Pulmonary thrombosis associated with COVID-19 pneumonia: Beyond classical pulmonary thromboembolism.

BACKGROUND: Classical pulmonary thromboembolism (TE) and local pulmonary thrombosis (PT) have been suggested as mechanisms of thrombosis in COVID-19. However, robust evidence is still lacking because this was mainly based on retrospective studies, in which patients were included when TE was suspected. METHODS: All patients with COVID-19 pneumonia underwent computed tomography and pulmonary angiography in a prospective study. The main objective was to determine the number and percentage of thrombi surrounded by lung opacification (TSO) in each patient, as well as their relationship with percentage of lung involvement (TLI), to distinguish classical TE (with a random location of thrombi that should correspond to a percentage of TSO equivalent to the TLI) from PT. We determined TLI by artificial intelligence. Analyses at patient level (TLI and percentage of TSO) and at thrombi level (TLI and TSO) were performed. RESULTS: We diagnosed TE in 70 out of 184 patients. Three (2-8) thrombi/patient were detected. The percentage of TSO was 100% (75-100) per patient, and TLI was 19.9% (4.6-35.2). Sixty-five patients (92.9%) were above the random scenario with higher percentage of TSO than TLI. Most thrombi were TSO (n = 299, 75.1%). When evaluating by TLI (<10%, 10%-20%, 20%-30% and >30%), percentage of TSO was higher in most groups. Thrombi were mainly in subsegmental/segmental arteries, and percentage of TSO was higher in all locations. CONCLUSIONS: Thrombi in COVID-19 were found within lung opacities in a higher percentage than lung involvement, regardless of TLI and clot location, supporting the hypothesis of local PT rather than "classic TE".

In Vivo and In Vitro Pro-Fibrotic Response of Lung-Resident Mesenchymal Stem Cells from Patients with Idiopathic Pulmonary Fibrosis.

Lung-resident mesenchymal stem cells (LR-MSC) are thought to participate in idiopathic pulmonary fibrosis (IPF) by differentiating into myofibroblasts. On the other hand, LR-MSC in IPF patients present senescence-related features. It is unclear how they respond to a profibrotic environment. Here, we investigated the profibrotic response of LR-MSC isolated from IPF and control (CON) patients. LR-MSC were inoculated in mice 48 h after bleomycin (BLM) instillation to analyze their contribution to lung damage. In vitro, LR-MSC were exposed to TGFß. Mice inoculated with IPF LR-MSC exhibited worse maintenance of their body weight. The instillation of either IPF or CON LR-MSC sustained BLM-induced histological lung damage, bronchoalveolar lavage fluid cell count, and the expression of the myofibroblast marker, extracellular matrix (ECM) proteins, and proinflammatory cytokines in the lungs. In vitro, IPF LR-MSC displayed higher basal protein levels of aSMA and fibronectin than CON LR-MSC. However, the TGFß response in the expression of TGFß, aSMA, and ECM genes was attenuated in IPF LR-MSC. In conclusion, IPF LR-MSC have acquired myofibroblastic features, but their capacity to further respond to profibrotic stimuli seems to be attenuated. In an advanced stage of the disease, LR-MSC may participate in disease progression owing to their limited ability to repair epithelial damage.

Mitochondrial Dysfunction in Lung Resident Mesenchymal Stem Cells from Idiopathic Pulmonary Fibrosis Patients.

Idiopathic pulmonary fibrosis (IPF) is characterized by an aberrant repair response with uncontrolled turnover of extracellular matrix involving mesenchymal cell phenotypes, where lung resident mesenchymal stem cells (LRMSC) have been supposed to have an important role. However, the contribution of LRMSC in lung fibrosis is not fully understood, and the role of LRMSC in IPF remains to be elucidated. Here, we performed transcriptomic and functional analyses on LRMSC isolated from IPF and control patients (CON). Both over-representation and gene set enrichment analyses indicated that oxidative phosphorylation is the major dysregulated pathway in IPF LRMSC. The most relevant differences in biological processes included complement activation, mesenchyme development, and aerobic electron transport chain. Compared to CON LRMSC, IPF cells displayed impaired mitochondrial respiration, lower expression of genes involved in mitochondrial dynamics, and dysmorphic mitochondria. These changes were linked to an impaired autophagic response and a lower mRNA expression of pro-apoptotic genes. In addition, IPF TGFß-exposed LRMSC presented different expression profiles of mitochondrial-related genes compared to CON TGFß-treated cells, suggesting that TGFß reinforces mitochondrial dysfunction. In conclusion, these results suggest that mitochondrial dysfunction is a major event in LRMSC and that their occurrence might limit LRMSC function, thereby contributing to IPF development.

Mesenchymal Stem Cells from COPD Patients Are Capable of Restoring Elastase-Induced Emphysema in a Murine Experimental Model.

COPD is a chronic lung disease that affects millions of people, declining their lung function and impairing their life quality. Despite years of research and drug approvals, we are still not capable of halting progression or restoring normal lung function. Mesenchymal stem cells (MSC) are cells with extraordinary repair capacity, and MSC-based therapy brings future hope for COPD treatment, although the best source and route of administration are unclear. MSC from adipose tissue (AD-MSC) represents an option for autologous treatment; however, they could be less effective than donor MSC. We compared in vitro behavior of AD-MSC from COPD and non-COPD individuals by migration/proliferation assay, and tested their therapeutic potential in an elastase mouse model. In addition, we tested intravenous versus intratracheal routes, inoculating umbilical cord (UC) MSC and analyzed molecular changes by protein array. Although COPD AD-MSC have impaired migratory response to VEGF and cigarette smoke, they were as efficient as non-COPD in reducing elastase-induced lung emphysema. UC-MSC reduced lung emphysema regardless of the administration route and modified the inflammatory profile in elastase-treated mice. Our data demonstrate equal therapeutic potential of AD-MSC from COPD and non-COPD subjects in the pre-clinical model, thus supporting their autologous use in disease.

A Prospective Study Evaluating Cumulative Incidence and a Specific Prediction Rule in Pulmonary Embolism in COVID-19.

Rationale: Abnormal values of hypercoagulability biomarkers, such as D-dimer, have been described in Coronavirus Disease 2019 (COVID-19), which has also been associated with disease severity and in-hospital mortality. COVID-19 patients with pneumonia are at greater risk of pulmonary embolism (PE). However, the real incidence of PE is not yet clear, since studies have been limited in size, mostly retrospective, and PE diagnostic procedures were only performed when PE was clinically suspected. Objectives: (1) To determine the incidence, clinical, radiological, and biological characteristics, and clinical outcomes of PE among patients hospitalized for COVID-19 pneumonia with D-dimer > 1,000 ng/mL. (2) To develop a prognostic model to predict PE in these patients. Methods: Single-center prospective cohort study. Consecutive confirmed cases of COVID-19 pneumonia with D-dimer > 1,000 ng/mL underwent computed tomography pulmonary angiography (CTPA). Demographic and laboratory data, comorbidities, CTPA scores, treatments administered, and clinical outcomes were analyzed and compared between patients with and without PE. A risk score was constructed from all these variables. Results: Between 6 April 2020 and 2 February 2021, 179 consecutive patients were included. The overall incidence of PE was 39.7% (71 patients) (CI 95%, 32-47%). In patients with PE, emboli were located mainly in segmental/subsegmental arteries (67%). Patients with PE did not differ from the non-PE group in sex, age, or risk factors for thromboembolic disease. Higher urea, D-Dimer, D-dimer-to-ferritin and D-dimer-to-lactate dehydrogenase (LDH) ratios, platelet distribution width (PDW), and neutrophil-to-lymphocyte ratio (NLR) values were found in patients with PE when compared to patients with non-PE. Besides, lymphocyte counts turned out to be lower in patients with PE. A score for PE prediction was constructed with excellent overall performance [area under the ROC curve-receiver operating characteristic (AUC-ROC) 0.81 (95% CI: 0.73-0.89)]. The PATCOM score stands for Pulmonary Artery Thrombosis in COVID-19 Mallorca and includes platelet count, PDW, urea concentration, and D-dimer-to-ferritin ratio. Conclusion: COVID-19 patients with pneumonia and D-dimer values > 1,000 ng/mL were presented with a very high incidence of PE, regardless of clinical suspicion. Significant differences in urea, D-dimer, PDW, NLR, and lymphocyte count were found between patients with PE and non-PE. The PATCOM score is presented in this study as a promising PE prediction rule, although validation in further studies is required.

SARS-CoV-2 detection in bioaerosols using a liquid impinger collector and ddPCR.

The airborne route is the dominant form of COVID-19 transmission, and therefore, the development of methodologies to quantify SARS-CoV-2 in bioaerosols is needed. We aimed to identify SARS-CoV-2 in bioaerosols by using a highly efficient sampler for the collection of 1-3 µm particles, followed by a highly sensitive detection method. 65 bioaerosol samples were collected in hospital rooms in the presence of a COVID-19 patient using a liquid impinger sampler. The SARS-CoV-2 genome was detected by ddPCR using different primer/probe sets. 44.6% of the samples resulted positive for SARS-CoV-2 following this protocol. By increasing the sampled air volume from 339 to 650 L, the percentage of positive samples went from 41% to 50%. We detected five times less positives with a commercial one-step RT-PCR assay. However, the selection of primer/probe sets might be one of the most determining factor for bioaerosol SARS-CoV-2 detection since with the ORF1ab set more than 40% of the samples were positive, compared to <10% with other sets. In conclusion, the use of a liquid impinger collector and ddPCR is an adequate strategy to detect SARS-CoV-2 in bioaerosols. However, there are still some methodological aspects that must be adjusted to optimize and standardize a definitive protocol.

Portopulmonary hypertension: prognosis and management in the current treatment era - results from the REHAP registry.

BACKGROUND: Portopulmonary hypertension (PoPH) is a rare condition with poorer survival compared to idiopathic/familial pulmonary arterial hypertension (IPAH/FPAH). AIMS: To compare the characteristics, survival, prognostic factors and management of PoPH and IPAH/FPAH patients and to assess the impact of treatment on survival of PoPH patients. METHODS: Analysis of data of prevalent and incident PoPH patients enrolled in the Spanish registry of PAH (REHAP) from January 1998 to December 2017 and comparison with IPAH/FPAH patients. Variables analysed: patient and disease (PAH and liver) characteristics, first-line PAH-targeted therapy, causes of death, prognostic factors and survival (according to aetiology and treatment in PoPH patients). RESULTS: Compared to IPAH/FPAH patients (n = 678), patients with PoPH (n = 237) were predominantly men, older and had better functional class and higher prevalence of ascites. Haemodynamics were better. Biomarkers for heart failure were worse. Age- and sex-adjusted 5-year survival rate from diagnosis was 49.3% for PoPH patients and 68.7% for IPAH patients (P < 0.001). Treated PoPH had better survival than non-treated. PAH- and liver-related causes accounted for 30.2% and 24.7% of deaths in PoPH patients. PoPH patients were less likely to receive first-line PAH-targeted therapy and this was associated with greater mortality. Increasing age, worse exercise capacity and ascites were independent prognostic factors of poorer survival; first-line oral monotherapy was associated with improved survival. Eight (3.4%) PoPH patients underwent liver transplantation. CONCLUSIONS: PoPH patients are undertreated and show poorer survival than IPAH/FPAH patients. First-line treatment with PAH-targeted therapy was associated with better survival. Presence of ascites was a predictor of mortality.

Prevalence of pulmonary embolism in patients with COVID-19 pneumonia and high D-dimer values: A prospective study.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) pneumonia is associated to systemic hyper-inflammation and abnormal coagulation profile. D-dimer elevation is particularly frequent, and values higher than 1µg/mL have been associated with disease severity and in-hospital mortality. Previous retrospective studies found a high pulmonary embolism (PE) prevalence, however, it should be highlighted that diagnoses were only completed when PE was clinically suspected. MATERIAL AND METHODS: Single-center prospective cohort study. Between April 6th and April 17th 2020, consecutive confirmed cases of COVID-19 pneumonia with D-dimer >1 µg/mL underwent computed tomography pulmonary angiography (CTPA) to investigate the presence and magnitude of PE. Demographic and laboratory data, comorbidities, CTPA scores, administered treatments, and, clinical outcomes were analysed and compared between patients with and without PE. RESULTS: Thirty consecutive patients (11 women) were included. PE was diagnosed in 15 patients (50%). In patients with PE, emboli were located mainly in segmental arteries (86%) and bilaterally (60%). Patients with PE were significantly older (median age 67.0 (IQR 63.0-73.0) vs. 57.0 (IQR 48.0-69.0) years, p = .048) and did not differ in sex or risk factors for thromboembolic disease from the non-PE group. D-dimer, platelet count, and, C reactive protein values were significantly higher among PE patients. D-dimer values correlated with the radiologic magnitude of PE (p<0.001). CONCLUSIONS: Patients with COVID-19 pneumonia and D-dimer values higher than 1 µg/mL presented a high prevalence of PE, regardless of clinical suspicion. We consider that these findings could contribute to improve the prognosis of patients with COVID-19 pneumonia, by initiating anticoagulant therapy when a PE is found.

Insights into the Role of Bioactive Food Ingredients and the Microbiome in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic disease mainly associated with aging and, to date, its causes are still largely unknown. It has been shown that dietary habits can accelerate or delay the occurrence of aging-related diseases; however, their potential role in IPF development has been underestimated so far. The present review summarizes the evidence regarding the relationship between diet and IPF in humans, and in animal models of pulmonary fibrosis, in which we discuss the bioactivity of specific dietary food ingredients, including fatty acids, peptides, amino acids, carbohydrates, vitamins, minerals and phytochemicals. Interestingly, many animal studies reveal preventive and therapeutic effects of particular compounds. Furthermore, it has been recently suggested that the lung and gut microbiota could be involved in IPF, a relationship which may be linked to changes in immunological and inflammatory factors. Thus, all the evidence so far puts forward the idea that the gut-lung axis could be modulated by dietary factors, which in turn have an influence on IPF development. Overall, the data reviewed here support the notion of identifying food ingredients with potential benefits in IPF, with the ultimate aim of designing nutritional approaches as an adjuvant therapeutic strategy.

Effects of simvastatin in chronic obstructive pulmonary disease: Results of a pilot, randomized, placebo-controlled clinical trial.

INTRODUCTION: Statins may have pleiotropic effects in COPD, but mechanisms remain unclear. OBJECTIVES: To assess the pleiotropic effect of statins in patients with stable COPD on (1): lung function (2); pulmonary and systemic inflammation (3); endothelial function (vascular stiffness) and circulating vascular growth factors; and (4), serum uric acid levels. METHOD: Pilot, double-blind, randomized, placebo-controlled clinical trial in 24 patients with stable COPD, all statin-naïve, who were randomized (1:1) to receive simvastatin 40 mg/24 h during 12 weeks (n = 12; 69.0 ± 7.3 years; post-bd FEV1 53.4 ± 10.0% pred.) or placebo (n = 12; 66.4 ± 4.6 years; post-bd FEV1 48.2 ± 12.6% pred.). Nine patients per group (total n = 18) completed the study. RESULTS: Lung function, pulmonary and systemic inflammatory markers and the degree of vascular stiffness did not change significantly in any group. However, treatment with simvastatin increased the plasma levels of erythropoietin (Epo) (4.2 ± 2.2 mIU/mL to 6.8 ± 3.2 mlU/mL, p < 0.05) and reduced those of serum uric acid (7.1 ± 1.3 mg/dL to 6.5 ± 1.4 mg/dL, p < 0.01). CONCLUSIONS: Short-term treatment with simvastatin in stable COPD patients did not modify lung function, pulmonary and systemic inflammation, or vascular stiffness, but it changed Epo and uric acid levels.

Unidades de cuidados intermedios en neumología / Respiratory intermediate care units

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Síndrome hepatopulmonar e infección por el virus de la inmunodeficiencia humana / Hepatopulmonary syndrome and HIV infection

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