Pathogenesis of Pulmonary Manifestations in ANCA-Associated Vasculitis and Goodpasture Syndrome.

Pulmonary manifestations of vasculitis are associated with significant morbidity and mortality in affected individuals. They result from a complex interplay between immune dysregulation, which leads to vascular inflammation and tissue damage. This review explored the underlying pathogenesis of pulmonary involvement in vasculitis, encompassing various forms such as granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and anti-GBM disease. Mechanisms involving ANCA and anti-GBM autoantibodies, neutrophil activation, and neutrophil extracellular trap (NETs) formation are discussed, along with the role of the complement system in inducing pulmonary injury. Furthermore, the impact of genetic predisposition and environmental factors on disease susceptibility and severity was considered, and the current treatment options were presented. Understanding the mechanisms involved in the pathogenesis of pulmonary vasculitis is crucial for developing targeted therapies and improving clinical outcomes in affected individuals.

Unraveling the Link between Ιnsulin Resistance and Bronchial Asthma.

Evidence from large epidemiological studies has shown that obesity may predispose to increased Th2 inflammation and increase the odds of developing asthma. On the other hand, there is growing evidence suggesting that metabolic dysregulation that occurs with obesity, and more specifically hyperglycemia and insulin resistance, may modify immune cell function and in some degree systemic inflammation. Insulin resistance seldom occurs on its own, and in most cases constitutes a clinical component of metabolic syndrome, along with central obesity and dyslipidemia. Despite that, in some cases, hyperinsulinemia associated with insulin resistance has proven to be a stronger risk factor than body mass in developing asthma. This finding has been supported by recent experimental studies showing that insulin resistance may contribute to airway remodeling, promotion of airway smooth muscle (ASM) contractility and proliferation, increase of airway hyper-responsiveness and release of pro-inflammatory mediators from adipose tissue. All these effects indicate the potential impact of hyperinsulinemia on airway structure and function, suggesting the presence of a specific asthma phenotype with insulin resistance. Epidemiologic studies have found that individuals with severe and uncontrolled asthma have a higher prevalence of glycemic dysfunction, whereas longitudinal studies have linked glycemic dysfunction to an increased risk of asthma exacerbations. Since the components of metabolic syndrome interact with one another so much, it is challenging to identify each one's specific role in asthma. This is why, over the last decade, additional studies have been conducted to determine whether treatment of type 2 diabetes mellitus affects comorbid asthma as shown by the incidence of asthma, asthma control and asthma-related exacerbations. The purpose of this review is to present the mechanism of action, and existing preclinical and clinical data, regarding the effect of insulin resistance in asthma.

Pulmonary Function Tests Post-Stroke. Correlation between Lung Function, Severity of Stroke, and Improvement after Respiratory Muscle Training.

Stroke is a significant cause of mortality and chronic morbidity caused by cardiovascular disease. Respiratory muscles can be affected in stroke survivors, leading to stroke complications, such as respiratory infections. Respiratory function can be assessed using pulmonary function tests (PFTs). Data regarding PFTs in stroke survivors are limited. We reviewed the correlation between PFTs and stroke severity or degree of disability. Furthermore, we reviewed the PFT change in stroke patients undergoing a respiratory muscle training program. We searched PubMed until September 2023 using inclusion and exclusion criteria in order to identify studies reporting PFTs post-stroke and their change after a respiratory muscle training program. Outcomes included lung function parameters (FEV1, FVC, PEF, MIP and MEP) were measured in acute or chronic stroke survivors. We identified 22 studies of stroke patients, who had undergone PFTs and 24 randomised controlled trials in stroke patients having PFTs after respiratory muscle training. The number of patients included was limited and studies were characterised by great heterogeneity regarding the studied population and the applied intervention. In general, PFTs were significantly reduced compared to healthy controls and predicted normal values and associated with stroke severity. Furthermore, we found that respiratory muscle training was associated with significant improvement in various PFT parameters and functional stroke parameters. PFTs are associated with stroke severity and are improved after respiratory muscle training.

Acute Exacerbations of Interstitial Lung Diseases: Focus on Biomarkers.

Interstitial lung diseases (ILDs) are a large group of pulmonary disorders characterized histologically by the cardinal involvement of the pulmonary interstitium. The prototype of ILDs is idiopathic pulmonary fibrosis (IPF), an incurable disease characterized by progressive distortion and loss of normal lung architecture through unchecked collagen deposition. Acute exacerbations are dramatic events during the clinical course of ILDs, associated with high morbidity and mortality. Infections, microaspiration, and advanced lung disease might be involved in the pathogenesis of acute exacerbations. Despite clinical scores, the prediction of the onset and outcome of acute exacerbations is still inaccurate. Biomarkers are necessary to characterize acute exacerbations better. We review the evidence for alveolar epithelial cell, fibropoliferation, and immunity molecules as potential biomarkers for acute exacerbations of interstitial lung disease.

The Role of the Microbiome in Connective-Tissue-Associated Interstitial Lung Disease and Pulmonary Vasculitis.

The microbiome can trigger and maintain immune-mediated diseases and is associated with the severity and prognosis of idiopathic pulmonary fibrosis, which is the prototype of interstitial lung diseases (ILDs). The latter can be a major cause of morbidity and mortality in patients with connective-tissue diseases (CTD). In the present review, we discuss the current evidence regarding microbiome in CTD-ILD and pulmonary vasculitis. In patients with rheumatoid arthritis (RA) the BAL microbiota is significantly less diverse and abundant, compared to healthy controls. These changes are associated with disease severity. In systemic sclerosis (SSc), gastrointestinal (GI)-dysbiosis is associated with ILD. Butyrate acid administration as a means of restoration of GI-microbiota has reduced the degree of lung fibrosis in animal models. Although related studies are scarce for SLE and Sjögren's syndrome, studies of the gut, oral and ocular microbiome provide insights into the pathogenesis of these diseases. In ANCA-associated vasculitis, disease severity and relapses have been associated with disturbed nasal mucosa microbiota, with immunosuppressive treatment restoring the microbiome changes. The results of these studies suggest however no causal relation. More studies of the lung microbiome in CTD-ILDs are urgently needed, to provide a better understanding of the pathogenesis of these diseases.

[Antifibrotic therapy - new approvals for non-IPF interstitial lung diseases]. / Antifibrotische Therapie ­ neue Indikationen bei Non-IPF-interstitiellen Lungenerkrankungen.

Interstitial lung diseases (ILD) encompass more than 200 disorders of known and unknow etiology. Until recently, the antifibrotic drugs nintedanib and pirfenidone had only been approved for the treatment of idiopathic pulmonary fibrosis (IPF), but not for other ILD. In the randomized, double-blind, placebo-controlled SENSCIS trial, the efficacy and safety of nintedanib was investigated in patients with ILD associated with systemic sclerosis (SSc-ILD). Nintedanib significantly reduced the annual rate of decline in FVC compared with placebo leading to the approval of nintedanib for the treatment of SSc-ILD. Very recently, nintedanib has got approval for chronic fibrosing ILD with a progressive phenotype based on the data from the INBUILD trial. In this randomized, double-blind, placebo-controlled, phase III trial, patients with chronic hypersensitivity pneumonitis, idiopathic non-specific interstitial pneumonia, unclassifiable ILD, autoimmune ILD, sarcoidosis, and others were included, and nintedanib slowed the annual decline of pulmonary function by 57 % in these patients. Promising data are also available for pirfenidone in the treatment of patients with progressive, non-IPF lung fibrosis and unclassifiable progressive fibrosing ILD. In this article, we summarize the new approvals of antifibrotic drugs in non-IPF ILD, the results from the underlying clinical trials and the clinical implications.

Exploring the Ability of Electronic Nose Technology to Recognize Interstitial Lung Diseases (ILD) by Non-Invasive Breath Screening of Exhaled Volatile Compounds (VOC): A Pilot Study from the European IPF Registry (eurIPFreg) and Biobank.

BACKGROUND: There is an increasing interest in employing electronic nose technology in the diagnosis and monitoring of lung diseases. Interstitial lung diseases (ILD) are challenging in regard to setting an accurate diagnosis in a timely manner. Thus, there is a high unmet need in non-invasive diagnostic tests. This single-center explorative study aimed to evaluate the usefulness of electronic nose (Aeonose®) in the diagnosis of ILDs. METHODS: Exhaled volatile organic compound (VOC) signatures were obtained by Aeonose® in 174 ILD patients, 23 patients with chronic obstructive pulmonary disease (COPD), and 33 healthy controls (HC). RESULTS: By dichotomous comparison of VOC's between ILD, COPD, and HC, a discriminating algorithm was established. In addition, direct analyses between the ILD subgroups, e.g., cryptogenic organizing pneumonia (COP, n = 28), idiopathic pulmonary fibrosis (IPF, n = 51), and connective tissue disease-associated ILD (CTD-ILD, n = 25) were performed. Area under the Curve (AUC) and Matthews's correlation coefficient (MCC) were used to interpret the data. In direct comparison of the different ILD subgroups to HC, the algorithms developed on the basis of the Aeonose® signatures allowed safe separation between IPF vs. HC (AUC of 0.95, MCC of 0.73), COP vs. HC (AUC 0.89, MCC 0.67), and CTD-ILD vs. HC (AUC 0.90, MCC 0.69). Additionally, to a case-control study design, the breath patterns of ILD subgroups were compared to each other. Following this approach, the sensitivity and specificity showed a relevant drop, which results in a poorer performance of the algorithm to separate the different ILD subgroups (IPF vs. COP with MCC 0.49, IPF vs. CTD-ILD with MCC 0.55, and COP vs. CT-ILD with MCC 0.40). CONCLUSIONS: The Aeonose® showed some potential in separating ILD subgroups from HC. Unfortunately, when applying the algorithm to distinguish ILD subgroups from each other, the device showed low specificity. We suggest that artificial intelligence or principle compound analysis-based studies of a much broader data set of patients with ILDs may be much better suited to train these devices.

Clinical characteristics of patients with familial idiopathic pulmonary fibrosis (f-IPF).

BACKGROUND: The aim of this study was to analyze the relative frequency, clinical characteristics, disease onset and progression in f-IPF vs. sporadic IPF (s-IPF). METHODS: Familial IPF index patients and their family members were recruited into the European IPF registry/biobank (eurIPFreg) at the Universities of Giessen and Marburg (UGMLC). Initially, we employed wide range criteria of f-IPF (e.g. relatives who presumably died of some kind of parenchymal lung disease). After narrowing down the search to occurrence of idiopathic interstitial pneumonia (IIP) in at least one first grade relative, 28 index patients were finally identified, prospectively interviewed and examined. Their family members were phenotyped with establishment of pedigree charts. RESULTS: Within the 28 IPF families, overall 79 patients with f-IPF were identified. In the same observation period, 286 f-IIP and s-IIP patients were recruited into the eurIPFreg at our UGMLC sites, corresponding to a familial versus s-IPF of 9.8%. The both groups showed no difference in demographics (61 vs. 79% males), smoking history, and exposure to any environmental triggers known to cause lung fibrosis. The f-IPF group differed by an earlier age at the onset of the disease (55.4 vs. 63.2 years; p < 0.001). On average, the f-IPF patients presented a significantly milder extent of functional impairment at the time point of inclusion vs. the s-IPF group (FVC 75% pred. vs. FVC 62% pred., p = 0.011). In contrast, the decline in FVC was found to be faster in the f-IPF vs. the s-IPF group (4.94% decline in 6 months in f-IPF vs. 2.48% in s-IPF, p = 0.12). The average age of death in f-IPF group was 67 years vs. 71.8 years in s-IPF group (p = 0.059). The f-IIP group displayed diverse inheritance patterns, mostly autosomal-dominant with variable penetrance. In the f-IPF, the younger generations showed a tendency for earlier manifestation of IPF vs. the older generation (58 vs. 66 years, p = 0.013). CONCLUSIONS: The 28 f-IPF index patients presented an earlier onset and more aggressive natural course of the disease. The disease seems to affect consecutive generations at a younger age. TRIAL REGISTRATION: Nr. NCT02951416 http://www.www.clinicaltrials.gov.

The European IPF registry (eurIPFreg): baseline characteristics and survival of patients with idiopathic pulmonary fibrosis.

BACKGROUND: Since 2009, IPF patients across Europe are recruited into the eurIPFreg, providing epidemiological data and biomaterials for translational research. METHODS: The registry data are based on patient and physician baseline and follow-up questionnaires, comprising 1700 parameters. The mid- to long-term objectives of the registry are to provide clues for a better understanding of IPF phenotype sub-clusters, triggering factors and aggravating conditions, regional and environmental characteristics, and of disease behavior and management. RESULTS: This paper describes baseline data of 525 IPF subjects recruited from 11/2009 until 10/2016. IPF patients had a mean age of 68.1 years, and seeked medical advice due to insidious dyspnea (90.1%), fatigue (69.2%), and dry coughing (53.2%). A surgical lung biopsy was performed in 32% in 2009, but in only 8% of the cases in 2016, possibly due to increased numbers of cryobiopsy. At the time of inclusion in the eurIPFreg, FVC was 68.4% ± 22.6% of predicted value, DLco ranged at 42.1% ± 17.8% of predicted value (mean value ± SD). Signs of pulmonary hypertension were found in 16.8%. Steroids, immunosuppressants and N-Acetylcysteine declined since 2009, and were replaced by antifibrotics, under which patients showed improved survival (p = 0.001). CONCLUSIONS: Our data provide important insights into baseline characteristics, diagnostic and management changes as well as outcome data in European IPF patients over time. TRIAL REGISTRATION: The eurIPFreg and eurIPFbank are listed in ClinicalTrials.gov( NCT02951416 ).

Respiratory training in Greece.

In Greece, respiratory medicine is a stand-alone specialty requiring a 5-year training programme. Acquisition of the general medicine specialty is not a prerequisite for entering the respiratory training programme. As background information, Greece's population is approximately 11 million and there are tertiary hospitals covering specific geographical areas of the country. The majority of the tertiary hospitals include respiratory wards and also train registrars. Although there is heterogeneity between different hospitals, our article highlights the training of respiratory physicians in the majority of respiratory departments in the country.

Decreased apoptotic rate of alveolar macrophages of patients with idiopathic pulmonary fibrosis.

Introduction. Increased apoptosis of epithelial cells and decreased apoptosis of myofibroblasts are involved in the pathogenesis of IPF. The apoptotic profile of alveolar macrophages (AMs) in IPF is unclear. Aim. To investigate whether AMs of patients with IPF exhibit a different apoptotic profile compared to normal subjects. Methods. We analyzed, by immunohistochemistry, the expression of the apoptotic markers fas, fas ligand , bcl-2, and bax in AM obtained from bronchoalveolar lavage fluid (BALF) of 20 newly diagnosed, treatment-naive IPF patients and of 16 controls. Apoptosis of AM was evaluated by Apoptag immunohistochemistry. IPF patients received either interferon-g and corticosteroids or azathioprine and corticosteroids for six months. Results. BALF AMs undergoing apoptosis were significantly less in IPF patients. No difference was found in the expression of fas or fas ligand, bcl-2 and bax between IPF and control group. No difference was found between the respiratory function parameters of the two treatment groups after six months. A positive correlation was found between the number of bcl-2 positive stained macrophages and DLCO after treatment. Conclusions. The decreased apoptotic rate of AM of patients with IPF is not associated with decreased expression of apoptosis mediators involved in the external or internal apoptotic pathway.

Mediterranean diet and metabolic syndrome in an urban population: the Athens Study.

BACKGROUND: Previous studies demonstrated the beneficial impact of the Mediterranean diet (MedDiet) on metabolic syndrome (MetS). The aim of this study was to retrospectively investigate the association between MedDiet and MetS in a representative sample of the Athenian population in the early 1980s, when MetS had not been established as an entity yet. METHODS: In a cross-sectional epidemiologic survey of cardiovascular disease (CVD), 2,074 randomly selected adults were examined: 900 men and 1,174 women (age, 46.9 ± 14.9 years). MetS was defined according to criteria of the National Cholesterol Education Program-Adult Treatment Panel III. A validated questionnaire concerning nutrition habits was administered, and MedDiet was assessed according to guidelines of the Division of Nutrition/Epidemiology, Athens University Medical School. RESULTS: Overall, 1,023 participants (49.3%) followed MedDiet (47.3% men, 52.0% women, P = .033) with similar rates across age groups (P = .337). MetS was diagnosed in 24.0% of those following MedDiet, compared with 27.9% of those not following it (P = .041). Participants with CVD or diabetes mellitus were less likely to follow MedDiet (43% vs 50%, P = .009). Multivariate analysis revealed that MedDiet is associated with a 20% reduction in MetS (odds ratio = 0.80, 95% confidence interval = 0.65-0.98), after adjustment for age, gender, smoking, light physical activity, serum levels of low-density lipoprotein cholesterol and γ-glutamyl transferase, diabetes mellitus, CVD, family history of hypertension, and/or hyperlipidemia. CONCLUSIONS: Results indicate that adherence to MedDiet may attenuate the prevalence of MetS and, consequently, the increasing burden of diabetes mellitus and CVD, especially in urban populations.

Pulmonary hypertension in a stable community-based COPD population.

STUDY OBJECTIVES: The etiology and prevalence of pulmonary hypertension (PH) in patients with stable chronic obstructive pulmonary disease (COPD) is uncertain. This study was done to determine the prevalence of PH in stable COPD outpatients and to evaluate the relationship between PH and indices of pulmonary function. DESIGN: The study was a retrospective review of outpatients with COPD and PH defined as a history of cigarette smoking, pulmonary function tests (PFTs) that met GOLD criteria for airway obstruction, an echocardiogram within 6 months of PFTs, and a left ventricular ejection fraction (LVEF) >55%. Of the 159 individuals who met all inclusion criteria, 105 had a sufficient tricuspid regurgitant jet to measure systolic pulmonary artery pressure (sPAP). PH was defined as sPAP ≥36 mmHg. MEASUREMENTS AND RESULTS: The prevalence of PH was 60% (63/105) in the study group. The mean sPAP in patients with PH was 45 ± 6 mmHg. COPD patients with PH were older (71.1 ± 11.8 vs. 63.7 ± 10.2 years, P = 0.001), had lower FEV(1)% predicted (51.8 ± 18.8 vs. 62.7 ± 20.5%, P = 0.006), a higher RV/TLC (0.55 ± 0.10 vs. 0.48 ± 0.11, P = 0.001), and a lower % predicted DL(CO) (59.6 ± 19.5% vs. 71.9 ± 24.9%, P = 0.006). Only age (P < 0.002) and prebronchodilator FEV(1)% predicted (P < 0.006) predicted PH by logistic regression analysis. No differences were observed in gender, BMI, smoking status, pack years, total lung capacity (TLC), or residual volume (RV). CONCLUSION: PH is common in COPD. Older individuals and those with more airway obstruction are at greater risk for developing PH.

Cryptogenic and secondary organizing pneumonia: clinical presentation, radiographic findings, treatment response, and prognosis.

BACKGROUND: Organizing pneumonia (OP) is a distinct clinical and pathologic entity. This condition can be cryptogenic (COP) or secondary to other known causes (secondary OP). In the present study, we reviewed the features associated with COP and secondary OP in patients from two teaching hospitals. METHODS: The medical records of 61 patients with biopsy-proven OP were retrospectively reviewed. Forty patients were diagnosed with COP and 21 patients with secondary OP. The clinical presentation, radiographic studies, pulmonary function tests (PFTs), laboratory data, BAL findings, treatment, and outcome were analyzed. RESULTS: The mean age at presentation was 60.46 ± 13.57 years. Malaise, cough, fever, dyspnea, bilateral alveolar infiltrates, and a restrictive pattern were the most common symptoms and findings. BAL lymphocytosis was observed in 43.8% of patients with OP. The relapse rate and mortality rate after 1 year of follow-up were 37.8% and 9.4%, respectively. The in-hospital mortality was 5.7%. The clinical presentation and radiographic findings did not differ significantly between patients with COP and secondary OP. A mixed PFT pattern (obstructive and restrictive physiology) and lower blood levels of serum sodium, serum potassium, platelets, albumin, protein, and pH were observed among patients with secondary OP. Higher blood levels of creatinine, bilirubin, Paco2, and BAL lymphocytes were also more common among patients with secondary OP. There were no differences in the relapse rate or mortality between patients with COP and secondary OP. The 1-year mortality correlated with an elevated erythrocyte sedimentation rate, low albumin, and low hemoglobin levels. CONCLUSIONS: The clinical and radiographic findings in patients with COP and secondary OP are similar and nonspecific. Although certain laboratory abnormalities are more common in secondary OP and can be associated with worse prognosis, they are likely due to the underlying disease. COP and secondary OP have similar treatment response, relapse rates, and mortality.

Acute exacerbations of interstitial lung diseases.

PURPOSE OF REVIEW: This review aims to highlight recent advances in pathogenesis, clinical presentation and treatment of interstitial lung diseases (ILDs). RECENT FINDINGS: Acute exacerbation is increasingly recognized as a major complication in the course of idiopathic pulmonary fibrosis. It is precipitated by a variety of intrinsic and extrinsic factors. Moreover, acute exacerbation is an apparently equally frequent event in hypersensitivity pneumonitis and collagen-vascular diseases associated ILDs, especially the rheumatoid pulmonary fibrosis. Treatment of acute exacerbations is unsatisfactory and prognosis extremely poor. SUMMARY: In a critically ill patient proper recognition of an acute exacerbation and of the underlying chronic ILD is warranted because treatment approach varies with the type of ILD. Advances in the understanding of the pathogenesis and treatment of this 'idiopathic' phenomenon are reviewed.

Estrogen replacement therapy prevents airway dysfunction in a murine model of allergen-induced asthma.

We previously reported that 17beta-estradiol (E2) prevents hyperresponsiveness to carbachol of murine asthmatic tracheal rings in vitro. We now investigated whether E2 is similarly effective in reducing airway hyperreactivity in a murine model of allergic asthma in vivo. Female ovariectomized BALB/c mice were rendered asthmatic by a 25-day protocol of sensitization to ovalbumin. Under positive-pressure ventilation, anesthetized asthmatic mice exhibited a dramatic increase in airway responsiveness to increasing doses of inhaled methacholine compared to PBS-sensitized controls, as reflected in decreased dynamic compliance of the respiratory system and increased tissue damping, tissue elastance, and airway resistance. Furthermore, asthmatic mice exhibited hypercellularity and increased protein concentration in the bronchoalveolar lavage, strong signs of peribronchial cuffing with inflammatory cells and increased goblet cell activity. To test the effects of estrogen, three additional groups of mice were implanted subcutaneously with different amounts of slow-release E2 pellets at the time of ovariectomy and rendered asthmatic as before. E2 dose-dependently inhibited airway hyperresponsiveness to methacholine, reduced bronchoalveolar lavage hypercellularity, and virtually eliminated histologic signs of inflammation and goblet cell hyperactivity. The inflammation and airway hyperactivity in asthmatic mice was associated with an increase in bronchoalveolar lavage levels of TGFbeta1, which was completely abolished in E2-treated asthmatic mice. We conclude that estrogen replacement therapy effectively ameliorates the pathologic profile of murine allergic asthma.

Estrogen as a new therapeutic target for asthma and chronic obstructive pulmonary disease.

Asthma and chronic obstructive pulmonary disease (COPD) affect the lives of a large portion of the population and can lead to morbidity and mortality. In many women, the incidence and severity of asthma exacerbations vary along their menstrual cycle. Estrogen, a natural occurring hormone, affects differently many of the cell types that are involved in asthma, including macrophages, eosinophils, neutrophils, lymphocyte, mast cells, fibroblasts, epithelial and smooth muscle cells. By binding to its receptors on the plasma or nuclear membrane, estrogen affects the expression of a plethora of proteins that are involved in the pathogenesis of asthma and COPD. In this review we will summarize the current knowledge of the role of estrogen in the expression, production and secretion of inflammatory agents that are involved in asthma and COPD and its potential therapeutic role in these diseases.