European Respiratory Journal最新文献

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

Aims: In this study, we aimed to characterise primary ciliary dyskinesia with a defective C1d projection of the ciliary central apparatus and we evaluated the applicability of the European Respiratory Society diagnostic guideline to this primary ciliary dyskinesia type.

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

Results: Careful evaluation revealed that C1d-defective primary ciliary dyskinesia is associated with normal situs composition, normal nasal nitric oxide production rates, normal ciliary ultrastructure by transmission electron microscopy and normal ciliary beating by high-speed videomicroscopy analysis. Despite chronic respiratory disease, PICADAR does not reliably detect this primary ciliary dyskinesia 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 primary ciliary dyskinesia genes and highlights that individuals with C1d-defective primary ciliary dyskinesia elude diagnosis when using the current diagnostic algorithm. To enable diagnosis, genetic testing should be prioritised in future diagnostic guidelines.

Streptococcus pneumoniae is the most common causative agent of community-acquired pneumonia worldwide. A key pathogenic mechanism that exacerbates severity of disease is the disruption of the alveolar-capillary barrier. However, the specific virulence mechanisms responsible for this in the human lung are not yet fully understood. In this study, we infected living human lung tissue with Strep. pneumoniae and observed a significant degradation of the central junctional proteins occludin and vascular endothelial cadherin, indicating barrier disruption. Surprisingly, neither pneumolysin, bacterial hydrogen peroxide nor pro-inflammatory activation were sufficient to cause this junctional degradation. Instead, pneumococcal infection led to a significant decrease of pH (∼6), resulting in the acidification of the alveolar microenvironment, which was linked to junctional degradation. Stabilising the pH at physiological levels during infection reversed this effect, even in a therapeutic-like approach. Further analysis of bacterial metabolites and RNA sequencing revealed that sugar consumption and subsequent lactate production were the major factors contributing to bacterially induced alveolar acidification, which also hindered the release of critical immune factors. Our findings highlight bacterial metabolite-induced acidification as an independent virulence mechanism for barrier disruption and inflammatory dysregulation in pneumonia. Thus, our data suggest that strictly monitoring and buffering alveolar pH during infections caused by fermentative bacteria could serve as an adjunctive therapeutic strategy for sustaining barrier integrity and immune response.

The Global initiative for chronic Obstructive Lung Disease (GOLD) report states that the diagnosis of chronic obstructive pulmonary disease (COPD) should be considered in individuals with chronic respiratory symptoms and / or exposure to risk factors. Forced spirometry demonstrating airflow obstruction after bronchodilation is required to confirm the diagnosis using a threshold of forced expiratory volume in 1 s (FEV₁) / forced vital capacity (FVC) ratio<0.7. This GOLD Science Committee review weighs the evidence for using pre- or post-bronchodilator (BD) spirometry to diagnose COPD.Cohort studies have shown that pre- and post-BD spirometry give concordant diagnostic results in most cases, although the prevalence of COPD is up to 36% lower with post-BD values. Discordant results may occur in "volume" or "flow" responders. Volume responders have reduced FVC due to gas trapping causing FEV₁/ FVC ratio >0.7 pre-BD, but a volume response occurs post-BD with a greater improvement in FVC relative to FEV₁ decreasing the ratio to <0.7. Flow responders show a greater FEV₁ improvement relative to FVC which may increase FEV₁/ FVC from <0.7 pre-BD to >0.7 post-BD; these individuals have an increased likelihood of developing post-BD obstruction during follow up and require monitoring longitudinally.GOLD 2025 recommends using pre-BD spirometry to rule out COPD and post-BD measurements to confirm the diagnosis. This will reduce clinical workload. Post-BD results close to the threshold should be repeated to ensure a correct diagnosis is made. Post-BD measurements ensure that volume responders are not overlooked and limit COPD overdiagnosis.