European Respiratory Journal最新文献

Background: Pneumonia caused by viral or bacterial pathogens such as severe acute respiratory syndrome coronavirus 2 or Pseudomonas aeruginosa may result in life-threatening disease with a strong contribution of protease dysregulation. The present study aimed to systematically characterise the contribution of ADAM10 and ADAM17 on leukocytes and circulating exosomes to viral and bacterial pneumonia.

Methods: The analysis of coronavirus disease 2019 (COVID-19) and bacterial pneumonia patient samples was combined with in vivo experiments in conditional knockout animals lacking either ADAM10 or ADAM17 in leukocytes and cell culture experiments for mechanistic studies.

Results: Hospitalised bacterial pneumonia and COVID-19 patients displayed a severity dependent increase of ADAM10 and ADAM17 activity on exosomes. These exosomes caused pathophysiological changes of cardiomyocytes and the endothelial barrier. In a pre-clinical murine pneumonia model, we observed that leukocytes contributed to this increase in exosomal proteolytic activity. In the local environment of the lung, ADAM10 orchestrated a pro-inflammatory response with M1 macrophage polarisation, increased reactive oxygen species (ROS) generation, cytokine release, tissue damage and oedema formation, whereas ADAM17 seemed to dampen the initial inflammatory response to an anti-infective, ROS-balanced level.

Conclusion: Leukocytic ADAM10 and ADAM17 and their release on exosomes may constitute relevant regulatory elements in bacterial and viral pneumonia, with a potential contribution of exosomes to disease progression and systemic inflammatory responses. Therefore, the diagnostic, prognostic and therapeutic value of ADAM10 and ADAM17 should be evaluated in further preclinical and translational studies, addressing the changes of the immune response and exosomes as cargo vehicles both at local site and for the prevention of systemic effects.

Sarcoidosis is a complex systemic granulomatous disease that can affect multiple organs, with pulmonary involvement being the most common. Its pathogenesis involves genetic predisposition and chronic immune dysregulation, which increase susceptibility to environmental or endogenous triggers, leading to an aberrant immune response. Imaging plays a central role in diagnosis and has evolved from traditional chest radiography Scadding staging to a computed tomography-based classification and radiomics that improves disease phenotyping. Due to its variable presentation, diagnosing sarcoidosis and attributing symptoms to the disease can be challenging; therefore, awareness and consideration of alternative diagnoses remain essential. The clinical course of sarcoidosis is unpredictable; many patients do not require therapy. Treatment decisions must be individualised, balancing disease severity, risk of organ damage, quality of life and potential toxicity of medication. However, the lack of both reliable prognostic tools and clear criteria for high-risk cases contributes to substantial heterogeneity in disease management. While the guidelines still recommend corticosteroids as first-line treatment, recent data show that methotrexate and prednisone have comparable effects on pulmonary function, although differ in side-effect profiles and time to efficacy. For refractory cases, second-line therapy involves combining or switching drugs, with anti-tumour necrosis factor agents representing third-line options, ideally in expert hands. Novel therapies targeting pathways involved in disease pathogenesis are under investigation. There is growing consensus on the need to revise current treatment algorithms to minimise corticosteroid use and adopt more evidence-based approaches. Future priorities include identifying prognostic biomarkers, refining trial design and establishing meaningful end-points to improve individualised care for the heterogeneous population of patients with sarcoidosis.

Background: Pulmonary vasodilators increase cardiac output (CO) in group 1 PH and can cause high CO with unclear implications.

Objectives: To describe pathophysiology of high CO in group 1 PH.

Methods: Clinical characteristics were compared among PVDOMICS group 1 PH participants by low (cardiac index (CI) <2.2 L·min^-1·m^-2),normal, or high output (CO>8 L·min^-1 or CI>4 L·min^-1·m^-2).

Measurements and main results: Of 449 group 1 PH participants, 23%(n=103) had low output, 68%(n=304) had normal CO and 9%(n=42) had high output. Increasing CO was associated with more intensive vasodilator use (triple therapy 11/19/33%,p=0.0008), with progressively lower PVR (p<0.0001). High output was associated with the lowest systemic vascular resistance (p<0.0001), with greater LV and LA enlargement (p<0.001 for all). High flow resulted in increase in LV and RV work at rest, and absolute/relative RV work during exercise (p<0.0001 for all). Despite greater exercise O₂ delivery (p<0.0001), peripheral O₂ utilization was impaired by O₂ extraction ratio (p=0.001) and AVO₂ difference (p=0.005), without incremental functional or survival benefit compared to normal output PH. After adjusting for baseline risk, high output had increased risk of death/transplant compared to normal output [adjusted HR 2.1 (95% 1.2-3.7), p=0.007]. In a validation cohort (n=37), 93% had normal CO at diagnosis, with the high output state developing in follow-up after vasodilator initiation.

Conclusions: 1 in 10 patients with group 1 PH has a high output state which is most common in prevalent PH and related to vasodilator intensity, with adverse cardiac remodeling and myocardial workload. Further studies are needed to determine optimal vasodilator dosing with high output, and therapeutic interaction with vasodilator sparing therapies such as sotatercept.