ERJ Open Research最新文献

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe complication of acute pulmonary embolism (PE) in which delayed diagnosis significantly affects patient health outcomes. This case-control study aimed to identify a set of microRNAs (miRNAs) in plasma with diagnostic potential to differentiate patients with CTEPH from those with PE.

Methods: Two groups were analysed: 22 patients with confirmed CTEPH and 13 patients with PE, followed by validation in an independent cohort of 48 CTEPH and 37 PE patients.

Results: Using real-time PCR, eight miRNAs were identified as significantly different between the groups: miR-574-3p, miR-146b-5p, miR-193a-5p, miR-885-5p, miR-122-5p, miR-365a-3p, miR-142-3p and miR-192-5p. These miRNAs target key biological pathways, including vascular smooth muscle contraction, apoptosis and VEGF signalling, underlying the pathophysiology of CTEPH. The miRNA panel demonstrated strong diagnostic accuracy with an area under the curve of 0.843 in the validation cohort.

Conclusions: The results highlight the potential of miRNA biomarkers as a diagnostic tool for early detection of CTEPH, representing a paradigm shift in its management, but further validation in larger cohorts is necessary to confirm their applicability. These insights could pave the way for improved clinical outcomes through timely diagnosis and targeted interventions.

Background: Social determinants of health (SDH) influence COPD prevalence, progression and treatment, yet their inclusion in clinical trials is poorly understood. This study examined recruitment strategies for diverse populations in COPD trials of long-acting muscarinic antagonists (LAMA) and/or long-acting β-agonists (LABA), with or without additional therapy including inhaled corticosteroids (ICS), and assessed SDH reporting in primary trial documents and publications.

Methods: Four clinical trials databases (CENTRAL, ClinicalTrials.gov, ISRCTN and ANZCTR) were searched to identify LAMA and/or LABA clinical trials with or without ICS in adults with COPD registered between 1 January 2000 and 8 May 2023. Extracted data included study locations, recruitment strategies, study outcomes, eligibility criteria, participant demographics and subgroup analyses.

Results: 1822 records were identified, with 491 primary trials included. Of these, 407 trials (256 271 participants) had results available and 341 trials had associated publications. 439 trials (89.4%) were completed. Age (n=387 (95.1%)) and sex (n=386 (94.8%)) were well reported, with a male preponderance (n=176 285 (68.8%)). Inclusion of women improved from 22.6% (2006) to 46.5% (2020). Ethnicity was reported in 209 (51.4%)) trials, with over-representation of White individuals (n=130 086 (83.2%)) and no change over time. Only one trial reported socioeconomic status or occupation; none reported education or rurality. Most trials (97.5%) were conducted in high- or upper-middle-income countries.

Conclusions: SDH, other than age and sex, were under-reported in LABA/LAMA COPD trials, and when reported, demonstrated a long-standing lack of diversity. Extrapolating efficacy from narrow populations may risk suboptimal care for diverse groups. Future trials must include and report on diverse populations to demonstrate safety and efficacy for all people in all contexts.

Background: Endothelin-1 (ET-1) is a proinflammatory mediator that plays a crucial role in regulating airway tone by activating G protein-coupled endothelin receptors A (ET_A) and B (ET_B). The endothelin system has been linked to asthma, but the impact of ET_B receptor deficiency on allergic airway inflammation remains uncharted. This study explores how the endothelin system influences allergic airway inflammation and hyperresponsiveness.

Methods: We used rescued ET_B receptor-deficient (ET_B ^-/-) mice to obviate lethal inherited Hirschsprung disease, prepro-ET-1 overexpressing (_preET^tg), and wild-type (WT) mice. Basal airway resistance and responsiveness to broncho-constrictive stimuli were assessed in isolated, perfused and ventilated lungs of naïve mice. Additionally, we analysed the humoral immune response and airway hyperresponsiveness following induction of type 2 airway inflammation induced by systemic ovalbumin (OVA) sensitisation and repeated airway challenge with aerosolised OVA.

Results: Naïve ET_B ^-/- mice exhibited significantly heightened airway responsiveness compared to naïve WT mice. After OVA sensitisation and challenge, ET_B ^-/- mice displayed increased OVA-specific immunoglobulin E levels, intensified allergic airway inflammation and hyperresponsiveness compared to WT mice. Conversely, _preET^tg mice displayed reduced immunoglobulin E levels, airway inflammation and hyperresponsiveness.

Conclusion: Our findings suggest ET_B receptors have a protective role in asthma-associated allergic airway inflammation and hyperresponsiveness. The increased asthma phenotype in sensitised and challenged ET_B ^-/- mice is attributed to ET_B-specific immunomodulatory mechanisms, rather than to elevated levels of ET-1 resulting from impaired ET_B-mediated ET-1 clearance. This conclusion is supported by the diminished asthma-phenotype observed in sensitised and challenged _preET^tg mice. Therefore, adjusting endothelin signalling could offer a promising approach to managing asthma.

Background: The role of lipid profiles in the pathogenesis of nontuberculous mycobacterial pulmonary disease (NTM-PD) remains largely unexplored. This study aimed to identify lipid profile variations across geospatial lung lesions, their reflection in serum relative to disease severity and their diagnostic discriminative ability using lipidomic analysis.

Methods: Lipidomics was performed using hydrophilic interaction liquid chromatography-tandem mass spectrometry on lung tissues and serum samples. 960 lipid species were analysed across geospatial lung lesions (cavity wall, centre of cavity, granuloma, bronchiectasis and normal lungs) and assessed in serum according to disease severity. Python-based machine-learning models in PyCaret were used to classify NTM-PD based on lipidomic signatures.

Results: This study included 23 lung specimens from seven patients with NTM-PD and 332 serum samples comprising 134 patients with NTM-PD, 136 with non-NTM bronchiectasis and 62 healthy controls. Triacylglycerol (TG) levels were elevated in lung lesions affected by NTM-PD, particularly in the centre of the cavity. In serum, TG levels were higher in patients with NTM-PD than controls but decreased in patients with more severe disease, including those with acid-fast bacilli smear positivity, cavitation or higher BACES (body mass index, age, cavity, erythrocyte sedimentation rate and sex) scores. The top five models, developed using lipid species characteristically altered in NTM-PD, effectively discriminated patients with NTM-PD from healthy controls.

Conclusion: TG levels were elevated in lung lesions affected by NTM-PD but decreased in serum as disease severity increased, suggesting TG accumulation in lung tissues. These findings highlighted the role of lipid metabolism in the pathogenesis of NTM-PD.

Background: Physical activity (PA) is a multidimensional behaviour influenced by various factors and is lower in youth with cystic fibrosis (YwCF). While regular PA is known to have a positive effect on health, research on its influencing factors is limited and inconsistent. Therefore, we aimed to explore the influencing factors of YwCF by applying the socioecological model (SEM), a comprehensive framework accounting for these influences.

Methods: YwCF between 6 and 17 years were recruited. PA was measured over 7 consecutive days with an ActiGraph GT3X-BT, and total PA and time in at least moderate-to-vigorous intensity PA (MVPA) were chosen as primary outcomes. Regression analyses were executed to test the association between influencing factors across the different levels of the SEM (i.e. intrapersonal, interpersonal, organisational and community) and PA outcomes (total PA and MPVA).

Results: This cross-sectional study included 49 YwCF (57% female; 11.3±3.3 years). For total PA, significant bivariable associations were found on all levels of the SEM: intrapersonal (age, waist circumference, functional performance, quality of life, attitudes towards PA, screen time), interpersonal (social support), organisational (participation in organised sports) and community (season). Based on the multivariable models, the sociodemographic factor age accounts for the highest variance in total PA (adjR²=42%), followed by the biological factors waist circumference and functional performance (adjR²=37%). Results for MVPA were comparable.

Conclusion: Our findings underscore the multifaceted nature of PA behaviour in YwCF and highlight the need for future PA interventions to recognise these multiple levels of influence.

Background: Mutations in telomere-related genes (TRGs) are the main cause of monogenic familial pulmonary fibrosis. Dyskerin, encoded by the X-localised gene DKC1, is involved in telomere maintenance.

Methods: This retrospective study aimed to further characterise the pulmonary phenotype of DKC1-deficient patients with pulmonary fibrosis identified between 2010 and 2025 in our laboratory.

Results: We reported eight, as yet undescribed, to our knowledge, probands affected by pulmonary fibrosis associated with X-linked DKC1 deficiency. The median age at interstitial lung disease (ILD) diagnosis was 47 years. Four had idiopathic pulmonary fibrosis, two unclassifiable fibrosis, one idiopathic nonspecific interstitial pneumonia and one unknown. All patients displayed ectodermal abnormalities (premature hair greying, nail dystrophies, reticulated hyper- or hypopigmentation, tooth abnormalities and oral leukoplasia). Haematological abnormalities were found in four patients. Seven patients died during follow-up and one patient received a transplant. Median survival after ILD diagnosis was 22 months (range 3-81 months).

Conclusions: Compared with patients with pulmonary fibrosis associated with other TRG variants, those with pulmonary fibrosis associated with X-linked recessive DKC1 variants are younger and have a shorter survival time. Early identification and referral of these patients to an expert transplantation centre should be considered.

Primary ciliary dyskinesia (PCD) is a genetically and clinically diverse disorder characterised by loss of normal ciliary function leading to chronic oto-sino pulmonary disease, situs abnormalities and subfertility in men and women. There is limited evidence to support robust guidelines on the management of children and adults with PCD; however, there is a clear clinical need to establish a framework of care for the follow-up of these patients. The European Respiratory Society (ERS) has published consensus statements on diagnostic and treatment approaches in children with PCD, and the BEAT-PCD (Better Experimental Approaches to Treat PCD) network provides guidance on infection prevention and control. This is a national consensus statement to outline a set of standards for the provision of specialist care for children and adults with PCD living in England. A national PCD expert panel made up of specialists working in both paediatric and adult UK highly specialist management services, was established to create a consensus statement on the minimum standards of care for PCD. Using a modified Delphi process, consensus to a statement required at least 80% agreement within the PCD expert panel group. Patient organisation representatives were involved in reviewing the statement and have produced an accompanying layperson summary. We present a consensus statement on 15 standards covering provision of pulmonary, ear, nose and throat, and fertility care, screening for situs abnormalities and transition from paediatric to adult care services. It is targeted at clinicians and allied health professionals managing paediatric and adult patients with PCD, patient organisations and patients and their families.

The application of machine learning in patients with community-acquired pneumonia allows the identification of high-risk phenotypes for post-acute mortality, improving the limitations of classical severity scores and personalised patient management https://bit.ly/3IT4MOO.

Background: Primary ciliary dyskinesia (PCD) is a rare disease caused by mutations in >50 genes that impair the function of motile cilia. The clinical phenotype is heterogeneous and recent studies have begun to investigate genotype-phenotype relationships to better understand disease pathogenesis and develop improved treatments. The major cause of morbidity and mortality among individuals with PCD is the lack of mucociliary clearance (MCC) that results in chronic respiratory infections and leads to bronchiectasis. Here we examine the relationship between MCC and genotype in two groups of PCD individuals; one with mutations in a gene (DNAH5) that causes PCD with mostly immotile cilia and one with mutations in a gene (RSPH1) that cause PCD with cilia that beat with a near-normal frequency, but an abnormal, sometimes circular waveform.

Methods: Patients with known pathogenic variants in DNAH5 (n=8) or RSPH1 (n=7), along with healthy controls (n=8), were assessed for clearance of an inhaled radioactive tracer by mucociliary and cough clearance as measured by gamma scintigraphy.

Results: Neither DNAH5 nor RSPH1 subjects showed clear evidence of MCC under either baseline or albuterol stimulated conditions. Unexpectedly, subjects with RSPH1 mutations demonstrated cough clearance (median 9.7%, IQR 6.2-17%) that was significantly higher than subjects with DNAH5 mutations (4.2% (0.94-5.1%); p=0.015) and was not significantly different from healthy control subjects (8.3% (4.2-16%); p=0.88).

Conclusions: The results confirm impaired MCC in people with PCD of both genotypes. However, in this small cohort, the results suggest cough clearance may differ between these two genotypes.

Introduction: Idiopathic pulmonary fibrosis (IPF) has high morbidity and mortality with limited treatment options. Goal-oriented management approaches, such as the "treatable traits" concept, have yet to be implemented in IPF. This study aims to identify specific treatment goals in IPF for potential interventions by analysing outcomes from two national registries.

Methods: We used data from the INSIGHTS-IPF registry, comprising 1232 IPF patients, enrolled from 2014 to 2020 as derivation cohort. Baseline and 6-month follow-up data were examined to assess clinical progression and predict 1-year mortality. Variables included forced vital capacity (FVC), diffusing capacity of the lung for carbon monoxide (D _LCO), 6-min walk distance (6MWD), body mass index (BMI) and comorbidities. For validation we used data from 490 IPF patients enrolled in the Canadian Registry for Pulmonary Fibrosis (CARE-PF) and the full 2576 fibrotic interstitial lung disease (ILD) cohort of the CARE-PF registry.

Results: Multivariable analysis identified FVC, D _LCO, 6MWD and BMI as independent predictors of 1-year survival. We established three risk groups based on these variables: low risk (<15% 1-year mortality), intermediate risk (15-30%) and high risk (>30%). Potential treatment goals were defined based on FVC, D _LCO, 6MWD and BMI, which are readily available and may be responsive to interventions. Our risk model showed equivalent accuracy in the validation cohort, both for IPF alone and the overall population.

Conclusion: This study provides a novel risk model for IPF patients, which may also apply to a broader spectrum of fibrotic ILD. It is based on potentially actionable variables which deserve further evaluation as measurable treatment goals in interventional clinical trials.