Thoracic endosonography (EBUS/EUS-b) in the diagnosis of different intrathoracic diseases: A 4-year experience at a single-centre in Greece.

BACKGROUND: In the last decade, the advent of thoracic endosonography has revolutionised the field of diagnostic bronchoscopy. METHODS: We conducted a single-centre prospective study in "Sotiria" Chest diseases hospital between January 2016 and December 2019. The study aimed to evaluate the efficacy and diagnostic value of combined EBUS/EUS-b in comparison with EBUS-TBNA and EUS-b FNA in different intrathoracic diseases. RESULTS: A total of 266 patients were enrolled (70.7% males, 85.7% smokers, mean age ± SD: 62.8 ± 11.8). Diagnosis and staging of suspected lung cancer (LC) were the main indications for EBUS/EUS-b in 56.7% of patients, followed by lymphadenopathy of unknown origin in 27%, lymphadenopathy in previous malignancy in 10.9%, and staging of proven LC in 5.3%. EUS-b FNA alone or combined with EBUS-TBNA was performed in 14.7% of patients. A total of 512 lymph nodes was sampled (481 through EBUS-TBNA and 31 through EUS-b FNA). EBUS/EUS-b led to a definitive diagnosis in 68.4% of the patients. Most cases (50.4%) were malignancies, while 18% represented benign diseases (83.3% sarcoidosis). Sensitivity of combined EBUS/EUS-b was higher in comparison with sensitivity of both procedures alone (100% vs 89.4% vs 88.9%). Accordingly, the overall sensitivity of EBUS/EUS-b for the detection of malignancy and sarcoidosis was 93% and 95.2%, respectively. No severe complications were observed. CONCLUSION: Thoracic endosonography is an efficient, safe, minimally invasive tool yielding high sensitivity and diagnostic accuracy in patients with suspected malignancy and mediastinal lymphadenopathy. Experienced pulmonologists in EBUS-TBNA should more routinely perform EUS-b FNA to avoid unnecessary surgical interventions.

Long-term efficacy and safety of omalizumab in patients with allergic asthma: A real-life study.

Background: The efficacy and safety of omalizumab in patients with severe allergic asthma have been established in both randomized controlled trials and real-life studies. Objective: To evaluate the sustained effectiveness and safety of long-term treatment with omalizumab in a real-world setting. Methods: In this retrospective study, we included patients treated with omalizumab for at least 8 years in four asthma clinics in Greece. Pulmonary function, asthma control, oral corticosteroids (OCS) dose, and exacerbations were recorded before treatment, 6 months later, and annually thereafter. Adverse events were also recorded. Results: Forty-five patients (66.7% women), mean ± standard deviation (SD) age 55.3 ± 12.2 years, were included. The duration of treatment with omalizumab was 10.6 ± 1.2 years. The annual exacerbation rate decreased from 4.1 before omalizumab initiation to 1.1 after 1 year of treatment and remained low up to the 8th year of treatment (p < 0.001). From the 19 patients who were receiving OCS at baseline, 21.1% patients discontinued after 6 months, 47.4% were still on OCS after 4 years of therapy, and 31.6% were on OCS after 8 years. With regard to the OCS dose, 36.8% of the patients reduced the dose ≥ 50% after 6 months and 68.4% achieved 50% reduction after 2 years. The mean daily OCS dose before omalizumab initiation was 7.8 mg of prednisolone or the equivalent, reduced to 4.7 mg/day after 6 months, which reached 1.6 mg/day after 8 years (p < 0.001). Treatment with omalizumab resulted in significant improvements of asthma control and lung function. No severe adverse events were reported. Conclusion: In this real-life study, omalizumab resulted in significant and sustained improvements in asthma exacerbations, asthma control, and lung function, and had a steroid sparing effect and a good safety profile.

Genetics and Epigenetics in Asthma.

Asthma is one of the most common respiratory disease that affects both children and adults worldwide, with diverse phenotypes and underlying pathogenetic mechanisms poorly understood. As technology in genome sequencing progressed, scientific efforts were made to explain and predict asthma's complexity and heterogeneity, and genome-wide association studies (GWAS) quickly became the preferred study method. Several gene markers and loci associated with asthma susceptibility, atopic and childhood-onset asthma were identified during the last few decades. Markers near the ORMDL3/GSDMB genes were associated with childhood-onset asthma, interleukin (IL)33 and IL1RL1 SNPs were associated with atopic asthma, and the Thymic Stromal Lymphopoietin (TSLP) gene was identified as protective against the risk to TH2-asthma. The latest efforts and advances in identifying and decoding asthma susceptibility are focused on epigenetics, heritable characteristics that affect gene expression without altering DNA sequence, with DNA methylation being the most described mechanism. Other less studied epigenetic mechanisms include histone modifications and alterations of miR expression. Recent findings suggest that the DNA methylation pattern is tissue and cell-specific. Several studies attempt to describe DNA methylation of different types of cells and tissues of asthmatic patients that regulate airway remodeling, phagocytosis, and other lung functions in asthma. In this review, we attempt to briefly present the latest advancements in the field of genetics and mainly epigenetics concerning asthma susceptibility.

Can steroids reverse the severe COVID-19 induced "cytokine storm"?

Severe coronavirus disease (COVID-19) is characterized by an excessive proinflammatory cytokine storm, resulting in acute lung injury and development of acute respiratory distress syndrome (ARDS). The role of corticosteroids is controversial in severe COVID-19 pneumonia and associated hyper-inflammatory syndrome. We reported a case series of six consecutive COVID-19 patients with severe pneumonia, ARDS and laboratory indices of hyper-inflammatory syndrome. All patients were treated early with a short course of corticosteroids, and clinical outcomes were compared before and after corticosteroids administration. All patients evaded intubation and intensive care admission, ARDS resolved within 11.8 days (median), viral clearance was achieved in four patients within 17.2 days (median), and all patients were discharged from the hospital in 16.8 days (median). Early administration of short course corticosteroids improves clinical outcome of patients with severe COVID-19 pneumonia and evidence of immune hyperreactivity.

Mepolizumab in Severe Eosinophilic Asthma: A 2-Year Follow-Up in Specialized Asthma Clinics in Greece: An Interim Analysis.

INTRODUCTION: Mepolizumab is a monoclonal antibody against IL-5 for the treatment of severe eosinophilic asthma. The aim of the current study was to present a predesigned interim analysis of the data of patients who have completed 1 year of therapy with mepolizumab. METHODS: This study is a prospective multicenter, noninterventional 2-year observational study and aims to describe the clinical benefit and safety profile of mepolizumab in patients with severe eosinophilic asthma. RESULTS: Compared to the year preceding the initiation of treatment, the annual rate of exacerbations decreased significantly, from 4.3 ± 2.3 to 1.3 ± 1.8; p < 0.0001. Forty-two patients received maintenance dose of oral corticosteroids (OCS) at baseline. From these patients at the end of 1 year of therapy with mepolizumab, 17 patients (40%) had achieved OCS discontinuation. A reduction in the median dose of OCS was also achieved. After 1 year of treatment with mepolizumab, the asthma control test score significantly increased from 16.3 ± 3.7 to 21.2 ± 3.8 (p < 0.0001). This marked clinical improvement was paralleled by a significant reduction of blood eosinophil count. All patients showed a considerable improvement of airflow limitation. In respect to adverse events of treatment with mepolizumab, 19 patients (27%) were recorded to have at least one such occurrence during their 1-year treatment. CONCLUSIONS: We have shown that in patients with severe eosinophilic asthma, 1 year of treatment with mepolizumab was safe, resulted in significant reduction of the annual exacerbation rate, reduction (or even discontinuation) of the needed dose of OCS, and improvements of asthma control and lung function.

Prospective evAluatIon foR inhalation devices in Greek patients with COPD and asthma: The PAIR study.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) and asthma remain a major health burden. Adherence to inhaled therapy is critical in order to optimize treatment effectiveness. Properly designed questionnaires can assess patients' satisfaction with their inhaler devices. PATIENTS AND METHODS: A total of 766 patients with COPD, asthma or Asthma-COPD Overlap (ACO) were initially enrolled. During their first visit, patients were classified into three groups (Diskus™, Elpenhaler®, Turbuhaler®). Patients completed the FSI-10 questionnaire on Day 0 and Day 60. Test-retest reliability was evaluated. RESULTS: A total of 705 patients completed the study. FSI-10 questionnaire had good test-retest reliability (Total Intraclass Correlation Coefficient: 0.86). All dry powder inhaler (DPIs) yielded satisfactory results. Median score of FSI-10 questionnaire in first visit (FSI-10-I) was significantly higher for patients receiving Elpenhaler® (45, 95% CI: 44 to 46) than patients receiving Diskus™ (42, 95% CI: 41 to 43) and Turbuhaler® (42, 95% CI: 41 to 43) (p < 0.001). Accordingly, median score of FSI-10 questionnaire in the final visit (FSI-10-II) was significantly higher for patients receiving Elpenhaler® (46, 95% CI: 45 to 47) than patients receiving Diskus™ (42, 95% CI: 41 to 43) and Turbuhaler® (43, 95% CI: 42 to 44) (p < 0.001). CONCLUSION: FSI-10 questionnaire had good test-retest reliability and thus can be used in the follow-up of patients with COPD, asthma and ACO. All DPIs were highly acceptable among all study groups. Elpenhaler® achieved significantly higher ratings than Diskus™ and Turbuhaler® in FSI-10 score and presented higher preference among patients with obstructive lung diseases.

ERS/EAACI statement on severe exacerbations in asthma in adults: facts, priorities and key research questions.

Despite the use of effective medications to control asthma, severe exacerbations in asthma are still a major health risk and require urgent action on the part of the patient and physician to prevent serious outcomes such as hospitalisation or death. Moreover, severe exacerbations are associated with substantial healthcare costs and psychological burden, including anxiety and fear for patients and their families. The European Academy of Allergy and Clinical Immunology (EAACI) and the European Respiratory Society (ERS) set up a task force to search for a clear definition of severe exacerbations, and to also define research questions and priorities. The statement includes comments from patients who were members of the task force.

T2-low asthma: current approach to diagnosis and therapy.

PURPOSE OF REVIEW: Asthma is a heterogeneous disease not only on a clinical but also on a mechanistic level. For a long time, the molecular mechanisms of asthma were considered to be driven by type 2 helper T cells (Th2) and eosinophilic airway inflammation; however, extensive research has revealed that T2-low subtypes that differ from the dominant T2 paradigm are also common. RECENT FINDINGS: Research into asthma pathways has led to the recognition that some asthma phenotypes show absence of T2 inflammation or alternate between T2 and non-T2 responses. Moreover, numerous immune response modifiers that block key-molecules such as interleukin (IL)-5, IL-13, and immunoglobulin E (IgE) have been identified. Along the way, these studies pointed that T2-low inflammation may also be responsible for lack of responsiveness to current treatment regimes. SUMMARY: Asthma pathogenesis is characterized by two major endotypes, a T2-high featuring increased eosinophilic airway inflammation, and a T2-low endotype presenting with either neutrophilic or paucigranulocytic airway inflammation and showing greater resistance to steroids. This clearly presents an unmet therapeutic challenge. A precise definition and characterization of the mechanisms that drive this T2-low inflammatory response in each patient phenotype is necessary to help identify novel drug targets and design more effective and targeted treatments.

Activin-A is overexpressed in severe asthma and is implicated in angiogenic processes.

Activin-A is a pleiotropic cytokine that regulates allergic inflammation. Its role in the regulation of angiogenesis, a key feature of airways remodelling in asthma, remains unexplored. Our objective was to investigate the expression of activin-A in asthma and its effects on angiogenesis in vitro.Expression of soluble/immunoreactive activin-A and its receptors was measured in serum, bronchoalveolar lavage fluid (BALF) and endobronchial biopsies from 16 healthy controls, 19 patients with mild/moderate asthma and 22 severely asthmatic patients. In vitro effects of activin-A on baseline and vascular endothelial growth factor (VEGF)-induced human endothelial cell angiogenesis, signalling and cytokine release were compared with BALF concentrations of these cytokines in vivo.Activin-A expression was significantly elevated in serum, BALF and bronchial tissue of the asthmatics, while expression of its protein receptors was reduced. In vitro, activin-A suppressed VEGF-induced endothelial cell proliferation and angiogenesis, inducing autocrine production of anti-angiogenic soluble VEGF receptor (R)1 and interleukin (IL)-18, while reducing production of pro-angiogenic VEGFR2 and IL-17. In parallel, BALF concentrations of soluble VEGFR1 and IL-18 were significantly reduced in severe asthmatics in vivo and inversely correlated with angiogenesis.Activin-A is overexpressed and has anti-angiogenic effects in vitro that are not propagated in vivo, where reduced basal expression of its receptors is observed particularly in severe asthma.

Successful and safe treatment of severe steroid depended eosinophilic asthma with mepolizumab in a woman during pregnancy.

A 26-year-old female with steroid dependent eosinophilic asthma and nasal polyps who had successfully been treated with mepolizumab for 17 consecutive months with complete steroid withdrawal and symptoms control, stopped biologic treatment due to pregnancy efforts. Mepolizumab discontinuation resulted in frequent exacerbations and daily symptoms despite high dose ICS/LABA and re-initiation of oral steroids. Mepolizumab was initiated again, followed by improvement of asthma control and gradual withdrawal of steroids within 2 months. The patient became pregnant during the fourth month of mepolizumab re-initiation. The patient presented two asthma exacerbations during pregnancy treated with short course (3 days) oral steroids and delivery was uneventful (female, Apgar 9, weight 2750 g, length 59 cm) in week 40 by caesarean section.

COVID-19 vaccination acceptance, safety and side-effects in European patients with severe asthma.

Background: Vaccination is vital for achieving population immunity to severe acute respiratory syndrome coronavirus 2, but vaccination hesitancy presents a threat to achieving widespread immunity. Vaccine acceptance in chronic potentially immunosuppressed patients is largely unclear, especially in patients with asthma. The aim of this study was to investigate the vaccination experience in people with severe asthma. Methods: Questionnaires about vaccination beliefs (including the Vaccination Attitudes Examination (VAX) scale, a measure of vaccination hesitancy-related beliefs), vaccination side-effects, asthma control and overall safety perceptions following coronavirus disease 2019 (COVID-19) vaccination were sent to patients with severe asthma in 12 European countries between May and June 2021. Results: 660 participants returned completed questionnaires (87.4% response rate). Of these, 88% stated that they had been, or intended to be, vaccinated, 9.5% were undecided/hesitant and 3% had refused vaccination. Patients who hesitated or refused vaccination had more negative beliefs towards vaccination. Most patients reported mild (48.2%) or no side-effects (43.8%). Patients reporting severe side-effects (5.7%) had more negative beliefs. Most patients (88.8%) reported no change in asthma symptoms after vaccination, while 2.4% reported an improvement, 5.3% a slight deterioration and 1.2% a considerable deterioration. Almost all vaccinated (98%) patients would recommend vaccination to other severe asthma patients. Conclusions: Uptake of vaccination in patients with severe asthma in Europe was high, with a small minority refusing vaccination. Beliefs predicted vaccination behaviour and side-effects. Vaccination had little impact on asthma control. Our findings in people with severe asthma support the broad message that COVID-19 vaccination is safe and well tolerated.

Evaluation of real-world mepolizumab use in severe asthma across Europe: the SHARP experience with privacy-preserving federated analysis.

Background: An objective of the Severe Heterogeneous Asthma Registry, Patient-centered (SHARP) is to produce real-world evidence on a pan-European scale by linking nonstandardised, patient-level registry data. Mepolizumab has shown clinical efficacy in randomised controlled trials and prospective real-world studies and could therefore serve as a proof of principle for this novel approach. The aim of the present study was to harmonise data from 10 national severe asthma registries and characterise patients receiving mepolizumab, assess its effectiveness on annual exacerbations and maintenance oral glucocorticoid (OCS) use, and evaluate treatment patterns. Methods: In this observational cohort study, registry data (5871 patients) were extracted for harmonisation. Where harmonisation was possible, patients who initiated mepolizumab between 1 January 2016 and 31 December 2021 were examined. Changes of a 12-month (range 11-18 months) period in frequent (two or more) exacerbations, maintenance OCS use and dose were analysed in a privacy-preserving manner using meta-analysis of generalised estimating equation parameters. Periods before and during the coronavirus disease 2019 pandemic were analysed separately. Results: In 912 patients who fulfilled selection criteria, mepolizumab significantly reduced frequent exacerbations (OR 0.18, 95% CI 0.13-0.25), maintenance OCS use (OR 0.75, 95% CI 0.61-0.92) and dose (mean -3.93 mg·day-1, 95% CI -5.24-2.62 mg·day-1) in the pre-pandemic group, with similar trends in the pandemic group. Marked heterogeneity was observed between registries in patient characteristics and mepolizumab treatment patterns. Conclusions: By harmonising patient-level registry data and applying federated analysis, SHARP demonstrated the real-world effectiveness of mepolizumab on asthma exacerbations and maintenance OCS use in severe asthma patients across Europe, consistent with previous evidence. This paves the way for future pan-European real-world severe asthma studies using patient-level data in a privacy-proof manner.

Reducing Tolerance for SABA and OCS towards the Extreme Ends of Asthma Severity.

Asthma is a heterogeneous chronic inflammatory airway disease that imposes a great burden on public health worldwide. In the past two years, fundamental changes have been addressed in the Global Initiative for Asthma (GINA) recommendations focusing mainly on the management of mild and severe asthma. The use of as-needed treatment containing inhaled corticosteroids plus fast-acting bronchodilators (either short or long-acting formoterol) in mild asthma has dominated the field, and both randomized and real-world studies favor such an approach and associate it with fewer exacerbations and good asthma control. At the same time, the effort to diminish the use of oral steroids (OCS) as maintenance treatment in severe asthma was substantially accomplished with the initiation of treatment with biologics. Still, these options are available at the moment only for severe asthmatics with a T2-high endotype, and relevant studies on biologics have yielded, as a primary outcome, the reduction or even cessation of OCS. Accordingly, OCS should be considered as a temporary option, mainly for the treatment of asthma exacerbations, and as a maintenance treatment only for a minority of patients with severe asthma, after ensuring good inhaler technique, modification of all possible contributory factors and comorbidities, and optimized pharmacotherapy using all other add-on treatments including biologics in the armamentarium of anti-asthma medication.

Greek Guidelines for the Management of COPD, a Proposal of a Holistic Approach Based on the needs of the Greek Community.

Despite that COPD remains one of the most common respiratory diseases worldwide, it can be managed effectively with certain treatments and, more importantly, be prevented by the early implementation of various measures. The pathology and pathophysiology of this disease continue to be studied, with new pharmacological and invasive therapies emerging. In this consensus paper, the Working Group of the Hellenic Thoracic Society aimed to consolidate the up-to-date information and new advances in the treatment of COPD. Local and international data on its prevalence are presented, with revised strategies on the diagnostic approach and the evaluation of risk assessment and disease severity classification. Emphasis is placed on the management and therapy of patients with COPD, covering both common principles, specialized modalities, and algorithms to distinguish between home care and the need for hospitalization. Although pharmacological treatment is commonly recognized in COPD, an integrative approach of pulmonary rehabilitation, physical activity, patient education, and self-assessment should be encountered for a comprehensive treatment, prevention of exacerbations, and increased quality of life in patients.

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.

Heterogeneity in the use of biologics for severe asthma in Europe: a SHARP ERS study.

Introduction: Treatment with biologics for severe asthma is informed by international and national guidelines and defined by national regulating bodies, but how these drugs are used in real-life is unknown. Materials and methods: The European Respiratory Society (ERS) SHARP Clinical Research Collaboration conducted a three-step survey collecting information on asthma biologics use in Europe. Five geographically distant countries defined the survey questions, focusing on seven end-points: biologics availability and financial issues, prescription and administration modalities, inclusion criteria, continuation criteria, switching biologics, combining biologics and evaluation of corticosteroid toxicity. The survey was then sent to SHARP National Leads of 28 European countries. Finally, selected questions were submitted to a broad group of 263 asthma experts identified by national societies. Results: Availability of biologics varied between countries, with 17 out of 28 countries having all five existing biologics. Authorised prescribers (pulmonologists and other specialists) also differed. In-hospital administration was the preferred deliverance modality. While exacerbation rate was used as an inclusion criterion in all countries, forced expiratory volume in 1 s was used in 46%. Blood eosinophils were an inclusion criterion in all countries for interleukin-5 (IL-5)-targeted and IL-4/IL-13-targeted biologics, with varying thresholds. There were no formally established criteria for continuing biologics. Reduction in exacerbations represented the most important benchmark, followed by improvement in asthma control and quality of life. Only 73% (191 out of 263) of surveyed clinicians assessed their patients for corticosteroid-induced toxicity. Conclusion: Our study reveals important heterogeneity in the use of asthma biologics across Europe. To what extent this impacts on clinical outcomes relevant to patients and healthcare services needs further investigation.