Evidence map›Paper›PMID 40739568›Full record

Trial reportRespiratory research2025

Extracellular vesicles from bronchoalveolar lavage fluid provide insights into the inhaled corticosteroids treatment response in COPD.

Jiahua Fang, Justina C Wolters, Karim Rafie, Changshuo Wang, Sabine Bartel, Maarten van den Berge, Machteld N Hylkema

Registry-linked trialAbstract readRandomized Controlled Trial
In one paragraph

Trial report in Respiratory research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT00158847 (Modification of Disease Outcome in COPD. Shortterm Versus Longterm Treatment With Inhaled Corticosteroids, Either or Not Combined With a Long-Acting Beta2-Agonist.), which is not on this map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT00158847 phase4terminatednot on this map

Modification of Disease Outcome in COPD. Shortterm Versus Longterm Treatment With Inhaled Corticosteroids, Either or Not Combined With a Long-Acting Beta2-Agonist.

TypeinterventionalSponsorLeiden University Medical CenterRan2000 to 2005Enrolled200ConditionsChronic Obstructive Pulmonary DiseaseArmsfluticasone 500 mcg, fluticasone 500 mcg + salmeterol 50 mcg
3 · Its place in the literature

Who cites it

6 citing papers in PubMed.

  1. Review
  2. Article
  3. Review
  4. The dual promise of extracellular vesicles in lung diseases: towards reliable biomarkers and drug delivery vectors.European respiratory review : an official journal of the European Respiratory Society · 2026
    Review
  5. Review
  6. Decreased Sputum Type-2 Gene Expression in COPD Current Smokers.International journal of chronic obstructive pulmonary disease · 2025
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors.

Jiahua FangDepartment of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, 9713 GZ, The Netherlands. j.fang@umcg.nl.ORCID http://orcid.org/0000-0002-1651-4028
Justina C WoltersDepartment of Pediatrics, University of Groningen, University Medical Center, Groningen, Groningen, 9713 GZ, The Netherlands.ORCID http://orcid.org/0000-0003-0066-3720
Karim RafieDepartment of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Groningen, 9713 AV, The Netherlands.ORCID http://orcid.org/0000-0003-2418-0061
Changshuo WangDepartment of Neurosciences, Laboratory of Neuro- and Psychophysiology, KU Leuven Medical School, Leuven, 3000, Belgium.
Sabine BartelDepartment of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, 9713 GZ, The Netherlands.
Maarten van den BergeGroningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, 9713 GZ, The Netherlands.ORCID http://orcid.org/0000-0002-9336-7340
Machteld N HylkemaDepartment of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, 9713 GZ, The Netherlands. m.n.hylkema@umcg.nl.ORCID http://orcid.org/0000-0002-6732-8903

Funding

the Noordelijke Cara Stichting NCS, Project 2019/02the Stichting Astma Bestrijding SAB, Project 2021-021
6 · The paper itself

Abstract

backgroundInhaled corticosteroids (ICS) are widely used to treat chronic obstructive pulmonary disease (COPD), but treatment responses vary among individuals. Identifying biomarkers that can improve our understanding of disease mechanisms and help predict ICS responsiveness is urgently needed. Extracellular vesicles (EVs), key mediators of intercellular communication, may offer novel insights and serve as a potential biomarker source.

methods34 COPD patients participated were treated for 6 months with either placebo or ICS (500 µg fluticasone ± 50 µg salmeterol). Lung function (FEV1% predicted, FEV1/FVC%, and RV/TLC% predicted) was assessed at baseline and 6 months. Proteins from BALF-derived EVs were analyzed at both time points using label-free quantitative proteomics. Weighted gene co-expression network analysis was applied to identify EV protein modules associated with lung function (n = 24) at baseline. Baseline EV protein levels were further correlated with changes in lung function after ICS treatment. Statistical analyses were performed in R (v4.3.2), using Mann-Whitney U (two groups) or Kruskal-Wallis with Dunn's post hoc (multiple groups), Student's t-test for paired data, and Pearson correlation. Statistical significance was set at p < 0.05.

resultsThirteen EV protein co-expression modules were identified. Each module was assigned a color-based label. The red and salmon modules showed significant associations with baseline lung function: FEV1% predicted (r = - 0.46, p = 0.02) and FEV1/FVC% (r = 0.43, p = 0.04), respectively. Furthermore, 25 proteins from the red and 11 from the salmon module were significantly correlated with lung function improvements post-ICS treatment. Members of the cystatin (CST) superfamily, particularly CST1, showed strong correlations with ΔFEV1% predicted (r = 0.61, p = 0.003) and ΔFEV1/FVC% (r = 0.46, p = 0.035). These proteins also exhibited contrasting expression patterns between ICS responders and non-responders, suggesting a potential role in treatment sensitivity and links to type 2 inflammation.

conclusionsOur findings highlight the potential of BALF-derived EVs as a biomarker source for predicting ICS responsiveness in COPD. The CST family, especially CST1, potentially serves as a valuable indicator for identifying patients who are more likely to benefit from ICS treatment.

trial registrationClinicalTrials.gov: NCT00158847, pre-registered April 2000.

Indexed as

Adrenal Cortex HormonesBronchoalveolar Lavage FluidExtracellular VesiclesFluticasonePulmonary Disease, Chronic ObstructiveAdministration, InhalationAgedBiomarkersDouble-Blind MethodFemaleHumansMaleMiddle AgedTreatment OutcomeAdrenal Cortex HormonesBiomarkersFluticasone

Identifiers

PMID40739568
PMCPMC12312508

What OpenQuestion holds

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.