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.

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.

Personalized medicine in sarcoidosis: unravelling biomarkers for targeted care.

PURPOSE OF REVIEW: This review provides an assessment of biomarkers in sarcoidosis, aiming to address the need for improved diagnostic, prognostic and management tools. Sarcoidosis presents diagnostic challenges, necessitating the search for reliable biomarkers to guide clinical decisions. RECENT FINDINGS: Established biomarkers such as serum angiotensin-converting enzyme (ACE) and serum interleukin-2 receptor (sIL-2R) have limitations in sensitivity and specificity. FDG-PET/CT imaging shows promising results in assessing disease activity and guiding immunosuppression. Gene expression profiling studies reveal potential biomarkers, particularly involving TH1 immune response and IFN-γ-driven signalling pathways. The field of omics sciences offers opportunities for novel biomarker discovery. SUMMARY: These findings have implications for clinical practice and research. The limitations of established biomarkers underscore the need for improved diagnostic tools in sarcoidosis. The potential of FDG-PET/CT imaging requires further exploration. Gene expression profiling and omics sciences offer avenues for discovering novel biomarkers to enhance diagnosis and predict disease progression. Such advancements can facilitate personalized treatment strategies and improve patient outcomes. Continued research is vital to validate the efficacy and clinical applicability of these biomarkers. Overall, this review emphasizes ongoing efforts to advance sarcoidosis biomarkers research and improve disease management.

Persistence of a SARS-CoV-2 T-cell response in patients with long COVID and lung sequelae after COVID-19.

1 year after an acute COVID-19 episode, patients with either lung sequelae or long COVID show a stronger SARS-CoV-2-specific T-cell response than fully recovered individuals, suggesting persistent cell stimulation by residual viral reservoirs https://bit.ly/40bPZm7.

Characterisation of the coexistence between sarcoidosis and Sjögren's syndrome. Analysis of 43 patients.

OBJECTIVES: To characterise the key epidemiological, clinical, immunological, imaging, and pathological features of the coexistence between sarcoidosis and Sjögren's syndrome (SS). METHODS: All centres included in two large multicentre registries (the Sjögren Syndrome Big Data Consortium and the Sarco-GEAS-SEMI Registry) were contacted searching for potential cases of coexistence between SS and sarcoidosis seen in daily practice. Inclusion criteria were the fulfilment of the current classification criteria both for SS (2016 ACR/EULAR) and sarcoidosis (WASOG). The following features were considered for evaluating a coexisting immunopathological scenario between the two diseases: non-caseating granulomas (NCG), focal lymphocytic sialadenitis (FLS) and positive anti-Ro antibodies. RESULTS: We identified 43 patients who fulfilled the inclusion criteria (38 women, with a mean age of 53 years at diagnosis of SS and of 52 years at diagnosis of sarcoidosis). In 28 (65%) cases, sarcoidosis was diagnosed concomitantly with SS, or during the follow-up of patients with an already diagnosed SS, while in the remaining 15 (35%), SS was diagnosed during the follow-up of an already diagnosed sarcoidosis. Patients in whom sarcoidosis was diagnosed first showed a lower mean age (43.88 vs. 55.67 years, p=0.005) and were less frequently women (73% vs. 96%, p=0.04) in comparison with those in whom sarcoidosis was diagnosed concomitantly with SS, or during the follow-up of an already diagnosed SS. We identified the following immunopathological scenarios: a combination of NCG involving extrasalivary tissues and anti-Ro antibodies in 55% of patients, a coexistence of both pathological scenarios (extrasalivary NCG and FLS in MSGB) in 42% (with positive anti-Ro antibodies in two thirds of cases), and NCG involving salivary glands and anti-Ro antibodies in 3% of cases. CONCLUSIONS: We have characterised the largest reported series of patients who fulfilled the current classification criteria for both SS and sarcoidosis. This implies that sarcoidosis (and not just the presence of isolated NCG on salivary gland biopsy) may, like other systemic autoimmune diseases, coexist with SS, and that a sarcoidosis diagnosis does not preclude the development of SS in the future.

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.

Deep learning-based lesion subtyping and prediction of clinical outcomes in COVID-19 pneumonia using chest CT.

The main objective of this work is to develop and evaluate an artificial intelligence system based on deep learning capable of automatically identifying, quantifying, and characterizing COVID-19 pneumonia patterns in order to assess disease severity and predict clinical outcomes, and to compare the prediction performance with respect to human reader severity assessment and whole lung radiomics. We propose a deep learning based scheme to automatically segment the different lesion subtypes in nonenhanced CT scans. The automatic lesion quantification was used to predict clinical outcomes. The proposed technique has been independently tested in a multicentric cohort of 103 patients, retrospectively collected between March and July of 2020. Segmentation of lesion subtypes was evaluated using both overlapping (Dice) and distance-based (Hausdorff and average surface) metrics, while the proposed system to predict clinically relevant outcomes was assessed using the area under the curve (AUC). Additionally, other metrics including sensitivity, specificity, positive predictive value and negative predictive value were estimated. 95% confidence intervals were properly calculated. The agreement between the automatic estimate of parenchymal damage (%) and the radiologists' severity scoring was strong, with a Spearman correlation coefficient (R) of 0.83. The automatic quantification of lesion subtypes was able to predict patient mortality, admission to the Intensive Care Units (ICU) and need for mechanical ventilation with an AUC of 0.87, 0.73 and 0.68 respectively. The proposed artificial intelligence system enabled a better prediction of those clinically relevant outcomes when compared to the radiologists' interpretation and to whole lung radiomics. In conclusion, deep learning lesion subtyping in COVID-19 pneumonia from noncontrast chest CT enables quantitative assessment of disease severity and better prediction of clinical outcomes with respect to whole lung radiomics or radiologists' severity score.

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

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[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

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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.