European Respiratory Journal最新文献

Background: Lung structure and cardiac structure and function are associated cross-sectionally. The classic literature suggests relationships of airways disease to cor pulmonale and emphysema to reduced cardiac output (CO) but longitudinal data are lacking.

Methods: The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease (COPD) Study was a multi-center longitudinal COPD case-control study of participants 50-79 years with ≥10 pack-years smoking without clinical cardiovascular disease. Segmental airway wall area (WA) and percent emphysema were measured on computed tomography. Right and left ventricle (RV, LV) parameters were assessed on magnetic resonance imaging (MRI) in exams six years apart. Longitudinal and period cross-sectional associations were evaluated with mixed models adjusted for demographics, body size, and smoking.

Results: The 187 participants with repeated MRI were 67±7 years old; 42% had COPD; 22% currently smoked; and the race/ethnicity distribution was 54% white, 30% Black, 14% Hispanic, and 3% Asian. Greater WA at enrollment was associated with longitudinal increase in RV mass (3.5 g per 10mm² WA, 95% CI: 1.1, 5.9). Greater percent emphysema was associated with stably lower LV end diastolic volume (-7.8 mL per 5% emphysema, 95% CI: -10.3, -3.0) and CO (-0.2 L·min^-1 per 5% emphysema, 95% CI: -0.4, -0.1).

Conclusion: Cardiac associations varied by lung structure over six years in this multi-ethnic study. Greater WA at enrollment was associated with longitudinal increases in RV mass; whereas greater percent emphysema was associated with stable decrements in LV filling and CO.

Background: House dust mite is the most frequent trigger of allergic asthma, with innate and adaptive immune mechanisms playing critical roles in outcomes. We recently identified the nucleotide-binding oligomerisation domain 1 (NOD1)/receptor-interacting serine/threonine protein kinase 2 (RIPK2) signalling pathway as a relevant contributor to murine house dust mite-induced asthma. This study aimed to evaluate the effectiveness of a pharmacological RIPK2 inhibitor administered locally as a preventive and therapeutic approach using a house dust mite-induced asthma model in wild-type and humanised NOD1 mice harbouring an asthma-associated risk allele, and its relevance using air-liquid interface epithelial cultures from asthma patients.

Methods: A RIPK2 inhibitor was administered intranasally either preventively or therapeutically in a murine house dust mite-induced asthma model. Airway hyperresponsiveness, bronchoalveolar lavage composition, cytokine/chemokine expression and mucus production were evaluated, as well as the effect of the inhibitor on precision-cut lung slices. Furthermore, the inhibitor was tested on air-liquid interface epithelial cultures from asthma patients and controls.

Results: While local preventive administration of the RIPK2 inhibitor reduced airway hyperresponsiveness, eosinophilia, mucus production, T-helper type 2 cytokines and interleukin 33 (IL-33) in wild-type mice, its therapeutic administration failed to reduce the above parameters, except IL-33. By contrast, therapeutic RIPK2 inhibition mitigated all asthma features in humanised NOD1 mice. Results in precision-cut lung slices emphasised an early role of thymic stromal lymphopoietin and IL-33 in the NOD1-dependent response to house dust mite, and a late effect of NOD1 signalling on IL-13 effector response. RIPK2 inhibitor downregulated thymic stromal lymphopoietin and chemokines in house dust mite-stimulated epithelial cultures from asthma patients.

Conclusion: These data support that local interference of the NOD1 signalling pathway through RIPK2 inhibition may represent a new therapeutic approach in house dust mite-induced asthma.

Fungal lung disease encompasses a wide spectrum of organisms and associated clinical conditions presenting a significant global health challenge with type and severity determined by underlying host immunity and infecting fungal strain. The most common group of diseases are associated with the filamentous fungus Aspergillus spp. and include allergic bronchopulmonary aspergillosis (ABPA), sensitization, aspergilloma, and chronic and invasive pulmonary aspergillosis. Fungal lung disease remains epidemiologically heterogenous and is influenced by geography, environment, and host comorbidities. Diagnostic modalities continue to evolve and now include novel molecular assays and biomarkers, however, persisting challenges include achieving rapid and accurate diagnosis, particularly in resource-limited settings and in differentiating fungal infection from other pulmonary conditions. Treatment strategies for fungal lung diseases rely mainly on antifungal agents, however, the emergence of drug-resistant strains poses a substantial global threat and adds complexity to existing therapeutic challenges. Emerging antifungal agents and increasing insight into lung mycobiome via may offer fresh and personalized approaches to diagnosis and treatment, while innovative methodologies are required to mitigate drug resistance and adverse effects of treatment. This state-of-the-art review describes the current landscape of fungal lung disease, highlighting key clinical insights, current challenges, and emerging approaches for its diagnosis and treatment.

Introduction: Pathogenic variants in the gene encoding for BMPR2 are a major genetic risk factor for heritable pulmonary arterial hypertension. Owing to incomplete penetrance, deep phenotyping of unaffected carriers of a pathogenic BMPR2 variant through multimodality screening may aid in early diagnosis and identify susceptibility traits for future development of pulmonary arterial hypertension.

Methods: 28 unaffected carriers (44±16 years, 57% female) and 21 healthy controls (44±18 years, 48% female) underwent annual screening, including cardiac magnetic resonance imaging, transthoracic echocardiography, cardiopulmonary exercise testing and right heart catheterisation. Right ventricular pressure-volume loops were constructed to assess load-independent contractility and compared with a healthy control group. A transgenic Bmpr2^Δ71Ex1/+ rat model was employed to validate findings from humans.

Results: Unaffected carriers had lower indexed right ventricular end-diastolic (79.5±17.6 mL·m^-2 versus 62.7±15.3 mL·m^-2; p=0.001), end-systolic (34.2±10.5 mL·m^-2 versus 27.1±8.3 mL·m^-2; p=0.014) and left ventricular end-diastolic (68.9±14.1 mL·m^-2 versus 58.5±10.7 mL·m^-2; p=0.007) volumes than control subjects. Bmpr2^Δ71Ex1/+ rats were also observed to have smaller cardiac volumes than wild-type rats. Pressure-volume loop analysis showed that unaffected carriers had significantly higher afterload (arterial elastance 0.15±0.06 versus 0.27±0.08 mmHg·mL^-1; p<0.001) and end-systolic elastance (0.28±0.07 versus 0.35±0.10 mmHg·mL^-1; p=0.047) in addition to lower right ventricular pulmonary artery coupling (end-systolic elastance/arterial elastance 2.24±1.03 versus 1.36±0.37; p=0.006). During the 4-year follow-up period, two unaffected carriers developed pulmonary arterial hypertension, with normal N-terminal pro-brain natriuretic peptide and transthoracic echocardiography indices at diagnosis.

Conclusion: Unaffected BMPR2 mutation carriers have an altered cardiac phenotype mimicked in Bmpr2^Δ71Ex1/+ transgenic rats. Future efforts to establish an effective screening protocol for individuals at risk for developing pulmonary arterial hypertension warrant longer follow-up periods.

Background: Primary ciliary dyskinesia (PCD) is a rare genetic disorder caused by insufficient mucociliary clearance leading to chronic airway infections. The diagnostic guideline of the European Respiratory Society (ERS) primarily recommends the evaluation of the clinical history (e. g. by the PICADAR prediction tool), nasal nitric oxide (nNO) production rate measurements, high-speed videomicroscopy analysis (HSVMA) of ciliary beating, and the assessment of ciliary axonemes via transmission electron microscopy (TEM). Genetic testing can be implemented as a last step.

Question: In this study, we aimed to characterise PCD with a defective C1d projection of the ciliary central apparatus (CA) and evaluated the applicability of the ERS diagnostic guideline to this PCD type.

Methods: Using a high-throughput sequencing approach of genes encoding C1d components, we identified pathogenic variants in the novel PCD genes CFAP46 and CFAP54, and the known PCD gene CFAP221. To fully assess this PCD type, we also analysed individuals with pathogenic variants in CFAP74.

Results: Careful evaluation revealed that C1d-defective PCD is associated with normal situs composition, normal nNO-production rates, normal ciliary ultrastructure by TEM, and normal ciliary beating by HSVMA. Despite chronic respiratory disease, PICADAR does not reliably detect this PCD type. However, we could show by in-vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance.

Conclusions: Overall, this study extends the spectrum of PCD genes and highlights that C1d-defective PCD individuals elude diagnosis in the current diagnostic algorithm. To enable diagnosis, genetic testing should be prioritised in future diagnostic guidelines.