Predictors of the response to phosphodiesterase-5 inhibitors in pulmonary arterial hypertension: an analysis of the Spanish registry.

BACKGROUND: Achieving and maintaining a low-risk profile is associated with favorable outcome in pulmonary arterial hypertension (PAH). The effects of treatment on risk profile are variable among patients. OBJECTIVE: To Identify variables that might predict the response to treatment with phosphodiesterase-5 inhibitors (PDE-5i) in PAH. METHODS: We carried out a cohort analysis of the Spanish PAH registry in 830 patients diagnosed with PAH that started PDE5i treatment and had > 1 year follow-up. 644 patients started PDE-5i either in mono- or add-on therapy and 186 started combined treatment with PDE-5i and endothelin receptor antagonist (ERA). Responders were considered when at 1 year they: (1) were alive; (2) did not present clinical worsening; and (3) improved European Society of Cardiology/European Respiratory Society (ESC/ERS) risk score or remained in low-risk. Univariate and multivariate logistic regression models were used to analyze variables associated with a favorable response. RESULTS: Two hundred and ten patients (33%) starting PDE-5i alone were classified as responders, irrespective of whether it was mono- or add-on therapy. In addition to known predictors of PAH outcome (low-risk at baseline, younger age), male sex and diagnosis of portopulmonary hypertension (PoPH) or HIV-PAH were independent predictors of favorable response to PDE-5i. Diffusing capacity for carbon monoxide (DLco) ≤ 40% of predicted was associated with an unfavorable response. When PDE-5i were used in upfront combination, 58% of patients were responders. In this group, diagnosis of idiopathic PAH (IPAH) was an independent predictor of favorable response, whereas connective tissue disease-PAH was associated with an unfavorable response. CONCLUSION: Male sex and diagnosis of PoPH or HIV-PAH are predictors of favorable effect of PDE-5i on risk profile when used as mono- or add-on therapy. Patients with IPAH respond more favorably to PDE-5i when used in upfront combination. These results identify patient profiles that may respond favorably to PDE-5i in monotherapy and those who might benefit from alternative treatment strategies.

Effects of Exercise Training on Circulating Biomarkers of Endothelial Function in Pulmonary Arterial Hypertension.

INTRODUCTION: In stable patients with pulmonary arterial hypertension (PAH), pulmonary rehabilitation (PR) is an effective, safe and cost-effective non-pharmacological treatment. However, the effects of PR on vascular function have been poorly explored. This study aimed to compare the amounts of circulating progenitor cells (PCs) and endothelial microvesicles (EMVs) in patients with PAH before and after 8 weeks of endurance exercise training as markers of vascular competence. METHODS: A prospective study of 10 consecutive patients with PAH that successfully finished a PR program (8 weeks) was carried out before and after this intervention. Levels of circulating PCs defined as CD34+CD45low progenitor cells and levels of EMVs (CD31+ CD42b-) were measured by flow cytometry. The ratio of PCs to EMVs was taken as a measure of the balance between endothelial damage and repair capacity. RESULTS: All patients showed training-induced increases in endurance time (mean change 287 s). After PR, the number of PCs (CD34+CD45low/total lymphocytes) was increased (p < 0.05). In contrast, after training, the level of EMVs (CD31+ CD42b-/total EMVs) was reduced. The ratio of PCs to EMVs was significantly higher after training (p < 0.05). CONCLUSION: Our study shows, for the first time, that endurance exercise training in patients with stable PAH has a positive effect, promoting potential mechanisms of damage/repair in favor of repair. This effect could contribute to a positive hemodynamic and clinical response.

Ampicillin-resistant and vancomycin-susceptible Enterococcus faecium bacteremia: a clinical narrative review.

INTRODUCTION: Enterococcus faecium is a commensal microorganism that can cause infections such as bacteremia. Incidence of ampicillin-resistant and vancomycin-susceptible E. faecium (EfARSV) bacteremia is on the rise, and the mortality rate is high. Despite much data, the most appropriate treatment remains a question. AREAS COVERED: This article mostly reviews the relevant aspects of EfARSV bacteremia: microbiology, gastrointestinal tract colonization and invasion, antibiotic resistance, epidemiology, risk factors, mortality, and treatment, including pharmacologic components of employed agents and related clinical evidence. A literature search was conducted on PubMed on 31 July 2022, which was updated on 15 November 2022. EXPERT OPINION: EfARSV bacteremia presents high mortality. However, it is uncertain whether mortality is attributable to or a marker of severity/comorbidities. Considering its antibiotic resistance pattern, EfARSV is considered a difficult-to-treat microorganism. Glycopeptides have been used to treat EfARSV, with linezolid and daptomycin serving as potential alternative agents. Yet, the use of daptomycin is controversial due to a higher risk of treatment failures. Clinical evidence on this issue is scarce, unfortunately, and subject to many limitations. Despite increased incidence and mortality, EfARSV bacteremia presents multiple aspects to be addressed in well-conducted studies.

Nitrosative and Oxidative Stress, Reduced Antioxidant Capacity, and Fiber Type Switch in Iron-Deficient COPD Patients: Analysis of Muscle and Systemic Compartments.

We hypothesized that a rise in the levels of oxidative/nitrosative stress markers and a decline in antioxidants might take place in systemic and muscle compartments of chronic obstructive pulmonary disease (COPD) patients with non-anemic iron deficiency. In COPD patients with/without iron depletion (n = 20/group), markers of oxidative/nitrosative stress and antioxidants were determined in blood and vastus lateralis (biopsies, muscle fiber phenotype). Iron metabolism, exercise, and limb muscle strength were assessed in all patients. In iron-deficient COPD compared to non-iron deficient patients, oxidative (lipofuscin) and nitrosative stress levels were greater in muscle and blood compartments and proportions of fast-twitch fibers, whereas levels of mitochondrial superoxide dismutase (SOD) and Trolox equivalent antioxidant capacity (TEAC) decreased. In severe COPD, nitrosative stress and reduced antioxidant capacity were demonstrated in vastus lateralis and systemic compartments of iron-deficient patients. The slow- to fast-twitch muscle fiber switch towards a less resistant phenotype was significantly more prominent in muscles of these patients. Iron deficiency is associated with a specific pattern of nitrosative and oxidative stress and reduced antioxidant capacity in severe COPD irrespective of quadriceps muscle function. In clinical settings, parameters of iron metabolism and content should be routinely quantify given its implications in redox balance and exercise tolerance.

Iron Depletion in Systemic and Muscle Compartments Defines a Specific Phenotype of Severe COPD in Female and Male Patients: Implications in Exercise Tolerance.

We hypothesized that iron content and regulatory factors, which may be involved in exercise tolerance, are differentially expressed in systemic and muscle compartments in iron deficient severe chronic obstructive pulmonary disease (COPD) patients. In the vastus lateralis and blood of severe COPD patients with/without iron depletion, iron content and regulators, exercise capacity, and muscle function were evaluated in 40 severe COPD patients: non-iron deficiency (NID) and iron deficiency (ID) (20 patients/group). In ID compared to NID patients, exercise capacity, muscle iron and ferritin content, serum transferrin saturation, hepcidin-25, and hemojuvelin decreased, while serum transferrin and soluble transferrin receptor and muscle IRP-1 and IRP-2 increased. Among all COPD, a significant positive correlation was detected between FEV1 and serum transferrin saturation. In ID patients, significant positive correlations were detected between serum ferritin, hepcidin, and muscle iron content and exercise tolerance and between muscle IRP-2 and serum ferritin and hepcidin levels. In ID severe COPD patients, iron content and its regulators are differentially expressed. A potential crosstalk between systemic and muscle compartments was observed in the ID patients. Lung function and exercise capacity were associated with several markers of iron metabolism regulation. Iron status should be included in the overall assessment of COPD patients given its implications in their exercise performance.

Intravenous Iron Replacement Improves Exercise Tolerance in COPD: A Single-Blind Randomized Trial

Introduction: Iron deficiency affects exercise capacity because of the critical role iron plays in the optimal functioning of skeletal muscle metabolism. We hypothesized that intravenous iron may improve exercise tolerance, quality of life (QoL), and daily physical activity (DPA) in patients with chronic obstructive pulmonary disease (COPD). Methods: This was a placebo-controlled, single-blind, parallel-group, randomized clinical trial. Iron deficiency was defined as a ferritin level<100ng/mL or a ferritin level between 100 and 299ng/mL with a transferrin saturation<20%, with or without mild anaemia. Patients were randomized at a 2:1 ratio to receive intravenous ferric carboxymaltose or placebo. The primary objective was to investigate whether intravenous iron replacement improved endurance time from baseline by at least 33%. The secondary objectives were to evaluate impact on QoL using the COPD Assessment Test (CAT) and on DPA by accelerometry. Results: We included 66 patients, 44 (66.7%) in the intervention group and 22 (33.3%) in the placebo group. Among patients receiving ferric carboxymaltose, 23 (52.3%) achieved the primary endpoint compared to 4 (18.2%) in the placebo group [p=0.009; relative risk 3.12, (95% CI, 1.19–8.12)]. CAT score decreased −3 (−6.0–1.3) points from baseline in the intervention group (p=0.007), in contrast to placebo group [−1 (−4.0–2.3) points, p=0.236] with no differences in DPA and adverse events in both groups. Conclusions: Iron replacement improved exercise capacity and QoL in stable COPD patients with iron deficiency. The treatment was well tolerated. (AU)

Intravenous Iron Replacement Improves Exercise Tolerance in COPD: A Single-Blind Randomized Trial.

INTRODUCTION: Iron deficiency affects exercise capacity because of the critical role iron plays in the optimal functioning of skeletal muscle metabolism. We hypothesized that intravenous iron may improve exercise tolerance, quality of life (QoL), and daily physical activity (DPA) in patients with chronic obstructive pulmonary disease (COPD). METHODS: This was a placebo-controlled, single-blind, parallel-group, randomized clinical trial. Iron deficiency was defined as a ferritin level<100ng/mL or a ferritin level between 100 and 299ng/mL with a transferrin saturation<20%, with or without mild anaemia. Patients were randomized at a 2:1 ratio to receive intravenous ferric carboxymaltose or placebo. The primary objective was to investigate whether intravenous iron replacement improved endurance time from baseline by at least 33%. The secondary objectives were to evaluate impact on QoL using the COPD Assessment Test (CAT) and on DPA by accelerometry. RESULTS: We included 66 patients, 44 (66.7%) in the intervention group and 22 (33.3%) in the placebo group. Among patients receiving ferric carboxymaltose, 23 (52.3%) achieved the primary endpoint compared to 4 (18.2%) in the placebo group [p=0.009; relative risk 3.12, (95% CI, 1.19-8.12)]. CAT score decreased -3 (-6.0-1.3) points from baseline in the intervention group (p=0.007), in contrast to placebo group [-1 (-4.0-2.3) points, p=0.236] with no differences in DPA and adverse events in both groups. CONCLUSIONS: Iron replacement improved exercise capacity and QoL in stable COPD patients with iron deficiency. The treatment was well tolerated. CLINICAL TRIAL REGISTRATION: EudraCT 2016-001238-89.

Pharmacological management of antifungal agents in pulmonary aspergillosis: an updated review.

INTRODUCTION: Aspergillus may cause different types of lung infections: invasive, chronic pulmonary or allergic bronchopulmonary aspergillosis. Pharmacological management with antifungals poses as a challenge. Patients diagnosed with pulmonary aspergillosis are complex, as well as the problems associated with antifungal agents. AREAS COVERED: This article reviews the pharmacology of antifungal agents in development and currently used to treat pulmonary aspergillosis, including the mechanisms of action, pharmacokinetics, pharmacodynamics, dosing, therapeutic drug monitoring and safety. Recommendations to manage situations that arise in daily clinical practice are provided. A literature search of PubMed was conducted on November 15th, 2020 and updated on March 30th, 2021. EXPERT OPINION: Recent and relevant developments in the treatment of pulmonary aspergillosis have taken place. Novel antifungals with new mechanisms of action that extend antifungal spectrum and improve pharmacokinetic-related aspects, drug-drug interactions and safety are under current study. For those antifungals already marketed, new data related to pharmacokinetics, pharmacodynamics, dose adjustments in special situations, therapeutic drug monitoring and safety are available. To maximize efficacy and reduce the risk of associated toxicities, it is essential to choose the most appropriate antifungal; optimize its dose, interval, route of administration and length of treatment; and prevent side effects.

Impact of high-flow oxygen therapy during exercise in idiopathic pulmonary fibrosis: a pilot crossover clinical trial.

BACKGROUND: Supplemental oxygen delivered with standard oxygen therapy (SOT) improves exercise capacity in patients with idiopathic pulmonary fibrosis (IPF). Although high-flow nasal cannula oxygen therapy (HFNC) improves oxygenation in other respiratory diseases, its impact on exercise performance has never been evaluated in IPF patients. We hypothesized that HFNC may improve exercise capacity in IPF subjects compared to SOT. METHODS: This was a prospective, crossover, pilot randomized trial that compared both oxygenation methods during a constant submaximal cardiopulmonary exercise test (CPET) in IPF patients with exertional oxygen saturation (SpO2) ≤ 85% in the 6-min walking test. The primary outcome was endurance time (Tlim). Secondary outcomes were muscle oxygen saturation (StO2) and respiratory and leg symptoms. RESULTS: Ten IPF patients [71.7 (6) years old, 90% males] were included. FVC and DLCO were 58 ± 11% and 31 ± 13% pred. respectively. Tlim during CPET was significantly greater using HFNC compared to SOT [494 ± 173 vs. 381 ± 137 s, p = 0.01]. HFNC also associated with a higher increase in inspiratory capacity (IC) [19.4 ± 14.2 vs. 7.1 ± 8.9%, respectively; p = 0.04], and a similar trend was observed in StO2 during exercise. No differences were found in respiratory or leg symptoms between the two oxygen devices. CONCLUSIONS: This is the first study demonstrating that HFNC oxygen therapy improves exercise tolerance better than SOT in IPF patients with exertional desaturation. This might be explained by changes in ventilatory mechanics and muscle oxygenation. Further and larger studies are needed to confirm the benefits of HFNC in IPF patients and its potential usefulness in rehabilitation programs.

Iron Replacement and Redox Balance in Non-Anemic and Mildly Anemic Iron Deficiency COPD Patients: Insights from a Clinical Trial.

In COPD patients, non-anemic iron deficiency (NAID) is a common systemic manifestation. We hypothesized that in COPD patients with NAID, iron therapy may improve systemic oxidative stress. The FACE (Ferinject assessment in patients with COPD and iron deficiency to improve exercise tolerance) study was a single-blind, unicentric, parallel-group, placebo-controlled clinical trial (trial registry: 2016-001238-89). Sixty-six patients were enrolled (randomization 2:1): iron arm, n = 44 and placebo arm, n = 22, with similar clinical characteristics. Serum levels of 3-nitrotyrosine, MDA-protein adducts, and reactive carbonyls, catalase, superoxide dismutase (SOD), glutathione, Trolox equivalent antioxidant capacity (TEAC), and iron metabolism biomarkers were quantified in both groups. In the iron-treated patients compared to placebo, MDA-protein adducts and 3-nitrotyrosine serum levels significantly declined, while those of GSH increased and iron metabolism parameters significantly improved. Hepcidin was associated with iron status parameters. This randomized clinical trial evidenced that iron replacement elicited a decline in serum oxidative stress markers along with an improvement in GSH levels in patients with stable severe COPD. Hepcidin may be a surrogate biomarker of iron status and metabolism in patients with chronic respiratory diseases. These findings have potential clinical implications in the management of patients with severe COPD.

Circulating Cell Biomarkers in Pulmonary Arterial Hypertension: Relationship with Clinical Heterogeneity and Therapeutic Response.

BACKGROUND: Endothelial dysfunction is central to PAH. In this study, we simultaneously analysed circulating levels of endothelial microvesicles (EMVs) and progenitor cells (PCs) in PAH and in controls, as biomarkers of pulmonary endothelial integrity and evaluated differences among PAH subtypes and as a response to treatment. METHODS: Forty-seven controls and 144 patients with PAH (52 idiopathic, 9 heritable, 31 associated with systemic sclerosis, 15 associated with other connective tissue diseases, 20 associated with HIV and 17 associated with portal hypertension) were evaluated. Forty-four patients with scleroderma and 22 with HIV infection, but without PAH, were also studied. Circulating levels of EMVs, total (CD31+CD42b-) and activated (CD31+CD42b-CD62E+), as well as circulating PCs (CD34+CD133+CD45low) were measured by flow cytometry and the EMVs/PCs ratio was computed. In treatment-naïve patients, measurements were repeated after 3 months of PAH therapy. RESULTS: Patients with PAH showed higher numbers of EMVs and a lower percentage of PCs, compared with healthy controls. The EMV/PC ratio was increased in PAH patients, and in patients with SSc or HIV without PAH. After starting PAH therapy, individual changes in EMVs and PCs were variable, without significant differences being observed as a group. Conclusion: PAH patients present disturbed vascular homeostasis, reflected in changes in circulating EMV and PC levels, which are not restored with PAH targeted therapy. Combined measurement of circulating EMVs and PCs could be foreseen as a potential biomarker of endothelial dysfunction in PAH.

EGFR and KRAS Mutations in Lung Parenchyma of Subjects With EGFR/KRAS Wild-Type Lung Adenocarcinoma.

The acquisition of driver mutations in non-tumoral cells appears to be very important during the carcinogenesis of adenocarcinoma (ADC). Recent studies suggest that cancer-related mutations may not necessarily be present only in malignant cells, but also in histologically "healthy cells". Objective: to demonstrate the presence of EGFR or KRAS mutations in non-tumoral lung cells in subjects with ADC and negative mutational status. Results: mutations in EGFR or KRAS oncogenes were identified in the normal lung in 9.7% of the subjects. Exon 21 substitution L858R in EGFR was detected in two cases while the exon 19 deletion E746-A750 in the EGFR, the G12C and G12D substitutions in the KRAS were detected once. One patient presented three different mutations in the normal lung parenchyma (EGFR_L858R, KRAS_G12C and KRAS_G12D). The negative-mutation status of the tumor and the mutations detected in the "normal lung" were confirmed using highly sensitive and specific TaqMan PCR (CAST-PCR). No differences were found in terms of progression, progression-free survival or overall survival during the 18 months follow-up. Conclusions: These results confirm the presence of driver mutations in the histologically normal lung parenchyma cells in the absence of mutations coexisting with the primary tumor.

Daptomycin versus Glycopeptides for the Treatment of Enterococcus faecium Bacteraemia: A Cohort Study.

BACKGROUND: Ampicillin resistant and glycopeptide susceptible Enterococcus faecium bloodstream infection (GSEF-BSI) incidence has risen. However, the treatment of choice remains unknown. Daptomycin use for the treatment of enterococcal infections has increased, despite effectiveness and safety concerns. The objective was to compare the effectiveness and safety of daptomycin and glycopeptides in the treatment of GSEF-BSI. METHODS: This was a single-centre, retrospective observational cohort study performed at Hospital del Mar (Barcelona, Spain), from January 2006-May 2018. The primary outcome was clinical cure at the end of the therapy, and secondary outcomes included 14-day, 30-day, in-hospital mortality, and length of stay. RESULTS: From a total of 192 patients with GSEF-BSI, 54 (28.1%) were treated with glycopeptides and 17 (8.9%) with daptomycin. Patients treated with daptomycin presented a lower clinical cure than patients treated with glycopeptides (58.8% vs. 83.3%, RR 0.416 (95% CI 0.189-0.915)). After controlling for confounding variables by means of multivariate analysis the significative difference was confirmed (aOR 4.313, 95% CI, 1.053-17.660). The need for treatment discontinuation due to adverse events was similar. CONCLUSIONS: Patients with GSEF-BSI treated with glycopeptides showed a higher clinical cure than those treated with daptomycin.

Azithromycin in the treatment of COVID-19: a review.

INTRODUCTION: SARS-CoV-2 is a novel virus that causes coronavirus disease-19 (COVID-19). Antiviral and immunomodulatory agents have been proposed as potential treatments. Azithromycin exhibits both properties and therefore may play a role. AREAS COVERED: This article reviews the pharmacology, pharmacokinetics, clinical efficacy, and safety of azithromycin in viral infections, with emphasis on COVID-19. A literature search of PUBMED was conducted on May 30th and updated on July 28th. EXPERT OPINION: Azithromycin presents in vitro activity against SARS-CoV-2 and could act in different points of the viral cycle. Its immunomodulatory properties include the ability to downregulate cytokine production, maintain epithelial cell integrity or prevent lung fibrosis. Azithromycin use was associated with a reduction in mortality and ventilation days in other viral infections. These properties could be beneficial throughout the COVID-19. However, the evidence of its use is scarce and of low quality. Azithromycin has been assessed in retrospective observational studies mainly in combination with hydroxychloroquine, which has shown to provide no benefit. This macrolide presents a well-known safety profile. Upcoming clinical trials will determine the role of azithromycin in the COVID-19 (including the stage of the disease where it offers the greatest benefits and the effect of its combination with other drugs).

Diagnóstico endoscópico de carcinoma pulmonar de célula pequeña y neoplasia folicular de tiroides / Endoscopic Diagnosis of Small Cell Lung Carcinoma and Follicular Thyroid Cancer

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Hipercaptación ósea en 18F-FDG-PET/TC en paciente con cáncer de pulmón, ¿es siempre una metástasis? / Hypermetabolic Bone on 18F-FDG-PET/CT in a Patient with Lung Cancer: Is it Always Metastasis?

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Is iron deficiency modulating physical activity in COPD?

There is evidence that iron plays a key role in the adequate functioning of skeletal muscle. While it has been demonstrated that nonanemic iron deficiency (NAID) affects exercise tolerance and response to exercise training in patients with COPD, the impact on daily physical activities (DPAs) remains unknown. Eighteen COPD patients with NAID (ferritin <100 ng/mL or ferritin 100-299 ng/mL with a transferrin saturation <20%) and 18 COPD patients without this abnormality, matched for age, gender, and the degree of airflow limitation (control group), were enrolled to the study. The primary outcome was the level of DPA assessed by accelerometers. Patients were (mean [SD]) 66 (7) years and were mostly male (70%) and former smokers (52%). Their forced expiratory volume at 1 second was 41 (16)% predicted, carbon monoxide diffusing capacity was 47 (14)% predicted and oxygen arterial pressure reached 70 (11) mmHg. DPA and the number of steps per day were lower in NAID COPD patients compared with controls (physical activity level 1.39 vs 1.59, P<0.05; and 4,402 vs 6,975 steps/day, P<0.05, respectively). The percentage of patients with increased time spent sitting per day (>6 hours) was higher in patients with NAID compared with controls (73% vs 37%, P<0.05). In addition, the percentage of patients doing moderate to vigorous physical activity per day (>3 metabolic equivalents of task, at least 30 minutes) was lower in this group (66% vs 100%, P<0.05). The presence of iron deficiency was associated with reduced DPA in COPD patients. Further studies are needed to evaluate iron reposition and their impact on the level of physical activity in these patients.

Molecular analysis of peripheral lung adenocarcinoma in brush cytology obtained by EBUS plus fluoroscopy-guided bronchoscopy.

BACKGROUND: More than 60% of patients with lung cancer are diagnosed at advanced stages. The introduction of targeted therapies requires molecular diagnosis to guide treatment. The aim of this study was to evaluate the feasibility of performing mutational analysis with brushing specimens obtained by radial-miniprobe endobronchial ultrasound (R-EBUS) plus fluoroscopy-guided bronchoscopy in patients with peripheral pulmonary adenocarcinoma. METHODS: Brushing specimens were deposited on cytological slides and were conserved in Roswell Park Memorial Institute (RPMI) culture medium. DNA was isolated to perform a mutational analysis with real-time quantitative polymerase chain reaction and Sanger sequencing for epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS). RESULTS: Thirty patients with adenocarcinoma were prospectively included. In 100% of the patients, the molecular study was viable with brushing specimens. In 16 (53.3%), KRAS or EGFR mutations were detected: 10 KRAS mutations (33.3%) and 6 EGFR mutations (20%). In a comparison with histological samples, a correlation of 86.6% was detected, and only 2 patients with wild-type results from brushing specimens presented with an EGFR mutation in histological samples. CONCLUSIONS: Brushing specimens conserved in RPMI medium and obtained by R-EBUS plus fluoroscopy-guided bronchoscopy are valid for molecular studies. They allow the detection of EGFR/KRAS mutations in patients with peripheral adenocarcinoma. In addition, invasive techniques are avoided, the risk of complications is reduced, and the obtained samples are optimized.