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.

Patients Hospitalized for COVID-19 in the Periods of Delta and Omicron Variant Dominance in Greece: Determinants of Severity and Mortality.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has been a pandemic since 2020, and depending on the SARS-CoV-2 mutation, different pandemic waves have been observed. The aim of this study was to compare the baseline characteristics of patients in two phases of the pandemic and evaluate possible predictors of mortality. METHODS: This is a retrospective multicenter observational study that included patients with COVID-19 in 4 different centers in Greece. Patients were divided into two groups depending on the period during which they were infected during the Delta and Omicron variant predominance. RESULTS: A total of 979 patients (433 Delta, 546 Omicron) were included in the study (median age 67 years (54, 81); 452 [46.2%] female). Compared to the Omicron period, the patients during the Delta period were younger (median age [IQR] 65 [51, 77] vs. 70 [55, 83] years, p < 0.001) and required a longer duration of hospitalization (8 [6, 13] vs. 7 [5, 12] days, p = 0.001), had higher procalcitonin levels (ng/mL): 0.08 [0.05, 0.17] vs. 0.06 [0.02, 0.16], p = 0.005, ferritin levels (ng/mL): 301 [159, 644] vs. 239 [128, 473], p = 0.002, C- reactive protein levels (mg/L): 40.4 [16.7, 98.5] vs. 31.8 [11.9, 81.7], p = 0.003, and lactate dehydrogenase levels (U/L): 277 [221, 375] vs. 255 [205, 329], p < 0.001. The Charlson Comorbidity Index was lower (3 [0, 5] vs. 4 [1, 6], p < 0.001), and the extent of disease on computed tomography (CT) was greater during the Delta wave (p < 0.001). No evidence of a difference in risk of death or admission to the intensive care unit was found between the two groups. Age, cardiovascular events, acute kidney injury during hospitalization, extent of disease on chest CT, D-dimer, and neutrophil/lymphocyte ratio values were identified as independent predictors of mortality for patients in the Delta period. Cardiovascular events and acute liver injury during hospitalization and the PaO2/FiO2 ratio on admission were identified as independent predictors of mortality for patients in the Omicron period. CONCLUSIONS: In the Omicron wave, patients were older with a higher number of comorbidities, but patients with the Delta variant had more severe disease and a longer duration of hospitalization.

Prognostic Value of Serum Biomarkers in Patients with Idiopathic Pulmonary Fibrosis in Relation to Disease Progression.

BACKGROUND: The aim of this present study was to determine serum biomarker levels and their correlation with respiratory function and the clinical course of patients with idiopathic pulmonary fibrosis (IPF). MATERIALS AND METHODS: This study included 72 IPF patients, according to the ATS/ERS criteria, in whom antifibrotic treatment was initiated. Blood samples were taken, and serum biomarkers, such as KL-6, SP-D, CCL18, CXCL13, VEGF-A, IL-8, IGFBP-1, IGFBP-2, IGFBP-7 and ICAM-1 were measured using ELISA methodology. Pulmonary function tests (FVC, TLC, DLCO-% pred) were determined at baseline and after 12 and 24 months and analyzed in correlation with the biomarkers. RESULTS: The majority of patients (mean age 72 ± 6 years) were men (83%). The FVC and DLCO values at the 12-month follow-up were found to be statistically decreased in deceased patients (p < 0.05). The SP-D (p < 0.001) and the IGFBP-1 (p = 0.021) levels were found to be increased at the 1-year follow-up in deceased patients, and similarly, the SP-D (p = 0.005) and ICAM-1 (p = 0.043) levels at the 2-year follow-up. A chi-square test revealed that 70% of the category IV GAP index was found with cut-off elevated levels of a biomarker combination (KL-6, SP-D, VEGF-A) from the ROC curve analysis (p < 0.05). CONCLUSION: This study provides evidence, for the first time in a Greek population, of the possibility of using a combination of KL-6, SP-D, and VEGF-A serum levels along with the GAP index.

Defining response to therapy with biologics in severe asthma: from global evaluation to super response and remission.

INTRODUCTION: In recent years, monoclonal antibodies targeting Type-2 inflammatory pathways have been developed for severe asthma treatment. However, even when patients are carefully selected, the response to treatment varies. AREAS COVERED: Different studies have evaluated response to therapy with biologics such as exacerbation reduction, symptom improvement, pulmonary function increase, improvement in QoL, or decrease of oral corticosteroids, showing that all patients do not respond to all disease aspects and leading to an extensive debate regarding the definition of response. EXPERT OPINION: Assessing response to therapy is of great importance, but since there is no uniform definition of treatment response, the recognition of patients who really benefit from these therapies remains an unmet need. In the same context, identifying non-responding patients in which biologic therapy should be switched or substituted by alternative treatment options is of paramount importance. In this review, we present the road trip of the definition of therapeutic response to biologics in severe asthmatics by presenting the current relevant medical literature. We also present the suggested predictors of response, with an emphasis on the so-called super-responders. Finally, we discuss the recent insights regarding asthma remission as a feasible treatment goal and provide a simple algorithm for the evaluation of response.

Cardiovascular Diseases in COPD: From Diagnosis and Prevalence to Therapy.

Chronic obstructive pulmonary disease (COPD) is considered one of the leading causes of mortality. Cardiovascular comorbidities are diagnosed often in COPD patients, not only because of the common risk factors these two diseases share, but also because of the systemic inflammation which characterizes COPD and has deleterious effects in the cardiovascular system. The comorbid cardiovascular diseases in COPD result in several difficulties in the holistic treatment of these patients and affect outcomes such as morbidity and mortality. Several studies have reported that mortality from cardiovascular causes is common among COPD patients, while the risk for acute cardiovascular events increases during COPD exacerbations and remains high for a long time even after recovery. In this review, we focus on the prevalence of cardiovascular comorbidities in COPD patients, presenting the evidence regarding the interaction of the pathophysiological pathways which characterize each disease. Furthermore, we summarize information regarding the effects of cardiovascular treatment on COPD outcomes and vice versa. Finally, we present the current evidence regarding the impact of cardiovascular comorbidities on exacerbations, quality of life and survival of COPD patients.

Patient-Reported Outcome Measurements in Patients with COPD-Obstructive Sleep Apnea Overlap Syndrome: Time for Action?

Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea syndrome (OSA) are common conditions that often coexist [Overlap syndrome (OS)]. OS has important implications in the diagnosis, treatment, and patient outcome of both disorders. Patient-reported outcomes (PROs) are essential to evaluate symptoms, impact of symptoms on activities of daily living, and treatment response. The present review aims to display the potential usefulness of PROs measurements (PROMs) regarding the initial evaluation and treatment of both conditions (COPD and OSA) in OS patients. More specifically, we review PROMs regarding symptoms, mental health indices and health-related quality of life in patients with OS. These PROMs have the potential to add value to clinical research and daily practice in certain aspects that are important to patients.

Recent insights in the role of biomarkers in severe asthma management.

Contemporary asthma management requires a proactive and individualized approach, combining precision diagnosis and personalized treatment. The introduction of biologic therapies for severe asthma to everyday clinical practice, increases the need for specific patient selection, prediction of outcomes and monitoring of these costly and long-lasting therapies. Several biomarkers have been used in asthma in disease identification, prediction of asthma severity and prognosis, and response to treatment. Novel advances in the area of personalized medicine regarding disease phenotyping and endotyping, encompass the development and application of reliable biomarkers, accurately quantified using robust and reproducible methods. The availability of powerful omics technologies, together with integrated and network-based genome data analysis, and microbiota changes quantified in serum, body fluids and exhaled air, will lead to a better classification of distinct phenotypes or endotypes. Herein, in this review we discuss on currently used and novel biomarkers for the diagnosis and treatment of asthma.

IL-26 in the Lung and Its Role in COPD Inflammation.

IL-26 is a cytokine expressed by infiltrating pro-inflammatory IL-17-producing T cells in the tissues of patients with chronic lung inflammation. IL-26 induces the chemotactic response of human neutrophils to bacteria and other inflammatory stimuli. In recent years, the innovative properties of IL-26 have been described. Studies have shown that, as DNA is released from damaged cells, it binds to IL-26, which plays the role of a carrier molecule for extracellular DNA, further contributing to its binding to the site of inflammation. This mechanism of action indicates that IL-26 may serve both as a driver as well as a stimulus of the inflammatory process, leading to the installation of a noxious amplification loop and, eventually, persistent inflammation. IL-26 also demonstrates direct antimicrobial effects derived from its capability to create pores and disrupt bacterial membranes, as indicated by the presence of membrane blebs on the surface of the bacteria and cytosolic leakage pores in bacterial walls, produced in response to microbial stimuli in human airways by several different immune and structural cells. Surprisingly, while this particular cytokine induces the gathering of neutrophils in areas of infection, it also exhibits inhibitory and pro-inflammatory effects on airway epithelial and immune cells. These remarkable effects underline the necessity of a better understating of its biological behavior and its role in the pathophysiology and disease burden in several smoking-related airway inflammatory disorders, such as Chronic Obstructive Pulmonary Disease (COPD) and chronic bronchitis. In this review, we aim to discuss the current role of IL-26 in the lung, with an emphasis on systemic inflammation in patients suffering from COPD and chronic bronchitis.

[Functional and morphological disorders of taste and olfaction in COVID-19 patients]. / Funktionelle und morphologische Geschmacks- und Geruchsstörungen bei COVID-19-Patienten.

OBJECTIVE: This study aimed to test the prevalence and evolution of acute olfactory and gustatory functional impairment and their morphologic correlates in COVID-19 patients who require hospitalization due to COVID-19-related respiratory conditions. METHODS: Included were 53 consecutive hospitalized patients (23 males, 30 females; age 42.54 ± 10.95 years) with an RT-PCR-confirmed COVID-19 diagnosis. Patients were examined twice: just after hospital discharge and 4-6 weeks later. Electrogustometric (EGM) thresholds at the tongue area supplied by the chorda tympani, at the soft palate, and in the region of the vallate papillae were recorded bilaterally. Olfaction was examined by Sniffin' sticks (Burghardt GmbH, Wedel, Germany). The patients' nasal and oral mucosa (fungiform papillae, fpap) were examined by contact endoscopy. Findings were compared to those of 53 healthy individuals matched for sex and age (23 males, 30 females; age 42.90 ± 10.64 years). RESULTS: EGM thresholds in patients were significantly higher than those of healthy subjects at both timepoints. EGM thresholds at the second measurement were significantly lower than those at the first measurement. Accordingly, patient-reported gustatory outcomes were improved at the second measurement. The same pattern was found using Sniffin' sticks. Significant alterations in form and vascularization of fPap were detected in patients, especially at the first instance. Interestingly we did not observe any significant changes in the morphology and vascularization of nasal mucosa. CONCLUSION: COVID-19 affects both gustatory and olfactory functions. In parallel, it also affects the structure and vascularization of both nasal and oral mucosa, albeit the nasal mucosa to a much lesser, non-significant extent. Our findings suggest that COVID-19 may cause a mild to profound neuropathy of multiple cranial nerves.

Clinical, imaging and functional determinants of sarcoidosis phenotypes in a Greek population.

Background: The aim of the present study was the application of the latest phenotype recommendations in Greek patients, in order to identify specific clinical, imaging and spirometric characteristics, at initial diagnosis of sarcoidosis, related to disease phenotypes. Methods: Our cohort included 147 patients coming from Northern Greece, recruited from the Outpatient Sarcoidosis Clinic, of Aristotle University of Thessaloniki. The observation period was 5 years. The Scadding staging system and the World Association of Sarcoidosis and other Granulomatous Disorders (WASOG) Clinical Outcome Status instrument were used. Phenotypes were defined by the latest DELPHI consensus recommendations. Results: The following clinical phenotypes were identified: asymptomatic 59%, acute 14.3%, chronic 12.9% and advanced 33.3%. The observed phenotypes were not related to Scadding stages. Lung function decline was in line with phenotype severity. The presence of fibrosis to any extent upon diagnosis differed among phenotypes (asymptomatic 13.8%, acute 38.1%, chronic 57.9%, advanced 61.2%, P<0.001) and was common for relapsing patients (P<0.001). In spontaneously remitting patients, fibrosis upon diagnosis was found less often than in non-remitting patients (P<0.001). Renal involvement was more frequently found in the advanced phenotype (P=0.032). Skin involvement was more common for patients with acute onset (P<0.001) and spontaneous remission (P=0.012). Ocular involvement was mainly found in relapsing patients (P<0.001). Conclusions: In our cohort, sarcoidosis clinical phenotypes have certain clinical, imaging and functional characteristics, at initial diagnosis of the disease, which could be assessed in everyday practice.

Eosinophilic Asthma, Phenotypes-Endotypes and Current Biomarkers of Choice.

Asthma phenotyping and endotyping are constantly evolving. Currently, several biologic agents have been developed towards a personalized approach to asthma management. This review will focus on different eosinophilic phenotypes and Th2-associated endotypes with eosinophilic inflammation. Additionally, airway remodeling is analyzed as a key feature of asthmatic eosinophilic endotypes. In addition, evidence of biomarkers is examined with a predictive value to identify patients with severe, uncontrolled asthma who may benefit from new treatment options. Finally, there will be a discussion on the results from clinical trials regarding severe eosinophilic asthma and how the inhibition of the eosinophilic pathway by targeted treatments has led to the reduction of recurrent exacerbations.

SARS-Cov-2 Infection in Severe Asthma Patients Treated With Biologics.

BACKGROUND: At the beginning of the pandemic, there have been considerable concerns regarding coronavirus disease 2019 (COVID-19) severity and outcomes in patients with severe asthma treated with biologics. OBJECTIVE: To prospectively observe a cohort of severe asthmatics treated with biologics for the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and disease severity during the COVID-19 pandemic. METHODS: Physicians from centers treating patients with severe asthma all over Greece provided demographic and medical data regarding their patients treated with biologics. Physicians were also asked to follow up patients during the pandemic and to perform a polymerase chain reaction test in case of a suspected SARS-Cov-2 infection. RESULTS: Among the 591 severe asthmatics (63.5% female) included in the study, 219 (37.1%) were treated with omalizumab, 358 (60.6%) with mepolizumab, and 14 (2.4%) with benralizumab. In total, 26 patients (4.4%) had a confirmed SARS-CoV-2 infection, 9 (34.6%) of whom were admitted to the hospital because of severe COVID-19, and 1 required mechanical ventilation and died 19 days after admission. Of the 26 infected patients, 5 (19.2%) experienced asthma control deterioration, characterized as exacerbation that required treatment with systemic corticosteroids. The scheduled administration of the biological therapy was performed timely in all patients with the exception of 2, in whom it was postponed for 1 week according to their doctors' suggestion. CONCLUSION: Our study confirms that despite the initial concerns, SARS-CoV-2 infection is not more common in asthmatics treated with biologics compared with the general population, whereas the use of biologic treatments for severe asthma during the COVID-19 pandemic does not seem to be related to adverse outcomes from severe COVID-19.

Asthma-COPD Overlap Syndrome: Recent Insights and Unanswered Questions.

The term asthma-COPD overlap (ACO) has been used to identify a heterogeneous condition in which patients present with airflow limitation that is not completely reversible and clinical and inflammatory features of both asthma and chronic obstructive pulmonary disease (COPD). ACO diagnosis may be difficult in clinical practice, while controversy still exists regarding its definition, pathophysiology, and impact. Patients with ACO experience a greater disease burden compared to patients with asthma or COPD alone, but in contrast they show better response to inhaled corticosteroid treatment than other COPD phenotypes. Current management recommendations focus on defining specific and measurable treatable clinical traits, according to disease phenotypes and underlying biological mechanisms for every single patient. In this publication, we review the current knowledge on definition, pathophysiology, clinical characteristics, and management options of ACO.

Paucigranulocytic Asthma: Potential Pathogenetic Mechanisms, Clinical Features and Therapeutic Management.

Asthma is a heterogeneous disease usually characterized by chronic airway inflammation, in which several phenotypes have been described, related to the age of onset, symptoms, inflammatory characteristics and treatment response. The identification of the inflammatory phenotype in asthma is very useful, since it allows for both the recognition of the asthmatic triggering factor as well as the optimization of treatment The paucigranulocytic phenotype of asthma (PGA) is characterized by sputum eosinophil levels <1−3% and sputum neutrophil levels < 60%. The precise characteristics and the pathobiology of PGA are not fully understood, and, in some cases, it seems to represent a previous eosinophilic phenotype with a good response to anti-inflammatory treatment. However, many patients with PGA remain uncontrolled and experience asthmatic symptoms and exacerbations, irrespective of the low grade of airway inflammation. This observation leads to the hypothesis that PGA might also be either a special phenotype driven by different kinds of cells, such as macrophages or mast cells, or a non-inflammatory phenotype with a low grade of eosinophilic inflammation. In this review, we aim to describe the special characteristics of PGA and the potential therapeutic interventions that could be offered to these patients.

Genotype-Phenotype Relationships in Inheritable Idiopathic Pulmonary Fibrosis: A Greek National Cohort Study.

BACKGROUND: Monogenic and polygenic inheritances are evidenced for idiopathic pulmonary fibrosis (IPF). Pathogenic variations in surfactant protein-related genes, telomere-related genes (TRGs), and a single-nucleotide polymorphism in the promoter of MUC5B gene encoding mucin 5B (rs35705950 T risk allele) are reported. This French-Greek collaborative study, Gen-Phen-Re-GreekS in inheritable IPF (iIPF), aimed to investigate genetic components and patients' characteristics in the Greek national IPF cohort with suspected heritability. PATIENTS AND METHODS: 150 patients with familial PF, personal-family extrapulmonary disease suggesting short telomere syndrome, and/or young age IPF were analyzed. RESULTS: MUC5B rs35705950 T risk allele was detected in 103 patients (90 heterozygous, 13 homozygous, allelic frequency of 39%), monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC, 2 RTEL1, 2 PARN, 1 NOP10, and 1 NHP2), and biallelic ABCA3 pathogenic variations in 3. Overlapping MUC5B rs35705950 T risk allele and TRG pathogenic variations were shown in 11 patients (5 TERT, 3 TERC, 1 PARN, 1 NOP10, and 1 NHP2), MUC5B rs35705950 T risk allele, and biallelic ABCA3 pathogenic variations in 2. In 38 patients, neither MUC5B rs35705950 T risk allele nor TRG pathogenic variations were detectable. Kaplan-Meier curves showed differences in time-to-death (p = 0.025) where patients with MUC5B rs35705950 T risk allele alone or in combination with TRG pathogenic variations presented better prognosis. CONCLUSION: The Gen-Phen-Re-GreekS in iIPF identified multiple and overlapping genetic components including the rarest, underlying disease's genetic "richesse," complexity and heterogeneity. Time-to-death differences may relate to diverse IPF pathogenetic mechanisms implicating "personalized" medical care driven by genotypes in the near future.