replication in a human respiratory cell line and was attenuated in both hamster and K18-hACE2 transgenic mouse models of SARS-CoV-2 pathogenesis. Despite reduced disease, the ΔPRRA mutant conferred protection against rechallenge with the parental SARS-CoV-2. Importantly, the neutralization values of sera from patients with coronavirus disease 2019 (COVID-19) and monoclonal antibodies against the receptor-binding domain of SARS-CoV-2 were lower against the ΔPRRA mutant than against parental SARS-CoV-2, probably owing to an increased ratio of particles to plaque-forming units in infections with the former. Together, our results demonstrate a critical role for the furin cleavage site in infection with SARS-CoV-2 and highlight the importance of this site for evaluating the neutralization activities of antibodies.

First results of the "Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS)".

PURPOSE: Knowledge regarding patients' clinical condition at severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection is sparse. Data in the international, multicenter Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS) cohort study may enhance the understanding of COVID-19. METHODS: Sociodemographic and clinical characteristics of SARS-CoV-2-infected patients, enrolled in the LEOSS cohort study between March 16, 2020, and May 14, 2020, were analyzed. Associations between baseline characteristics and clinical stages at diagnosis (uncomplicated vs. complicated) were assessed using logistic regression models. RESULTS: We included 2155 patients, 59.7% (1,287/2,155) were male; the most common age category was 66-85 years (39.6%; 500/2,155). The primary COVID-19 diagnosis was made in 35.0% (755/2,155) during complicated clinical stages. A significant univariate association between age; sex; body mass index; smoking; diabetes; cardiovascular, pulmonary, neurological, and kidney diseases; ACE inhibitor therapy; statin intake and an increased risk for complicated clinical stages of COVID-19 at diagnosis was found. Multivariable analysis revealed that advanced age [46-65 years: adjusted odds ratio (aOR): 1.73, 95% CI 1.25-2.42, p = 0.001; 66-85 years: aOR 1.93, 95% CI 1.36-2.74, p < 0.001; > 85 years: aOR 2.38, 95% CI 1.49-3.81, p < 0.001 vs. individuals aged 26-45 years], male sex (aOR 1.23, 95% CI 1.01-1.50, p = 0.040), cardiovascular disease (aOR 1.37, 95% CI 1.09-1.72, p = 0.007), and diabetes (aOR 1.33, 95% CI 1.04-1.69, p = 0.023) were associated with complicated stages of COVID-19 at diagnosis. CONCLUSION: The LEOSS cohort identified age, cardiovascular disease, diabetes and male sex as risk factors for complicated disease stages at SARS-CoV-2 diagnosis, thus confirming previous data. Further data regarding outcomes of the natural course of COVID-19 and the influence of treatment are required.

SARS-CoV-2 pathophysiology and its clinical implications: An integrative overview of the pharmacotherapeutic management of COVID-19.

Common manifestations of COVID-19 are respiratory and can extend from mild symptoms to severe acute respiratory distress. The severity of the illness can also extend from mild disease to life-threatening acute respiratory distress syndrome (ARDS). SARS-CoV-2 infection can also affect the gastrointestinal tract, liver and pancreatic functions, leading to gastrointestinal symptoms. Moreover, SARS-CoV-2 can cause central and peripheral neurological manifestations, affect the cardiovascular system and promote renal dysfunction. Epidemiological data have indicated that cancer patients are at a higher risk of contracting the SARS-CoV-2 virus. Considering the multitude of clinical symptoms of COVID-19, the objective of the present review was to summarize their pathophysiology in previously healthy patients, as well as in those with comorbidities. The present review summarizes the current, though admittedly fluid knowledge on the pathophysiology and symptoms of COVID-19 infection. Although unclear issues still remain, the present study contributes to a more complete understanding of the disease, and may drive the direction of new research. The recognition of the severity of the clinical symptoms of COVID-19 is crucial for the specific therapeutic management of affected patients.

Modeling lung perfusion abnormalities to explain early COVID-19 hypoxemia.

Early stages of the novel coronavirus disease (COVID-19) are associated with silent hypoxia and poor oxygenation despite relatively minor parenchymal involvement. Although speculated that such paradoxical findings may be explained by impaired hypoxic pulmonary vasoconstriction in infected lung regions, no studies have determined whether such extreme degrees of perfusion redistribution are physiologically plausible, and increasing attention is directed towards thrombotic microembolism as the underlying cause of hypoxemia. Herein, a mathematical model demonstrates that the large amount of pulmonary venous admixture observed in patients with early COVID-19 can be reasonably explained by a combination of pulmonary embolism, ventilation-perfusion mismatching in the noninjured lung, and normal perfusion of the relatively small fraction of injured lung. Although underlying perfusion heterogeneity exacerbates existing shunt and ventilation-perfusion mismatch in the model, the reported hypoxemia severity in early COVID-19 patients is not replicated without either extensive perfusion defects, severe ventilation-perfusion mismatch, or hyperperfusion of nonoxygenated regions.

Critical care ultrasonography during COVID-19 pandemic: The ORACLE protocol.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is characterized by severe lung involvement and hemodynamic alterations. Critical care ultrasonography is vital because it provides real time information for diagnosis and treatment. Suggested protocols for image acquisition and measurements have not yet been evaluated. METHODS: This cross-sectional study was conducted at two centers from 1 April 2020 to 30 May 2020 in adult patients with confirmed COVID-19 infection admitted to the critical care unit. Cardiac and pulmonary evaluations were performed using the ORACLE protocol, specifically designed for this study, to ensure a structured process of image acquisition and limit staff exposure to the infection. RESULTS: Eighty-two consecutively admitted patients were evaluated. Most of the patients were males, with a median age of 56 years, and the most frequent comorbidities were hypertension and type 2 diabetes, and 25% of the patients had severe acute respiratory distress syndrome. The most frequent ultrasonographic findings were elevated pulmonary artery systolic pressure (69.5%), E/e' ratio > 14 (29.3%), and right ventricular dilatation (28%) and dysfunction (26.8%). A high rate of fluid responsiveness (82.9%) was observed. The median score (19 points) on pulmonary ultrasound did not reveal any variation between the groups. Elevated pulmonary artery systolic pressure was associated with higher in-hospital mortality. CONCLUSION: The ORACLE protocol was a feasible, rapid, and safe bedside tool for hemodynamic and respiratory evaluation of patients with COVID-19. Further studies should be performed on the alteration in pulmonary hemodynamics and right ventricular function and its relationship with outcomes.

Epithelial Dysfunction in Lung Diseases: Effects of Amino Acids and Potential Mechanisms.

Lung diseases affect millions of individuals all over the world. Various environmental factors, such as toxins, chemical pollutants, detergents, viruses, bacteria, microbial dysbiosis, and allergens, contribute to the development of respiratory disorders. Exposure to these factors activates stress responses in host cells and disrupt lung homeostasis, therefore leading to dysfunctional epithelial barriers. Despite significant advances in therapeutic treatments for lung diseases in the last two decades, novel interventional targets are imperative, considering the side effects and limited efficacy in patients treated with currently available drugs. Nutrients, such as amino acids (e.g., arginine, glutamine, glycine, proline, taurine, and tryptophan), peptides, and bioactive molecules, have attracted more and more attention due to their abilities to reduce oxidative stress, inhibit apoptosis, and regulate immune responses, thereby improving epithelial barriers. In this review, we summarize recent advances in amino acid metabolism in the lungs, as well as multifaceted functions of amino acids in attenuating inflammatory lung diseases based on data from studies with both human patients and animal models. The underlying mechanisms for the effects of physiological amino acids are likely complex and involve cell signaling, gene expression, and anti-oxidative reactions. The beneficial effects of amino acids are expected to improve the respiratory health and well-being of humans and other animals. Because viruses (e.g., coronavirus) and environmental pollutants (e.g., PM2.5 particles) induce severe damage to the lungs, it is important to determine whether dietary supplementation or intravenous administration of individual functional amino acids (e.g., arginine-HCl, citrulline, N-acetylcysteine, glutamine, glycine, proline and tryptophan) or their combinations to affected subjects may alleviate injury and dysfunction in this vital organ.

Epidemiological and clinical course of 483 patients with COVID-19 in Wuhan, China: a single-center, retrospective study from the mobile cabin hospital.

During the COVID-19 outbreak, the mobile cabin hospital has effectively isolated and treated patients diagnosed as mild-moderate disease. However, a detailed clinical course has not been well described. We included 483 patients who were isolated and treated from Feb 6, 2020, to Feb 15, 2020, including definite outcome (discharge or deterioration). Sixty-two patients were transferred to severe cases, of whom were trasfered to designated hospital for intensive care. By March 9, 2020, all patients were discharged without dead. The mobile cabin hospital provides feasible strategy of isolation of mild-moderate cases and timely intervention during the virus outbreak.

The renin-angiotensin system: An integrated view of lung disease and coagulopathy in COVID-19 and therapeutic implications.

The renin-angiotensin system (RAS) has long been appreciated as a major regulator of blood pressure, but has more recently been recognized as a mechanism for modulating inflammation as well. While there has been concern in COVID-19 patients over the use of drugs that target this system, the RAS has not been explored fully as a druggable target. The abbreviated description of the RAS suggests that its dysregulation may be at the center of COVID-19.

Novel insights on the pulmonary vascular consequences of COVID-19.

In the last few months, the number of cases of a new coronavirus-related disease (COVID-19) rose exponentially, reaching the status of a pandemic. Interestingly, early imaging studies documented that pulmonary vascular thickening was specifically associated with COVID-19 pneumonia, implying a potential tropism of the virus for the pulmonary vasculature. Moreover, SARS-CoV-2 infection is associated with inflammation, hypoxia, oxidative stress, mitochondrial dysfunction, DNA damage, and lung coagulopathy promoting endothelial dysfunction and microthrombosis. These features are strikingly similar to what is seen in pulmonary vascular diseases. Although the consequences of COVID-19 on the pulmonary circulation remain to be explored, several viruses have been previously thought to be involved in the development of pulmonary vascular diseases. Patients with preexisting pulmonary vascular diseases also appear at increased risk of morbidity and mortality. The present article reviews the molecular factors shared by coronavirus infection and pulmonary vasculature defects, and the clinical relevance of pulmonary vascular alterations in the context of COVID-19.

COVID-19 and restrictive lung disease: A deadly combo to trip off the fine balance.

Coronavirus Disease (COVID-19) pandemic has so far led to innumerable deaths worldwide. The risk factors so far that have been most studied as poor prognostic factors are old age, individuals with multiple comorbidities and immunocompromised patients. Amongst the chronic lung diseases, most patients with COVID-19 reported so far had asthma, chronic obstructive pulmonary disease (COPD), and interstitial lung disease. Herein, we discuss the significance of restrictive lung disease during the COVID-19 pandemic as a potential risk factor via an example of a patient with kyphoscoliosis who succumbed to death due to COVID-19 pneumonia.