Significance of clinical-immunological patterns and diagnostic yield of biopsies in microscopic polyangiitis and granulomatosis with polyangiitis.

BACKGROUND: Microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are the two major antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). OBJECTIVES: To characterize a homogenous AAV cohort and to assess the impact of clinicopathological profiles and ANCA serotypes on clinical presentation and prognosis. Clinical differences in GPA patients according to ANCA serotype and the diagnostic yield for vasculitis of biopsies in different territories were also investigated. RESULTS: This retrospective study (2000-2021) included 152 patients with AAV (77 MPA/75 GPA). MPA patients (96.1% myeloperoxidase [MPO]-ANCA and 2.6% proteinase 3 [PR3]-ANCA) presented more often with weight loss, myalgia, renal involvement, interstitial lung disease (ILD), cutaneous purpura, and peripheral nerve involvement. Patients with GPA (44% PR3-ANCA, 33.3% MPO, and 22.7% negative/atypical ANCA) presented more commonly with ear, nose, and throat and eye/orbital manifestations, more relapses, and higher survival than patients with MPA. GPA was the only independent risk factor for relapse. Poor survival predictors were older age at diagnosis and peripheral nerve involvement. ANCA serotypes differentiated clinical features in a lesser degree than clinical phenotypes. A mean of 1.5 biopsies were performed in 93.4% of patients in different territories. Overall, vasculitis was identified in 80.3% (97.3% in MPA and 61.8% in GPA) of patients. CONCLUSIONS: The identification of GPA presentations associated with MPO-ANCA and awareness of risk factors for relapse and mortality are important to guide proper therapeutic strategies in AAV patients. Biopsies of different affected territories should be pursued in difficult-to-diagnose patients based on their significant diagnostic yield.

Iron accumulation drives fibrosis, senescence and the senescence-associated secretory phenotype.

Fibrogenesis is part of a normal protective response to tissue injury that can become irreversible and progressive, leading to fatal diseases. Senescent cells are a main driver of fibrotic diseases through their secretome, known as senescence-associated secretory phenotype (SASP). Here, we report that cellular senescence, and multiple types of fibrotic diseases in mice and humans are characterized by the accumulation of iron. We show that vascular and hemolytic injuries are efficient in triggering iron accumulation, which in turn can cause senescence and promote fibrosis. Notably, we find that senescent cells persistently accumulate iron, even when the surge of extracellular iron has subdued. Indeed, under normal conditions of extracellular iron, cells exposed to different types of senescence-inducing insults accumulate abundant ferritin-bound iron, mostly within lysosomes, and present high levels of labile iron, which fuels the generation of reactive oxygen species and the SASP. Finally, we demonstrate that detection of iron by magnetic resonance imaging might allow non-invasive assessment of fibrotic burden in the kidneys of mice and in patients with renal fibrosis. Our findings suggest that iron accumulation plays a central role in senescence and fibrosis, even when the initiating events may be independent of iron, and identify iron metabolism as a potential therapeutic target for senescence-associated diseases.

COPI vesicle formation and N-myristoylation are targetable vulnerabilities of senescent cells.

Drugs that selectively kill senescent cells (senolytics) improve the outcomes of cancer, fibrosis and age-related diseases. Despite their potential, our knowledge of the molecular pathways that affect the survival of senescent cells is limited. To discover senolytic targets, we performed RNAi screens and identified coatomer complex I (COPI) vesicle formation as a liability of senescent cells. Genetic or pharmacological inhibition of COPI results in Golgi dispersal, dysfunctional autophagy, and unfolded protein response-dependent apoptosis of senescent cells, and knockdown of COPI subunits improves the outcomes of cancer and fibrosis in mouse models. Drugs targeting COPI have poor pharmacological properties, but we find that N-myristoyltransferase inhibitors (NMTi) phenocopy COPI inhibition and are potent senolytics. NMTi selectively eliminated senescent cells and improved outcomes in models of cancer and non-alcoholic steatohepatitis. Our results suggest that senescent cells rely on a hyperactive secretory apparatus and that inhibiting trafficking kills senescent cells with the potential to treat various senescence-associated diseases.

Pulmonary rehabilitation in sarcoidosis: A systematic review and meta-analysis.

BACKGROUND: Exercise intolerance, muscle weakness, dyspnoea, and fatigue are frequent complications in symptomatic sarcoidosis patients. Pulmonary rehabilitation improves exercise capacity, symptoms, and quality of life in patients with chronic respiratory diseases. Our objective was to systematically determine the effects of pulmonary rehabilitation in patients with sarcoidosis. METHODS: A systematic review was conducted in seven databases. Studies that applied pulmonary rehabilitation in patients with sarcoidosis were reviewed. Two independent reviewers analysed the studies, extracted the data and assessed the quality of evidence. RESULTS: Of the 406 reports returned by the initial search, five articles reporting on 184 patients were included in the data synthesis. Two studies included multi-component exercise, one inspiratory muscle training, one a physical activity incentivisation programme, and one a telerehabilitation program. In the intervention group (IG), we found significant improvement in exercise capacity (SMD 1.65, 95%CI 0.45, 2.86 points, p = 0.006). If we only analyse the studies that performed the 6-min walking test, the IG walked 40.3 (CI95% 20.3, 60.2) m higher than the control group (CG) (p < 0.001). Additionally, dyspnoea score was reduced (MD -0.42 95%CI -0.75, -0.10, p = 0.002). However, fatigue, quality of life and pulmonary function did not show any change. CONCLUSION: Pulmonary rehabilitation could improve exercise capacity and dyspnoea perception in patients with sarcoidosis.

Lung immune signatures define two groups of end-stage IPF patients.

BACKGROUND: The role of the immune system in the pathobiology of Idiopathic Pulmonary Fibrosis (IPF) is controversial. METHODS: To investigate it, we calculated immune signatures with Gene Set Variation Analysis (GSVA) and applied them to the lung transcriptome followed by unbiased cluster analysis of GSVA immune-enrichment scores, in 109 IPF patients from the Lung Tissue Research Consortium (LTRC). Results were validated experimentally using cell-based methods (flow cytometry) in lung tissue of IPF patients from the University of Pittsburgh (n = 26). Finally, differential gene expression and hypergeometric test were used to explore non-immune differences between clusters. RESULTS: We identified two clusters (C#1 and C#2) of IPF patients of similar size in the LTRC dataset. C#1 included 58 patients (53%) with enrichment in GSVA immune signatures, particularly cytotoxic and memory T cells signatures, whereas C#2 included 51 patients (47%) with an overall lower expression of GSVA immune signatures (results were validated by flow cytometry with similar unbiased clustering generation). Differential gene expression between clusters identified differences in cilium, epithelial and secretory cell genes, all of them showing an inverse correlation with the immune response signatures. Notably, both clusters showed distinct features despite clinical similarities. CONCLUSIONS: In end-stage IPF lung tissue, we identified two clusters of patients with very different levels of immune signatures and gene expression but with similar clinical characteristics. Weather these immune clusters differentiate diverse disease trajectories remains unexplored.

Blood Immunophenotypes of Idiopathic Pulmonary Fibrosis: Relationship with Disease Severity and Progression.

(1) The role of the immune response in the pathogenesis of idiopathic pulmonary fibrosis (IPF) remains controversial. We hypothesized that peripheral blood immune phenotypes will be different in IPF patients and may relate to the disease severity and progression. (2) Whole blood flow cytometry staining was performed at diagnosis in 32 IPF patients, and in 32 age- and smoking-matched healthy controls. Thirty-one IPF patients were followed up for one year and categorized as stable or progressors based on lung function, deterioration and/or death. At 18-60 months, immunophenotypes were characterized again. (3) The main results showed that: (1) compared to matched controls, at diagnosis, patients with IPF showed more neutrophils, CD8+HLA-DR+ and CD8+CD28- T cells, and fewer B lymphocytes and naïve T cells; (2) in IPF, circulating neutrophils, eosinophils and naïve T cells were associated with lung function abnormalities; (3) patients whose disease progressed during the 12 months of follow-up showed evidence of cytotoxic dysregulation, with increased CD8+CD28- T cells, decreased naïve T cells and an inverted CD4/CD8 ratio at baseline; and (4) blood cell alterations were stable over time in survivors. (4) IPF is associated with abnormalities in circulating immune cells, particularly in the cytotoxic cell domain. Patients with progressive IPF, despite antifibrotic therapy, present an over-activated and exhausted immunophenotype at diagnosis, which is maintained over time.

Human senescent fibroblasts trigger progressive lung fibrosis in mice.

Cell senescence has recently emerged as a potentially relevant pathogenic mechanism in fibrosing interstitial lung diseases (f-ILDs), particularly in idiopathic pulmonary fibrosis. We hypothesized that senescent human fibroblasts may suffice to trigger a progressive fibrogenic reaction in the lung. To address this, senescent human lung fibroblasts, or their secretome (SASP), were instilled into the lungs of immunodeficient mice. We found that: (1) human senescent fibroblasts engraft in the lungs of immunodeficient mice and trigger progressive lung fibrosis associated to increasing levels of mouse senescent cells, whereas non-senescent fibroblasts do not trigger fibrosis; (2) the SASP of human senescent fibroblasts is pro-senescence and pro-fibrotic both in vitro when added to mouse recipient cells and in vivo when delivered into the lungs of mice, whereas the conditioned medium (CM) from non-senescent fibroblasts lacks these activities; and, (3) navitoclax, nintedanib and pirfenidone ameliorate lung fibrosis induced by senescent human fibroblasts in mice, albeit only navitoclax displayed senolytic activity. We conclude that human senescent fibroblasts, through their bioactive secretome, trigger a progressive fibrogenic reaction in the lungs of immunodeficient mice that includes the induction of paracrine senescence in the cells of the host, supporting the concept that senescent cells actively contribute to disease progression in patients with f-ILDs.

Management of Pulmonary Hypertension Associated with Chronic Lung Disease.

Pulmonary hypertension (PH) is a common complication of chronic lung diseases, particularly in chronic obstructive pulmonary disease (COPD) and interstitial lung diseases (ILD) and especially in advanced disease. It is associated with greater mortality and worse clinical course. Given the high prevalence of some respiratory disorders and because lung parenchymal abnormalities might be present in other PH groups, the appropriate diagnosis of PH associated with respiratory disease represents a clinical challenge. Patients with chronic lung disease presenting symptoms that exceed those expected by the pulmonary disease should be further evaluated by echocardiography. Confirmatory right heart catheterization is indicated in candidates to surgical treatments, suspected severe PH potentially amenable with targeted therapy, and, in general, in those conditions where the result of the hemodynamic assessment will determine treatment options. The treatment of choice for these patients who are hypoxemic is long-term oxygen therapy and pulmonary rehabilitation to improve symptoms. Lung transplant is the only curative therapy and can be considered in appropriate cases. Conventional vasodilators or drugs approved for pulmonary arterial hypertension (PAH) are not recommended in patients with mild-to-moderate PH because they may impair gas exchange and their lack of efficacy shown in randomized controlled trials. Patients with severe PH (as defined by pulmonary vascular resistance >5 Wood units) should be referred to a center with expertise in PH and lung diseases and ideally included in randomized controlled trials. Targeted PAH therapy might be considered in this subset of patients, with careful monitoring of gas exchange. In patients with ILD, inhaled treprostinil has been shown to improve functional ability and to delay clinical worsening.

Predictors and changes of physical activity in idiopathic pulmonary fibrosis.

BACKGROUND: Different clinical predictors of physical activity (PA) have been described in idiopathic pulmonary fibrosis (IPF), but studies are lacking evaluating the potential role of muscle strength and anxiety and depression symptoms in PA limitation. Moreover, little is known about the impact of changes in PA in the course of the disease. The aim of the present study was to investigate the relationship between baseline PA and a wide range of variables in IPF, to assess its longitudinal changes at 12 months and its impact on progression free-survival. METHODS: PA was assessed by accelerometer and physiological, clinical, psychological factors and health-related quality of life were evaluated in subjects with IPF at baseline and at 12 month follow-up. Predictors of PA were determined at baseline, evolution of PA parameters was described and the prognostic role of PA evolution was also established. RESULTS: Forty participants with IPF were included and 22 completed the follow-up. At baseline, subjects performed 5765 (3442) daily steps and spent 64 (44) minutes/day in moderate to vigorous PA. Multivariate regression models showed that at baseline, a lower six-minute walked distance, lower quadriceps strength (QMVC), and a higher depression score in the Hospital Anxiety and Depression scale were associated to lower daily step number. In addition, being in (Gender-Age-Physiology) GAP III stage, having a BMI ≥ 25 kg/m2 and lower QMVC or maximum inspiratory pressure were factors associated with sedentary behaviour. Adjusted for age, gender and forced vital capacity (FVC) (%pred.) a lower progression-free survival was evidenced in those subjects that decreased PA compared to those that maintained, or even increased it, at 12 months [HR 12.1 (95% CI, 1.9-78.8); p = 0.009]. CONCLUSION: Among a wide range of variables, muscle strength and depression symptoms have a predominant role in PA in IPF patients. Daily PA behaviour and its evolution should be considered in IPF clinical assessment and as a potential complementary indicator of disease prognosis.

Estudio histológico mediante biopsia pulmonar post mortem en pacientes con neumonía por COVID-19 / Histology Study of Postmortem Lung Biopsies in Patients with Covid-19 Pneumonia

No disponible

[Translated article] Histology Study of Postmortem Lung Biopsies in Patients With Covid-19 Pneumonia / Estudio histológico mediante biopsia pulmonar post mortem en pacientes con neumonía por COVID-19

No disponible

SARS-CoV-2 T-cell response in COVID-19 convalescent patients with and without lung sequelae.

A specific T-cell response persists in the majority of COVID-19 patients 6 months after hospital discharge. This response is more prominent in those who required critical care during the acute COVID-19 episode but is reduced in patients with lung sequelae. https://bit.ly/3fBuVA4.