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.

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.

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.

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.

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.

Cellular Senescence in Lung Fibrosis.

Fibrosing interstitial lung diseases (ILDs) are chronic and ultimately fatal age-related lung diseases characterized by the progressive and irreversible accumulation of scar tissue in the lung parenchyma. Over the past years, significant progress has been made in our incomplete understanding of the pathobiology underlying fibrosing ILDs, in particular in relation to diverse age-related processes and cell perturbations that seem to lead to maladaptation to stress and susceptibility to lung fibrosis. Growing evidence suggests that a specific biological phenomenon known as cellular senescence plays an important role in the initiation and progression of pulmonary fibrosis. Cellular senescence is defined as a cell fate decision caused by the accumulation of unrepairable cellular damage and is characterized by an abundant pro-inflammatory and pro-fibrotic secretome. The senescence response has been widely recognized as a beneficial physiological mechanism during development and in tumour suppression. However, recent evidence strengthens the idea that it also drives degenerative processes such as lung fibrosis, most likely by promoting molecular and cellular changes in chronic fibrosing processes. Here, we review how cellular senescence may contribute to lung fibrosis pathobiology, and we highlight current and emerging therapeutic approaches to treat fibrosing ILDs by targeting cellular senescence.

Current treatment of sarcoidosis.

PURPOSE OF REVIEW: Sarcoidosis is a granulomatous systemic disease of unknown cause where the lung is the most frequently affected organ. Therapeutic management of the disease is challenging as clinical presentation and prognosis are very heterogeneous. In the present review, we will summarize the main advances in sarcoidosis therapy. RECENT FINDINGS: Current sarcoidosis therapies are categorized in three lines: glucocorticoids (first line), immunosuppressants (second line), and biologics (third line). Recent glucocorticoid studies have reported that efficacy could be similar with high and low doses, but with an increase in side effects with higher doses. In immunosuppressants, recent publications in mycophenolate and repository corticotropin injection (RCI) have added more information in their use and efficacy. Finally, new evidence has been published in the use of antitumor necrosis factor (anti-TNFα) agents in refractory cardiac sarcoidosis and neurosarcoidosis. SUMMARY: Sarcoidosis therapy is constantly evolving, and new drugs have been added to the recommended treatments. However, extensive clinical trials are still necessary to optimize the current recommendations.

Acute exacerbations of idiopathic pulmonary fibrosis: Does clinical stratification or steroid treatment matter?

Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is defined as a sudden acceleration of the disease with the appearance of pulmonary infiltrates superimposed on the characteristic pattern of IPF that leads to a significant decline in lung function. It has high in-hospital mortality rates, despite medical treatment with systematic steroids. We sought to investigate whether there were in-hospital mortality differences according to clinical stratification (AE, suspected AE, or AE of known cause) and/or treatment with systemic steroids. We reviewed the clinical characteristics and outcomes of patients with IPF admitted to our hospital during the years 2003-2014 due to a worsening of their clinical status. We identified 50 IPF patients, 9 with AE (18%), 12 with suspected exacerbation (24%), and 29 with AE of known cause (58%), mostly respiratory infections. In-hospital mortality was similar in the three groups (33% vs. 17% vs. 34%, respectively). Likewise, we did not find differences between them with respect to the use of systemic steroids (length of treatment duration or total dose). Nevertheless, there was an independent association between in-hospital mortality and high average daily steroid dose. We did not observe significant differences in prognosis or use of systemic steroids according to current diagnostic stratification groups in patients hospitalized because of an exacerbation of IPF.

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.

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.

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.

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.

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.

Improving home oxygen therapy in patients with interstitial lung diseases: application of a noninvasive ventilation device.

BACKGROUND: Proper adjustment of arterial oxygen saturation (SaO2) during daily activities in patients with interstitial lung disease (ILD) requiring long-term oxygen therapy is challenging. Given the multifactorial nature of the limited exercise tolerance in patients with ILDs, the isolated use of oxygen therapy may not be enough. As demonstrated previously in patients with chronic obstructive pulmonary disease, the use of a noninvasive ventilation (NIV) device combined with oxygen therapy may prevent the falling of oxygen saturation during exercise, due to an improvement of the ventilation-perfusion ratio and a reduction of the respiratory work, thus enhancing exercise tolerance. We sought to assess in patients diagnosed with ILD who are in need of oxygen therapy, the effect of associating an NIV to improve oxygen parameters and the distance covered during the 6 min walking test (6MWT). METHODS: We conducted a prospective observational study in patients with ILDs. After a clinical characterization, we performed a 6MWT in two different situations: using a portable oxygen concentrator with the regular flow used by the patient during their daily life activities and afterwards adding the additional support of a NIV. The oxygen saturation parameters were registered with a portable oximeter. RESULTS: We included 16 patients with different ILDs who have oxygen therapy prescribed. The use of NIV associated with oxygen therapy in comparison with the use of oxygen therapy alone showed an increase of the average SaO2 [91% (88-93) versus 88% (86-90%); p = 0.0005] and a decrease in the percentage of time with oxygen saturation <90%: 36% (6-56%) versus 58% (36-77%); p < 0.0001. There were no changes in the 6MWT distance: 307 m (222-419 m) versus 316 m (228-425 m); p = 0.10. CONCLUSIONS: In our study the use of a NIV system associated with long-term oxygen therapy during exercise showed beneficial effects, especially improvement of oxygen saturation.The reviews of this paper are available via the supplemental material section.

Impact of a systematic evaluation of connective tissue disease on diagnosis approach in patients with interstitial lung diseases.

To date, there is no clear agreement regarding which is the best method to detect a connective tissue disease (CTD) during the initial diagnosis of interstitial lung diseases (ILD). The aim of our study was to explore the impact of a systematic diagnostic strategy to detect CTD-associated ILD (CTD-ILD) in clinical practice, and to clarify the significance of interstitial pneumonia with autoimmune features (IPAF) diagnosis in ILD patients.Consecutive patients evaluated in an ILD Diagnostic Program were divided in 3 groups: IPAF, CTD-ILD, and other ILD forms. Clinical characteristics, exhaustive serologic testing, high resolution computed tomography (HRCT) images, lung biopsy specimens, and follow-up were prospectively collected and analyzed.Among 139 patients with ILD, CTD was present in 21 (15.1%), 24 (17.3%) fulfilled IPAF criteria, and 94 (67.6%) were classified as other ILD forms. Specific systemic autoimmune symptoms such as Raynaud phenomenon (19%), inflammatory arthropathy (66.7%), and skin manifestations (38.1%) were more frequent in CTD-ILD patients than in the other groups (all P < .001). Among autoantibodies, antinuclear antibody was the most frequently found in IPAF (42%), and CTD-ILD (40%) (P = .04). Nonspecific interstitial pneumonia, detected by HRCT scan, was the most frequently seen pattern in patients with IPAF (63.5%), or CTD-ILD (57.1%) (P < .001). In multivariate analysis, a suggestive radiological pattern by HRCT scan (odds ratio [OR] 15.1, 95% confidence interval [CI] 4.7-48.3, P < .001) was the strongest independent predictor of CTD-ILD or IPAF, followed by the presence of clinical features (OR 14.6, 95% CI 4.3-49.5, P < .001), and serological features (OR 12.4, 95% CI 3.5-44.0, P < .001).This systematic diagnostic strategy was useful in discriminating an underlying CTD in patients with ILD. The defined criteria for IPAF are fulfilled by a considerable proportion of patients referred for ILD.

ERS International Congress, Madrid, 2019: highlights from the Interstitial Lung Diseases Assembly.

This article discusses a selection of the scientific presentations in the field of interstitial lung diseases (ILDs) that took place at the 2019 European Respiratory Society International Congress in Madrid, Spain. There were sessions from all four groups within Assembly 12: group 12.01 "Idiopathic interstitial pneumonias", group 12.02 "ILDs/diffuse parenchymal lung diseases (DPLDs) of known origin", group 12.03 "Sarcoidosis and other granulomatous ILDs/DPLDs" and group 12.04 "Rare ILDs/DPLDs". The presented studies brought cutting-edge developments on several aspects of these conditions, including pathogenesis, diagnosis and treatment. As many of the ILDs are individually rare, the sharing of experiences and new data that occur during the Congress are very important for physicians interested in ILDs and ILD patients alike.

Author Correction: Identification and characterization of Cardiac Glycosides as senolytic compounds.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Influence of MUC5B gene on antisynthetase syndrome.

MUC5B rs35705950 (G/T) is strongly associated with idiopathic pulmonary fibrosis (IPF) and also contributes to the risk of interstitial lung disease (ILD) in rheumatoid arthritis (RA-ILD) and chronic hypersensitivity pneumonitis (CHP). Due to this, we evaluated the implication of MUC5B rs35705950 in antisynthetase syndrome (ASSD), a pathology characterised by a high ILD incidence. 160 patients with ASSD (142 with ILD associated with ASSD [ASSD-ILD+]), 232 with ILD unrelated to ASSD (comprising 161 IPF, 27 RA-ILD and 44 CHP) and 534 healthy controls were genotyped. MUC5B rs35705950 frequency did not significantly differ between ASSD-ILD+ patients and healthy controls nor when ASSD patients were stratified according to the presence/absence of anti Jo-1 antibodies or ILD. No significant differences in MUC5B rs35705950 were also observed in ASSD-ILD+ patients with a usual interstitial pneumonia (UIP) pattern when compared to those with a non-UIP pattern. However, a statistically significant decrease of MUC5B rs35705950 GT, TT and T frequencies in ASSD-ILD+ patients compared to patients with ILD unrelated to ASSD was observed. In summary, our study does not support a role of MUC5B rs35705950 in ASSD. It also indicates that there are genetic differences between ILD associated with and that unrelated to ASSD.