BACKGROUND:The association between immune-cell-specific transcriptomic profiles and mortality in idiopathic pulmonary fibrosis (IPF) is unknown. METHODS:We profiled peripheral blood mononuclear cells by single-cell RNA sequencing (scRNA-seq) and investigated which immune-cell-specific transcriptomic profile predicted IPF outcomes consistently. Prognostic accuracy was investigated in peripheral blood mononuclear cells (PBMCs), bronchoalveolar lavage (BAL) and lung tissue. Findings were validated by flow cytometry, analysis of independent scRNA-seq datasets and cellular deconvolution. We investigated the function of this transcriptomic profile and its cellular source in lung tissue (overall sample size, n=1054; IPF, n=555; other, n=499). Connectivity map analysis and LASSO regression were used to identify drug candidates and a subset of genes with prognostic potential, respectively. RESULTS:A 230-gene up-score (Pittsburgh PBMC cohort) from CD14+CD163-HLA-DRlow monocytes predicted mortality in the Chicago PBMC cohort (HR 6.58, 95% CI 2.15-20.13; p=0.001), in BAL pooled analysis (HR 2.20, 95% CI 1.44-3.37; p=0.0003), and negatively correlated with forced vital capacity in lung tissues (ρ= -0.2, p=0.02). Proportions of CD14+CD163-HLA-DRlow monocytes were higher in progressive versus stable IPF (12.59%, 95% CI 9.66-16.23%, versus 7.61%, 95% CI 6.68-10.21%; p=0.014). High-risk patients with IPF had decreased expression of T-cell co-stimulatory genes (Pittsburgh and Chicago, p<0.01). CD14+HLA-DRlow monocytes had higher expression of profibrotic, proangiogenic and chemotactic factors compared to CD14+HLA-DRhi monocytes (p<0.05). The 230-gene up-score correlated with the secreted phosphoprotein 1 (SPP1)+ fibrosis-associated macrophages gene-score in lung tissues (ρ=0.19, p<2.2e-16). Connectivity map analysis identified drug categories to reverse the 230-gene signature. A subset of six genes retained predictive performance (pooled PBMC cohorts HR 4.79, 95% CI 2.58-8.92; p<0.0001). CONCLUSIONS:The transcriptome of CD14+CD163-HLA-DRlow monocytes is associated with increased mortality in patients with IPF. Its reversal should be investigated as a precision-based therapy in IPF.

Objectives:This study aimed to provide real-world data on the clinical presentation and management of long COVID in Greece. Methods:This non-interventional, nationwide, multicenter, cross-sectional study included adults with a history of symptomatic SARS-CoV-2 infection who presented with suspected long-term COVID-19 manifestations ≥4 weeks after acute infection. Results:Among 1011 patients (mean ± SD age: 55.95 ± 15.74 years; 56.18% female; 5.04% hospitalized) enrolled between December 2022 and May 2023, the most affected Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) was General disorders and administration site conditions (75.67%), with fatigue/malaise as the predominant symptom (69.93%). This was followed by Respiratory, thoracic, and mediastinal disorders (60.34%), with cough (50.64%) and dyspnea (24.83%) as leading symptoms. Social circumstances, specifically impairments in daily living activities (44.21%), Nervous system disorders (40.26%), mainly headache (23.24%), and Musculoskeletal and connective tissue disorders (27.70%), mainly myalgia (24.63%), were also prominent. The majority (74.38%) had been vaccinated prior to infection, with vaccination shown to be protective against nervous and musculoskeletal symptoms. Females were more prone to systemic, psychiatric, nervous, and musculoskeletal symptoms and impairments in daily activities, but less prone to respiratory symptoms. Conclusions:Multisystem long-term COVID-19 complications were observed, underscoring the importance of multidisciplinary management of this complex, multifaceted condition.

Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) are characterised by an irreversible progression of pulmonary fibrosis and functional lung decline. Current antifibrotic therapies (nintedanib and pirfenidone for IPF and nintedanib for PPF) can reduce disease progression but not halt or reverse it. PPF and IPF share common pathophysiological pathways that need to be further elucidated for the development of novel therapeutic strategies. The educational aim of this review is to explain the pathogenic pathways that have led to the discovery of new therapeutic agents and their favourable implementation in phase 2 and 3 studies. This includes phosphodiesterase 4 inhibitors, αvβ6 and αvβ1 integrin inhibitors, lymphosphatidic acid antagonists, inhaled treprostinil, hedgehog inhibitors, tyrosine kinase inhibitors and angiotensin type 2 receptor agonists. The aim is also to better understand current therapeutic challenges and future perspectives, including cellular therapies, exosomes and their cargoes, as well as the integration of transcriptomics and proteomics, plus gene therapy.

Rationale: Deupirfenidone (DPF) is a deuterated form of pirfenidone with a differentiated pharmacokinetic profile that enables higher plasma exposure, potentially allowing for improved efficacy and tolerability in individuals with idiopathic pulmonary fibrosis (IPF). Methods: Phase 2b, international, multi-center, randomized, double-blind, active- and placebo-comparator trial investigated the safety, tolerability, and efficacy of DPF 550 mg TID and DPF 825 mg TID compared to placebo and pirfenidone 801 mg TID (PFD). The primary endpoint was the rate of change in forced vital capacity (FVC) over 26 weeks and the key secondary endpoint was the rate of change in FVC percent predicted (FVCpp) over 26 weeks. Additional endpoints included time to disease progression and safety. The primary statistical analyses compared absolute FVC (mL) and FVCpp between the combined arms of DPF and the placebo arm using a Bayesian approach. Secondary statistical analyses used a frequentist approach. Both utilized a mixed model for repeated measures (MMRM), treating time as a continuous variable. Results: 257 patients were enrolled from 14 countries; median age: 72.0; 71.2% male; median baseline FVC (n= 254): 2580.0 mL; and FVCpp: 77.5%. Double-blinded study treatment completion was 80.0%, 68.3%, 64.6%, and 78.1% for placebo, PFD, DPF 550 mg, and DPF 825 mg arms, respectively. Using Bayesian analysis, the posterior probability that the pooled DPF arms had less decline compared to placebo in FVC (mL) was 98.5% and in FVCpp was 99.6%. Using a frequentist analysis, the change from baseline in FVC (mL) and FVCpp over 26 weeks is shown in the Figure. Treatment-emergent adverse events commonly associated with antifibrotics (%) were nausea (7.7, 27.0, 16.9, 20.3), dyspepsia (3.1, 22.2, 12.3, 14.1), diarrhea (9.2, 11.1, 10.8, 7.8), abdominal pain (4.6, 7.9, 6.2, 14.1), photosensitivity reaction (0, 7.9, 6.2, 7.8), decreased appetite (7.7, 14.3, 18.5, 20.3), fatigue (1.5, 11.1, 7.7, 9.4), dizziness (3.1, 7.9, 9.2, 12.5), and headache (4.6, 12.7, 7.7, 3.1) for placebo, PFD, DPF 550 mg, and DPF 825 mg arms, respectively. Conclusions: Deupirfenidone met both FVC and FVCpp endpoints in the primary Bayesian approach and a dose response between 550 mg and 825 mg was demonstrated. DPF 825 mg also met both endpoints, demonstrated statistical significance by a frequentist approach, and had an FVC decline that approached the level seen with the normal aging process. Deupirfenidone was well tolerated at both doses and safety was consistent with previous studies. These data support continued development of deupirfenidone in patients with IPF.

INTRODUCTION Severe asthma (SA) is a complex, heterogeneous disease. This survey aimed to understand SA patients' healthcare management in Greece and their perception of symptoms and well-being, and evaluate the impact of biological therapy on patients' quality of life (QoL). METHODS A quantitative cross-sectional descriptive survey was conducted from June 2021 to April 2023. The final sample consisted of 221 SA patients, based on questionnaires either provided by the healthcare professional in hardcopy or completed online. Patient-reported outcomes were how they feel or function in relation to their disease and treatment (based on Likert scales from 1 to 5). RESULTS Approximately 40% of patients expressed either neutral or poor/very poor QoL. The ability for intense physical activity was negatively influenced for all SA patient segments, yet to a lesser degree for patients receiving biological treatment (49% vs 69%, p=0.0029). A greater percentage of patients on biologic treatment compared to those not on biologic treatment reported no influence of SA on their mental health (44% vs 21%, p=0.0003) and no stress considering the possibility of exacerbations (46% vs 23%, p=0.0004). Cough/phlegm were the most frequent symptoms reported by 35% of SA patients followed by dyspnea/shortness of breath. Patients receiving biological treatment reported a significantly lower frequency of symptoms compared to patients not on biological treatment, indicating therapy effectiveness, particularly in dyspnea (26% vs 30%, p<0.0001) and cough (28% vs 41%, p<0.0001). Reduction of exacerbations (91%) followed by discontinuation of systemic corticosteroids use (83%) was the most important consideration for SA patients in assessing control of their asthma. CONCLUSIONS Severe asthma is associated with a significant health-related QoL burden due to excessive symptoms. We have shown that SA patients on biological treatment exhibit better HRQoL and fewer symptoms, compared to those not on biological treatment.

Abstract Background Data on type 2 (T2)‐low severe asthma (SA) frequency is scarce, resulting in an undefined unmet therapeutic need in this patient population. Our objective was to assess the frequency and characterize the profile and burden of T2‐low SA in Greece. Methods PHOLLOW was a cross‐sectional study of adult SA patients. Based on a novel proposed classification system, patients were classified as T2‐low if blood eosinophil count (BEC; cells/μL) was <150, fractional exhaled nitric oxide (FeNO) < 25 ppb and any allergy status or BEC < 150/FeNO < 50 ppb/no allergy or BEC < 300/FeNO < 25 ppb/no allergy. For patients receiving biologics and/or oral corticosteroids, only those with BEC < 150/FeNO < 25 ppb/no allergy/no response to therapy were classified as T2‐low. Secondary outcome measures were: Asthma Control Test (ACTTM), Mini‐Asthma Quality of Life Questionnaire (Mini‐AQLQ), hospital anxiety and depression scale (HADS), and Work Productivity and Activity Impairment:Respiratory Symptoms (WPAI:RS) questionnaire. Results From 22‐Mar‐2022 to 15‐Mar‐2023, 602 eligible SA patients were enrolled. The frequency of T2‐low asthma was 20.1%. Of those, 71.1% had experienced ≥1 clinically significant exacerbations in the past year, 62.8% had ACT score <20 (uncontrolled asthma), and 22.3% were biologic‐treated. Mini‐AQLQ score was <6 (impairment) in 79.5% of patients, HADS‐total score was ≥15 (clinically significant emotional distress) in 43.8%, while median percent activity impairment and work productivity loss were 30.0 for both domains. Clinical and patient‐reported outcomes were worse among patients with ACT‐defined uncontrolled asthma. Conclusions One‐fifth of SA patients present with a T2‐low endotype. These patients frequently have uncontrolled disease and experience impairments in their quality of life, emotions and work ability.

Several interstitial lung diseases (ILDs) with different aetiologies and pathogenic mechanisms may exhibit a progressive behaviour, similar to idiopathic pulmonary fibrosis, with comparable functional decline and early mortality. Progressive pulmonary fibrosis (PPF) is not a diagnosis but rather reflects a clinical phenotype. Identifying progression is challenging as variability exists, both between different ILDs as well as in the context of the same entity. The American Thoracic Society/European Respiratory Society guidelines provide a useful framework for recognising the progressive behaviour of individual ILDs. Nevertheless, sometimes the "one-size-fits-all" approach to PPF may not lead to the best management decisions for individual patients. Real-life clinical practice presents multiple hurdles for practising clinicians and it is of utmost importance to target early those individuals that will benefit from antifibrotic treatment. This review aims to highlight several clinical points and suggest that, in certain cases, the strict rule of initiating antifibrotic treatment only upon disease progression may warrant some flexibility, particularly in the context of everyday clinical practice. Emphasis is placed on critically examining the criteria used to define progression across different ILDs, commenting on clinical issues such as disease severity at baseline, prevention of acute exacerbations, the definition of "standard treatment", the need for early access to appropriate treatment, prediction of progression, personalised medicine and an aetiologic approach. Engaging technology and artificial intelligence will play a role in the future. Until then, the best possible management decisions will rely on the judgment of treating clinicians, guided by existing evidence and patient needs.

Fibrotic diseases of the skin and lung, such as systemic sclerosis, hypertrophic scars, keloids, and pulmonary fibrosis, share core molecular mechanisms despite their distinct anatomical settings. Central to their pathogenesis are persistent fibroblast activation, immune dysregulation, ECM remodeling, and failure of resolution pathways, all modulated by an ever-changing environment and epigenetic regulation. Increasing evidence reveals that chronic injury from air pollution, ultraviolet radiation, climate stressors, and occupational hazards accelerates fibroinflammatory remodeling across these barrier organs. Moreover, shared signaling networks, including TGF-β, IL-4/IL-13, Wnt/β-catenin, and epigenetic regulators like miR-21 and miR-29, suggest convergent fibrotic programs may be subject to cross-organ therapeutic targeting. This review integrates recent insights into the exposome’s role in driving fibrosis, highlights novel RNA- and epigenetic-based interventions, and evaluates the repurposing of antifibrotic agents approved for pulmonary disease within dermatologic contexts. We emphasize the emerging concept of fibrosis-aware precision medicine and propose a unifying framework to guide integrated therapeutic strategies. In the face of global climate change and rising environmental insults, a cross-organ perspective on fibrosis offers a timely and translationally relevant approach to addressing this growing burden on human health.

We aimed to study transcriptional and phenotypic changes in circulating immune cells associated with increased risk of mortality in COVID-19, resolution of pulmonary fibrosis in post-COVID-19-interstitial lung disease (ILD), and persistence of idiopathic pulmonary fibrosis (IPF). Whole blood and peripheral blood mononuclear cells (PBMCs) were obtained from 227 subjects with COVID-19, post-COVID-19 interstitial lung disease (ILD), IPF, and controls. We measured a 50-gene signature (nCounter, Nanostring) previously found to be predictive of IPF and COVID-19 mortality along with plasma levels of several biomarkers by Luminex. In addition, we performed single-cell RNA sequencing (scRNA-seq) in PBMCs (10x Genomics) to determine the cellular source of the 50-gene signature. We identified the presence of three genomic risk profiles in COVID-19 based on the 50-gene signature associated with low-, intermediate-, or high-risk of mortality and with significant differences in proinflammatory and profibrotic cytokines. Patients with COVID-19 in the high-risk group had increased expression of seven genes in CD14(+)HLA-DR(low)CD163(+) monocytic-myeloid-derived suppressive cells (7Gene-M-MDSCs) and decreased expression of 43 genes in CD4 and CD8 T cell subsets. The loss of 7Gene-M-MDSCs and increased expression of these 43 genes in T cells was seen in survivors with post-COVID-19-ILD. On the contrary, patients with IPF had low expression of the 43 genes in CD4 and CD8 T cells. Collectively, we showed that a 50-gene, high-risk profile, predictive of IPF and COVID-19 mortality is characterized by a genomic imbalance in monocyte and T-cell subsets. This imbalance reverses in survivors with post-COVID-19-ILD highlighting genomic differences between post-COVID-19-ILD and IPF. NEW & NOTEWORTHY Changes in the 50-gene signature, reflective of increase in CD14(+)HLA-DR(low)CD163(+) monocytes and decrease in CD4 and CD8 T cells, are associated with increased mortality in COVID-19. A reversal of this pattern can be seen in post-COVID-19-ILD, whereas its persistence can be seen in IPF. Modulating the imbalance between HLA-DRlow monocytes and T cell subsets should be investigated as a potential strategy to treat pulmonary fibrosis associated with severe COVID-19 and progressive IPF.

Background: Obstructive sleep apnea (OSA) is a common disorder associated with major cardiovascular and neurocognitive sequelae. Continuous positive airway pressure (CPAP) is the standard treatment for OSA. The aim of this study was to investigate the prevalence and associations of long-term CPAP adherence in newly diagnosed OSA patients. Methods: We enrolled patients who were diagnosed with OSA during the COVID-19 pandemic. Adherence was defined as CPAP use ≥4 h per night on ≥70% of nights over 30 consecutive days. Patient demographics were retrieved from medical records, and CPAP adherence at 6 months and 1 year after initiation was monitored. Results: Overall, 107 patients were included in the analysis. A number of 73 (68%) and 63 (59%) patients were adherent to CPAP treatment at 6 months and 12 months accordingly. Among the factors examined and analyzed (age, gender, BMI, Apnea–Hypopnea Index (AHI)), no significant correlation was found. Further analysis revealed the potential role of comorbidities. CPAP compliance at 6 months was shown to be associated with better CPAP adherence at 12 months. Conclusions: CPAP adherence at 6 months is correlated to long-term adherence to treatment. Therefore, early close follow-up is important. Further prospective studies are needed to identify other potential predictors.

1. Rajan SK, Cottin V, Dhar R, et al. Progressive pulmonary fibrosis: an expert group consensus statement. Eur Respir J. 2023;61(3):2103187. doi:10.1183/13993003.03187-2021 CrossRef Google Scholar

Rationale:The association between immune-cell-specific transcriptomic profiles and Idiopathic Pulmonary Fibrosis (IPF) mortality is unknown. Objectives:To determine immune-cell-specific transcriptomic profiles associated with IPF mortality. Methods:We profiled peripheral blood mononuclear cells (PBMC) in 18 participants [University of South Florida: IPF, COVID-19, post-COVID-19 Interstitial Lung Disease (Post-COVID-19 ILD), controls] by single-cell RNA sequencing (scRNA-seq) and identified 16 immune-cell-specific transcriptomic profiles. The Scoring Algorithm of Molecular Subphenotypes (SAMS) was used to calculate Up-scores based on these 16 gene profiles. Their association with outcomes was investigated in peripheral blood, Bronchoalveolar Lavage (BAL) and lung tissue of N=416 IPF patients from six cohorts. Findings were validated in an independent IPF, PBMC scRNA-seq dataset (N=38). Measurements and main results:Cox-regression models demonstrated that 230 genes from CD14 + CD163 - HLA-DR low circulating monocytes predicted IPF mortality [Pittsburgh (p=0.02), Chicago (p=0.003)]. PBMC proportions of CD14 + CD163 - HLA-DR low monocytes were higher in progressive versus stable IPF (Yale, 0.13±0.05 versus 0.09±0.05, p=0.034). Receiving operating characteristic identified a 230 gene, Up-score >41.84 (Pittsburgh) predictive of mortality in Chicago (HR: 6.58, 95%CI: 2.15-20.13, p=0.001) and in pooled analysis of BAL cohorts (HR: 2.20, 95%CI: 1.44-3.37, p=0.0003). High-risk patients had decreased expression of the T-cell co-stimulatory genes CD28 , ICOS , ITK and LCK (Pittsburgh and Chicago, p<0.01). 230 gene-up-scores negatively correlated with Forced Vital Capacity (FVC) in IPF lung tissues (LGRC, rho=-0.2, p=0.02). Results were replicated using a subset of 13 genes from the 230-gene signature (pooled PBMC cohorts - HR: 5.34, 95%CI: 2.83-10.06, p<0.0001). Conclusions:The transcriptome of CD14 + CD163 - HLA-DR low monocytes is associated with increased IPF mortality.

Background There is limited data on the reasons for escalation or de-escalation of COPD inhaled therapies in routine clinical practice, especially after the follow-up pharmacological treatment guidance on the 2019 GOLD report and the 2020 ERS guideline on ICS withdrawal.Methods The STEPINCOPD study was a 12-week, two-visit, prospective observational study that aimed to describe the reasons for change of inhaled therapies, in accordance with GOLD recommendations 2021. Only patients that had a recent change in their inhaled medication were enrolled. Moreover, we investigated associations between physicians’ and patients’ characteristics and adherence to GOLD recommendations.Results 1429 patients were enrolled from 146 centers (138 private practice and 8 hospitals) throughout Greece. At enrollment, the most frequent reasons for treatment change were lack of clinical (78.9%) or spirometric (49.5%) response to previous treatment, change in CAT score (45.1%), and mMRC score (28.2%). At the follow-up visit, most common reasons were lack of clinical response to previous treatment (71.4%), COPD exacerbations (59.5%), changes in CAT score (52.4%), lack of spirometric response (42.9%) and lower respiratory tract infections (31%). We observed high adherence to the GOLD 2021 recommendations (81.6% at enrollment and 92.9% at follow-up). Physicians’ age and consideration of GOLD recommendations for prescription choice, as well as patients’ CAT score were significant predictors of adherence to GOLD.Conclusion The STEPINCOPD study highlights the reasons for inhaled treatment change in Greek physicians with high adherence to GOLD recommendations and provides insights for future research that may inform the development of decision support tools.