The extend of lung disease remains the most important prognostic factor for survival in patients with cystic fibrosis (CF), and lack of adherence is the main reason for treatment failure. Early ...detection of deterioration in lung function and optimising adherence are therefore crucial in CF care. We implement a randomized controlled trial to evaluate efficacy of telemonitoring of adherence, lung function, and health condition in combination with behavior change interventions using innovative digital technologies.
This is a multi-centre, randomized, controlled, non-blinded trial aiming to include 402 patients ≥ 12 years-of-age with CF. A standard-of-care arm is compared to an arm receiving objective, continuous monitoring of adherence to inhalation therapies, weekly home spirometry using electronic devices with data transmission to patients and caring physicians combined with video-conferencing, a self-management app and professional telephone coaching. The duration of the intervention phase is 18 months. The primary endpoint is time to the first protocol-defined pulmonary exacerbation. Secondary outcome measures include number of and time between pulmonary exacerbations, adherence to inhalation therapy, changes in forced expiratory volume in 1 s from baseline, number of hospital admissions, and changes in health-related quality of life. CF-associated medical treatment and care, and health care related costs will be assessed by explorative analysis in both arms.
This study offers the opportunity to evaluate the effect of adherence interventions using telemedicine capable devices on adherence and lung health, possibly paving the way for implementation of telemedicine in routine care for patients with CF.
This study has been registered with the German Clinical Trials Register (Identifier: DRKS00024642, date of registration 01 Mar 2021, URL: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00024642 ).
Multiple-breath washout (MBW)-derived lung clearance index (LCI) detects lung disease in children with cystic fibrosis (CF). Correction of a cross-talk error in the software of the MBW device ...Exhalyzer D in a new software version has generated significant interest regarding its impact on previous MBW findings. Since LCI and chest magnetic resonance imaging (MRI) correlated before in CF children, this study aims to reassess previous MBW data after correction.
Reanalysis of the main findings from a previously published study comparing MBW and MRI in a pediatric CF cohort by reassessment of nitrogen (N
) MBW of 61 stable children with CF, 75 age-matched healthy controls (HC), and 15 CF children with pulmonary exacerbation (PEx) in the corrected software version.
The corrected LCI (N
LCI
) decreased in the entire cohort (-17.0 (11.2)%), HC (-8.5 (8.2)%), stable CF children (-22.2 (11.1)%), and within the PEx group at baseline, at PEx and after antibiotic therapy (-21.5 (7.3)%; -22.5 (6.1)%; -21.4 (6.6)%; all P<0.01). N
LCI
and N
LCI
correlated with chest MRI scores in stable CF (r=0.70 to 0.84; all P<0.01) without a significant difference between N
LCI
and N
LCI
. Change in LCI from baseline to PEx and from PEx to after therapy decreased from N
LCI
to N
LCI
, but these changes remained significant (all P=0.001).
Our results indicate that N
LCI
is significantly lower than N
LCI
, but key results published in the original study demonstrating N
MBW and MRI as complementary methods for clinical surveillance in children with CF remain unaffected.
T lymphocytes accumulate in inflamed tissues of patients with chronic inflammatory diseases (CIDs) and express pro‐inflammatory cytokines upon re‐stimulation in vitro. Further, a significant genetic ...linkage to MHC genes suggests that T lymphocytes play an important role in the pathogenesis of CIDs including juvenile idiopathic arthritis (JIA). However, the functions of T lymphocytes in established disease remain elusive. Here we dissect the transcriptional and the clonal heterogeneity of synovial T lymphocytes in JIA patients by single‐cell RNA sequencing combined with T cell receptor profiling on the same cells. We identify clonally expanded subpopulations of T lymphocytes expressing genes reflecting recent activation by antigen in situ. A PD‐1+TOX+EOMES+ population of CD4+ T lymphocytes expressed immune regulatory genes and chemoattractant genes for myeloid cells. A PD‐1+TOX+BHLHE40+ population of CD4+, and a mirror population of CD8+ T lymphocytes expressed genes driving inflammation, and genes supporting B lymphocyte activation in situ. This analysis points out that multiple types of T lymphocytes have to be targeted for therapeutic regeneration of tolerance in arthritis.
By combined analysis of single cell transcriptomes and T‐cell receptor profiling we identified functionally distinct populations of in situ antigen‐activated T‐cells in the inflamed joints of patients with juvenile idiopathic arthritis (JIA). The results could be the basis for the development of novel biomarkers and therapeutic approaches for JIA.
Changes in the airway microbiome may be important in the pathophysiology of chronic lung disease in patients with cystic fibrosis. However, little is known about the microbiome in early cystic ...fibrosis lung disease and the relationship between the microbiomes from different niches in the upper and lower airways. Therefore, in this cross-sectional study, we examined the relationship between the microbiome in the upper (nose and throat) and lower (sputum) airways from children with cystic fibrosis using next generation sequencing. Our results demonstrate a significant difference in both α and β-diversity between the nose and the two other sampling sites. The nasal microbiome was characterized by a polymicrobial community while the throat and sputum communities were less diverse and dominated by a few operational taxonomic units. Moreover, sputum and throat microbiomes were closely related especially in patients with clinically stable lung disease. There was a high inter-individual variability in sputum samples primarily due to a decrease in evenness linked to increased abundance of potential respiratory pathogens such as Pseudomonas aeruginosa. Patients with chronic Pseudomonas aeruginosa infection exhibited a less diverse sputum microbiome. A high concordance was found between pediatric and adult sputum microbiomes except that Burkholderia was only observed in the adult cohort. These results indicate that an adult-like lower airways microbiome is established early in life and that throat swabs may be a good surrogate in clinically stable children with cystic fibrosis without chronic Pseudomonas aeruginosa infection in whom sputum sampling is often not feasible.
The next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-659, in triple combination with tezacaftor and ivacaftor (VX-659-tezacaftor-ivacaftor), was developed to ...restore the function of Phe508del CFTR protein in patients with cystic fibrosis.
We evaluated the effects of VX-659-tezacaftor-ivacaftor on the processing, trafficking, and function of Phe508del CFTR protein using human bronchial epithelial cells. A range of oral VX-659-tezacaftor-ivacaftor doses in triple combination were then evaluated in randomized, controlled, double-blind, multicenter trials involving patients with cystic fibrosis who were heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del-MF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del genotype). The primary end points were safety and the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV
).
VX-659-tezacaftor-ivacaftor significantly improved the processing and trafficking of Phe508del CFTR protein as well as chloride transport in vitro. In patients, VX-659-tezacaftor-ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. VX-659-tezacaftor-ivacaftor resulted in significant mean increases in the percentage of predicted FEV
through day 29 (P<0.001) of up to 13.3 points in patients with Phe508del-MF genotypes; in patients with the Phe508del-Phe508del genotype already receiving tezacaftor-ivacaftor, adding VX-659 resulted in a further 9.7-point increase in the percentage of predicted FEV
. The sweat chloride concentrations and scores on the respiratory domain of the Cystic Fibrosis Questionnaire-Revised improved in both patient populations.
Robust in vitro activity of VX-659-tezacaftor-ivacaftor targeting Phe508del CFTR protein translated into improvements for patients with Phe508del-MF or Phe508del-Phe508del genotypes. VX-659 triple-combination regimens have the potential to treat the underlying cause of disease in approximately 90% of patients with cystic fibrosis. (Funded by Vertex Pharmaceuticals; VX16-659-101 and VX16-659-001 ClinicalTrials.gov numbers, NCT03224351 and NCT03029455 .).
The CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to improve clinical outcomes and sweat chloride ...concentration in patients with cystic fibrosis (CF) and one or two
alleles. However, the effect of ELX/TEZ/IVA on CFTR function in the airways and intestine has not been studied.
To assess the effect of ELX/TEZ/IVA on CFTR function in airway and intestinal epithelia in patients with CF and one or two
alleles aged 12 years and older.
This prospective, observational, multicenter study assessed clinical outcomes including FEV
% predicted and body mass index and the CFTR biomarkers sweat chloride concentration, nasal potential difference, and intestinal current measurement before and 8-16 weeks after initiation of ELX/TEZ/IVA.
A total of 107 patients with CF including 55 patients with one
and a minimal function mutation and 52
homozygous patients were enrolled in this study. In patients with one
allele, nasal potential difference and intestinal current measurement showed that ELX/TEZ/IVA improved CFTR function in nasal epithelia to a level of 46.5% (interquartile range IQR, 27.5-72.4;
< 0.001) and in intestinal epithelia to 41.8% of normal (IQR, 25.1-57.6;
< 0.001). In
homozygous patients, ELX/TEZ/IVA exceeded improvement of CFTR function observed with TEZ/IVA and increased CFTR-mediated Cl
secretion to a level of 47.4% of normal (IQR, 19.3-69.2;
< 0.001) in nasal and 45.9% (IQR, 19.7-66.6;
< 0.001) in intestinal epithelia.
Treatment with ELX/TEZ/IVA results in effective improvement of CFTR function in airway and intestinal epithelia in patients with CF and one or two
alleles. Clinical trial registered with www.clinicaltrials.gov (NCT04732910).
Previous studies showed that lumacaftor-ivacaftor therapy results in partial rescue of CFTR (cystic fibrosis CF transmembrane conductance regulator) activity and a moderate improvement of spirometry ...in Phe508del homozygous patients with CF. However, the effects of lumacaftor-ivacaftor on lung clearance index (LCI), lung morphology and perfusion detected by chest magnetic resonance imaging (MRI), and effects on the airway microbiome and inflammation remain unknown.
To investigate the effects of lumacaftor-ivacaftor on LCI, lung MRI scores, and airway microbiome and inflammation.
In this prospective observational study we assessed clinical outcomes including spirometry and body mass index, LCI, lung MRI scores, sputum microbiome, and proinflammatory cytokines in 30 Phe508del homozygous patients with CF 12 years and older before and 8-16 weeks after initiation of lumacaftor-ivacaftor therapy.
Lumacaftor-ivacaftor had no effects on forced expiratory volume in 1 second (FEV
% predicted) (1.7%; 95% confidence interval CI, -1.0% to 4.3%;
= 0.211) but improved LCI (-1.6; 95% CI, -2.6 to -0.5;
< 0.01) and MRI morphology (-1.3; 95% CI, -2.3 to -0.3;
< 0.05) and perfusion score (-1.2; 95% CI, -2.3 to -0.2;
< 0.05) in our study cohort. Furthermore, lumacaftor-ivacaftor decreased the total bacterial load (-1.8; 95% CI, -3.3 to -0.34;
< 0.05) and increased the Shannon diversity of the airway microbiome (0.4; 95% CI, 0.1 to 0.8;
< 0.05), and reduced IL-1β (interleukin-1β) concentration (median change, -324.2 pg/ml; 95% CI, -938.7 to 290.4 pg/ml;
< 0.05) in sputum of Phe508del homozygous patients.
This study shows that lumacaftor-ivacaftor has beneficial effects on lung ventilation, morphology, and perfusion, as well as on the airway microbiome and inflammation in Phe508del homozygous patients. Our results suggest that LCI and MRI may be more sensitive than FEV
% predicted to detect response to CFTR modulator therapy in patients with chronic CF lung disease. Clinical trial registered with ClinicalTrials.gov (NCT02807415).
Recent evidence from clinical studies suggests that neutrophil elastase (NE) released in neutrophilic airway inflammation is a key risk factor for the onset and progression of lung disease in young ...children with cystic fibrosis (CF). However, the role of NE in the complex in vivo pathogenesis of CF lung disease remains poorly understood.
To elucidate the role of NE in the development of key features of CF lung disease including airway inflammation, mucus hypersecretion, goblet cell metaplasia, bacterial infection, and structural lung damage in vivo.
We used the Scnn1b-Tg mouse as a model of CF lung disease and determined effects of genetic deletion of NE (NE(-/-)) on the pulmonary phenotype. Furthermore, we used novel Foerster resonance energy transfer (FRET)-based NE reporter assays to assess NE activity in bronchoalveolar lavage from Scnn1b-Tg mice and sputum from patients with CF.
Lack of NE significantly reduced airway neutrophilia, elevated mucin expression, goblet cell metaplasia, and distal airspace enlargement, but had no effect on airway mucus plugging, bacterial infection, or pulmonary mortality in Scnn1b-Tg mice. By using FRET reporters, we show that NE activity was elevated on the surface of airway neutrophils from Scnn1b-Tg mice and patients with CF.
Our results suggest that NE plays an important role in the in vivo pathogenesis and may serve as a therapeutic target for inflammation, mucus hypersecretion, and structural lung damage and indicate that additional rehydration strategies may be required for effective treatment of airway mucus obstruction in CF.
Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathology, and it remains unclear whether T cells contribute to disease pathology. Here, we combined single-cell ...transcriptomics and single-cell proteomics with mechanistic studies to assess pathogenic T cell functions and inducing signals. We identified highly activated CD16+ T cells with increased cytotoxic functions in severe COVID-19. CD16 expression enabled immune-complex-mediated, T cell receptor-independent degranulation and cytotoxicity not found in other diseases. CD16+ T cells from COVID-19 patients promoted microvascular endothelial cell injury and release of neutrophil and monocyte chemoattractants. CD16+ T cell clones persisted beyond acute disease maintaining their cytotoxic phenotype. Increased generation of C3a in severe COVID-19 induced activated CD16+ cytotoxic T cells. Proportions of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a were associated with fatal outcome of COVID-19, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19.
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•Severe COVID-19 is marked by activated, highly cytotoxic CD16+ T cells•Immune-complex-mediated degranulation of CD16+ T cells causes endothelial cell injury•C3a-rich environment in severe COVID-19 promotes differentiation of CD16+ T cells•Activated CD16+ T cells and complement proteins are associated with fatal outcome
Generation of the C3a complement protein fragment by SARS-CoV-2 infection drives differentiation of a CD16-expressing T cell population that associates with severe COVID-19 disease outcomes.
Recent studies found that expression of NEDD4-2 is reduced in lung tissue from patients with idiopathic pulmonary fibrosis (IPF) and that the conditional deletion of
in lung epithelial cells causes ...IPF-like disease in adult mice via multiple defects, including dysregulation of the epithelial Na
channel (ENaC), TGFβ signaling and the biosynthesis of surfactant protein-C proprotein (proSP-C). However, knowledge of the impact of congenital deletion of
on the lung phenotype remains limited. In this study, we therefore determined the effects of congenital deletion of
in the lung epithelial cells of neonatal doxycycline-induced triple transgenic
mice, with a focus on clinical phenotype, survival, lung morphology, inflammation markers in BAL, mucin expression, ENaC function and proSP-C trafficking. We found that the congenital deletion of
caused a rapidly progressive lung disease in neonatal mice that shares key features with interstitial lung diseases in children (chILD), including hypoxemia, growth failure, sterile pneumonitis, fibrotic lung remodeling and high mortality. The congenital deletion of
in lung epithelial cells caused increased expression of
and mucus plugging of distal airways, increased ENaC activity and proSP-C mistrafficking. This model of congenital deletion of
may support studies of the pathogenesis and preclinical development of therapies for chILD.
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