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Aims and Objectives: To explore the prevalence of psychological distress such as anxiety, depression and post-traumatic stress disorder and its associations with medication adherence in lung transplant patients., Background: Psychological distress after lung transplantation may impact clinical outcomes by associated behaviours such as non-adherence to medication. Evidence about the relation between psychological distress and medication adherence in lung transplant patients is limited and not well explained., Design and Methods: We conducted a single-centre study with a cross-sectional design in 73 lung transplant candidates and 116 recipients. Questionnaires were the Brief Symptom Inventory, Impact of Event Scale and Basel Assessment of Adherence to Immunosuppressive Medications Scale. The STROBE checklist was monitored., Results: In candidates, 39.7% reported (sub)clinical symptoms of depression, in recipients this was 21.6%. We observed suicidal ideation in recipients (8.6%), and candidates (5.5%). The prevalence of (sub)clinical symptoms of anxiety was 38.3% in candidates and 33.7% in recipients. After lung transplantation, 12% of the recipients reported clinical symptoms of PTSD related to the transplantation. Symptoms of anxiety and medication adherence were significantly and positively related in transplant recipients. We found no association between depressive or post-traumatic stress symptoms, and medication adherence., Conclusions: In lung transplant patients, we found a high prevalence of symptoms of depression and anxiety. Recipients had high levels of post-traumatic stress symptoms related to the transplantation. The prevalence of suicidal ideation was unexpectedly high in recipients. After lung transplantation, higher levels of anxiety were related to better medication adherence. We propose that LTX recipients are very anxious to develop dyspnoea and therefore take their medication more conscientiously., Relevance to Clinical Practice: The clinical nurse specialist can play a key role in identifying and addressing psychological and behavioural problems. More prospective research on the role of anxiety and dyspnoea in lung transplant recipients is recommended., (© 2021 The Authors. Journal of Clinical Nursing published by John Wiley & Sons Ltd.)

A non-invasive diagnostic tool to assess remodeling of the lung airways caused by disease is currently missing in the clinic. Measuring key features such as airway smooth muscle (ASM) thickness would increase the ability to improve diagnosis and enable treatment evaluation. In this research, polarization-sensitive optical coherence tomography (PS-OCT) has been used to image a total of 24 airways from two healthy lungs and four end-stage diseased lungs ex vivo , including fibrotic sarcoidosis, chronic obstructive pulmonary disease (COPD), fibrotic hypersensitivity pneumonitis, and cystic fibrosis. In the diseased lungs, except COPD, the amount of measured airway smooth muscle was increased. In COPD, airway smooth muscle could not be distinguished from surrounding collagen. COPD lungs showed increased alveolar size. 3D pullbacks in the same lumen provided reproducible assessment of airway smooth muscle (ASM). Image features such as thickened ASM and size/presence of alveoli were recognized in histology. The results of this study are preliminary and must be confirmed with further ex vivo and in vivo studies. PS-OCT is applicable for in vivo assessment of peribronchial and peribronchiolar lung structures and may become a valuable tool for diagnosis in pulmonology., Competing Interests: JFdB: Terumo, inc., Heidelberg Engineering, Spectrawave. (P, R),, (© 2021 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

Competing Interests: Declaration of Competing Interest The authors have no financial or other conflicts of interest to disclose. The corresponding author thanks the patients for participation in the study.

Background and Objective: Oral tacrolimus is initiated perioperatively in heart and lung transplantation patients. There have been few studies on oral tacrolimus pharmacokinetics early post-transplantation, even though tacrolimus-related toxicity may occur early, potentially leading to morbidity and mortality. Therefore, we aimed to study the pharmacokinetics of oral tacrolimus in thoracic organ recipients during the first days after transplantation., Methods: We conducted a pharmacokinetic study in 30 thoracic organ transplants at intensive care at the University Medical Center Utrecht in the first week post-transplantation. Twelve-hour whole-blood tacrolimus profiles were examined using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) and analysed via population pharmacokinetic modelling., Results: The concentration-time profiles showed high variability. Concentrations at 12 h were outside the target range in 69% of the cases. A two-compartment model with mixed first-order and zero-order absorption adequately described tacrolimus concentrations. The typical value of the apparent clearance was 19.6 L/h (95% CI 16.2-22.9), and the apparent distribution volumes of central and peripheral compartments, V1 and V2, were 231 L (95% CI 199-267) and 521 L (95% CI 441-634), respectively. Inter-occasion (dose-to-dose) variability far exceeded the interindividual variability (IIV), with an estimated variability in relative bioavailability of 55% (95% CI 48.5-64.4)., Conclusions: The high variability of tacrolimus pharmacokinetics early after thoracic organ transplantation is largely due to excessive variability in bioavailability, making individualised dosing based on measured concentrations futile. To bypass this bioavailability issue, we suggest administering tacrolimus intravenously and aiming below the upper therapeutic range early post-transplantation. Clinical Trial Registraion: NTR 3912/EudraCT 2012-001909-24.

Background: Nutritional status affects pulmonary function in cystic fibrosis (CF) patients and can be monitored by using bioelectrical impedance analysis (BIA). BIA measurements are commonly performed in the fasting state, which is burdensome for patients. We investigated whether fasting is necessary for clinical practice and research., Methods: Fat free mass (FFM) and fat mass (FM) were determined in adult CF patients (n = 84) by whole body single frequency BIA (Bodystat 500) in a fasting and non-fasting state. Fasting and non-fasting BIA outcomes were compared with Bland-Altman plots. Pulmonary function was expressed as Forced Expiratory Volume at 1 s percentage predicted (FEV1%pred). Comparability of the associations between fasting and non-fasting body composition measurements with FEV1%pred was assessed by multiple linear regression., Results: Fasting FFM, its index (FFMI), and phase angle were significantly lower than non-fasting estimates (-0.23 kg, p = 0.006, -0.07 kg/m 2 , p = 0.002, -0.10°, p = 0.000, respectively). Fasting FM and its index (FMI) were significantly higher than non-fasting estimates (0.22 kg, p = 0.008) 0.32%, p = 0.005, and 0.07 kg/m 2 , (p = 0.005). Differences between fasting and non-fasting FFM and FM were <1 kg in 86% of the patients. FFMI percentile estimates remained similar in 83% of the patients when measured after nutritional intake. Fasting and non-fasting FFMI showed similar associations with FEV1%pred (β: 4.3%, 95% CL: 0.98, 7.70 and β: 4.6%, 95% CI: 1.22, 8.00, respectively)., Conclusion: Differences between fasting and non-fasting FFM and FM were not clinically relevant, and associations with pulmonary function remained similar. Therefore, BIA measurements can be performed in a non-fasting state., (Copyright © 2019. Published by Elsevier B.V.)

Background: Development of chronic rejection is still a severe problem and causes high mortality rates after lung transplantation (LTx). Complement activation is important in the development of acute rejection (AR) and bronchiolitis obliterans syndrome, with C3 as a key complement factor. Methods: We investigated a single nucleotide polymorphism (SNP) in the C3 gene (rs2230199) in relation to long-term outcome after LTx in 144 patient-donor pairs. In addition, we looked at local production of donor C3 by analyzing bronchoalveolar lavage fluid (BALF) of 6 LTx patients using isoelectric focusing (IEF). Results: We demonstrated the presence of C3 in BALF and showed that this is produced by the donor lung based on the genotype of SNP rs2230199. We also analyzed donor and patient SNP configurations and observed a significant association between the SNP configuration in patients and episodes of AR during 4-years follow-up. Survival analysis showed a lower AR-free survival in homozygous C3 slow patients ( p = 0.005). Furthermore, we found a significant association between the SNP configuration in donors and BOS development. Patients receiving a graft from a donor with at least one C3 fast variant for rs2230199 had an inferior BOS-free survival ( p = 0.044). Conclusions: In conclusion, our data indicate local C3 production by donor lung cells. In addition, a single C3 SNP present in recipients affects short-term outcome after LTx, while this SNP in donors has an opposite effect on long-term outcome after LTx. These results could contribute to an improved risk stratification after transplantation., (Copyright © 2019 Kardol-Hoefnagel, Budding, van de Graaf, van Setten, van Rossum, Oudijk and Otten.)

In vitro drug tests using patient-derived stem cell cultures offer opportunities to individually select efficacious treatments. Here, we provide a study that demonstrates that in vitro drug responses in rectal organoids from individual patients with cystic fibrosis (CF) correlate with changes in two in vivo therapeutic endpoints. We measured individual in vitro efficaciousness using a functional assay in rectum-derived organoids based on forskolin-induced swelling and studied the correlation with in vivo effects. The in vitro organoid responses correlated with both change in pulmonary response and change in sweat chloride concentration. Receiver operating characteristic curves indicated good-to-excellent accuracy of the organoid-based test for defining clinical responses. This study indicates that an in vitro assay using stem cell cultures can prospectively select efficacious treatments for patients and suggests that biobanked stem cell resources can be used to tailor individual treatments in a cost-effective and patient-friendly manner., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Obstructive chronic lung allograft dysfunction (BOS) is the major limiting factor for lung transplantation (LTx) outcome. PTPN22 is described as the hallmark autoimmunity gene, and one specific single nucleotide polymorphism (SNP), rs2476601, is associated with multiple autoimmune diseases, impaired T cell regulation, and autoantibody formation. Taking into consideration the contribution of autoimmunity to LTx outcome, we hypothesized that polymorphisms in the PTPN22 gene could be associated with BOS incidence. We selected six SNPs within PTPN22 and analyzed both patient and donor genotypes on BOS development post-LTx. A total of 144 patients and matched donors were included, and individual SNPs and haplotype configurations were analyzed. We found a significant association between patients carrying the heterozygous configuration of rs2476601 and a higher risk for BOS development ( p = 0.005, OR: 4.400, 95%CI: 1.563-12.390). Kaplan-Meier analysis showed that heterozygous patients exhibit a lower BOS-free survival compared to patients homozygous for rs2476601 ( p = 0.0047). One haplotype, which solely contained the heterozygous risk variant, was associated with BOS development ( p = 0.015, OR: 7.029, 95%CI: 1.352-36.543). Our results show that LTx patients heterozygous for rs2476601 are more susceptible for BOS development and indicate a deleterious effect of the autoimmune-related risk factor of PTPN22 in patients on LTx outcome.

Cellular protection against undesired effects of complement activation is provided by expression of membrane-bound complement regulatory proteins including CD59. This protein prevents membrane attack complex formation and is considered to be involved in graft accommodation. Also, CD59 downregulates CD4+ and CD8+ T-cell activation and proliferation. It is unknown whether CD59 expression is affected by transplantation. The aim of this study was to evaluate the quantitative CD59 antigen expression on distinct leukocyte subsets following lung transplantation ( n  = 26) and to investigate whether this differs from pretransplantation ( n  = 9). The results show that CD59 expression on leukocytes is significantly lower posttransplantation compared with healthy controls ( p  = 0.002) and pretransplantation ( p  < 0.0001). Moreover, the CD59 expression diminishes posttransplantation on all distinct lymphocyte subsets ( p  < 0.02). This effect appeared to be specific for CD59 since the expression of other surface markers remained stable or inclined following transplantation. The highest antigen expression posttransplantation was observed on CD4+ T cells and monocytes ( p  ≤ 0.002). These findings show that CD59 expression on leukocytes diminishes posttransplantation, which could result in decreased resistance against complement and enhanced T-cell activation. If such reduction in CD59 expression also occurs on endothelial cells from the transplanted organ, this could lead to a change into a prothrombotic and proinflammatory phenotype.

Background: Enteral tube feeding (ETF) is widely used in patients with cystic fibrosis (CF) and end-stage lung disease, but previous studies have been limited to investigating whether ETF improves outcomes in patients with moderately or mildly impaired pulmonary function., Objective: This study investigated body weight, body mass index (BMI; calculated as kg/m 2 ), pulmonary function, and the presence of CF-related diabetes before and after the start of ETF., Design: This was a retrospective observational study., Participants/setting: Data from 26 adult patients in an outpatient setting who had end-stage CF (19 women) and had been using ETF for at least 6 months between 2000 and 2014 were analyzed., Main Outcome Measures: Body weight, BMI, pulmonary function (forced expiratory volume in 1 second as percent of predicted) and incidence of CF-related diabetes from 6 months before to 6 months after starting ETF., Statistical Analyses Performed: Time effects were tested with one-way analysis of variance for data that were normally distributed and the Friedman test for non-parametric data. Correlations were tested with Pearson's r or Spearman's ρ, depending on the distribution of the data., Results: Mean body weight increased by 3.5 kg (95% CI 2.2 to 4.8 kg) after patients started ETF. In women, mean BMI decreased by 0.7 in the 6 months before the start of ETF (P<0.05) and increased by 1.4 in the 6 months thereafter (P<0.05). In men, BMI changes were similar (-0.8 and +1.1), but not statistically significant. Forced expiratory volume in 1 second as percent of predicted significantly decreased in time from a median of 28% to 26% at the start of ETF to 25% after 6 months (P=0.0013), with similar trends in women and men. There was no correlation between changes in weight and lung function. CF-related diabetes was already present in 12 patients and developed in 1 more patient after the start of ETF., Conclusions: ETF improved body weight and BMI but not pulmonary function in 26 patients with end-stage CF. Clinical outcomes were similar in women and men, but the sample size of men was too small to determine statistical significance., (Copyright © 2017 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

The implementation of donation after circulatory death category 3 (DCD3) was one of the attempts to reduce the gap between supply and demand of donor lungs. In the Netherlands, the total number of potential lung donors was greatly increased by the availability of DCD3 lungs in addition to the initial standard use of donation after brain death (DBD) lungs. From the three lung transplant centers in the Netherlands, 130 DCD3 recipients were one-to-one nearest neighbor propensity score matched with 130 DBD recipients. The primary end points were primary graft dysfunction (PGD), posttransplant lung function, freedom from chronic lung allograft dysfunction (CLAD), and overall survival. PGD did not differ between the groups. Posttransplant lung function was comparable after bilateral lung transplantation, but seemed worse after DCD3 single lung transplantation. The incidence of CLAD (p = 0.17) nor the freedom from CLAD (p = 0.36) nor the overall survival (p = 0.40) were significantly different between both groups. The presented multicenter results are derived from a national context where one third of the lung transplantations are performed with DCD3 lungs. We conclude that the long-term outcome after lung transplantation with DCD3 donors is similar to that of DBD donors and that DCD3 donation can substantially enlarge the donor pool., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Lung transplantation (LTx) outcome is hampered by development of chronic rejection, often manifested as the bronchiolitis obliterans syndrome (BOS). Low serum levels of thymus and activation-regulated chemokine (TARC/CCL17), a chemoattractant, measured during the first month post-LTx are predictive for BOS development. Since TARC/CCL17 promotor polymorphisms correlate with serum TARC/CCL17 levels, we investigated seven single-nucleotide polymorphisms (SNPs) within this region and their potential association with LTx outcome. We analyzed donor and patient SNP configurations and haplotypes and observed a trend between a donor SNP (rs223899) configuration and patient TARC/CCL17 serum levels post-LTx ( p  = 0.066). Interestingly, this SNP configuration in patients did not show any correlation with pre-LTx TARC/CCL17 serum levels ( p  = 0.776). Survival analysis showed that receiving a graft from a donor heterozygous for rs223899 has a disadvantageous impact on transplantation outcome. When stratified per donor SNP genotype, patients receiving a transplant from a heterozygous donor showed a lower BOS-free survival ( p  = 0.023) and survival rate ( p  = 0.0079). Since rs223899 is located within a NFκB binding site, heterozygosity at this position could result in a reduced TARC/CCL17 expression. Our data indicate that a single TARC/CCL17 promotor SNP in the donor correlates with lower serum TARC/CCL17 levels measured 1 month after LTx and affects clinical outcome after LTx.

Lung transplantation (LTx) is the last treatment for patients suffering from end-stage lung diseases. Survival post-LTx is hampered by the development of the bronchiolitis obliterans syndrome (BOS) and diagnosis is often late. Given the urgent clinical need to recognize BOS patients at an early stage, we analyzed circulating miRNAs to identify possible stratification markers for BOS development post-transplantation. Therefore, pro-fibrotic (miR-21, miR-155), anti-fibrotic (miR-29a) and fibrosis-unrelated (miR-103, miR-191) miRNAs were analyzed in serum of end-stage lung disease patients and during LTx follow-up. Significant elevated levels of serum miRNAs were observed for all investigated miRNAs in both chronic obstructive pulmonary disease and interstitial lung disease patients compared to healthy controls. The same miRNAs were also significantly increased in the serum of BOS+ vs. BOS- patients. Most importantly, miR-21, miR-29a, miR-103, and miR-191 levels were significantly higher in BOS+ patients prior to clinical BOS diagnosis. We demonstrated that a selected group of miRNAs investigated is elevated in end-stage lung disease and BOS+ patients, prior to clinical BOS diagnosis. Even if further research is expedient on the prognostic value of circulating miRNAs in BOS and lung conditions in general, these results strongly suggest that circulating miRNAs could be used as potential biomarkers for BOS development., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: Lung transplant recipients often develop acute kidney injury (AKI) evolving into chronic kidney disease (CKD). The immunosuppressant tacrolimus might be associated with the emergence of AKI. We analyzed the development and recovery of kidney injury after lung transplantation and related AKI to whole-blood tacrolimus trough concentrations and other factors causing kidney injury., Methods: We retrospectively studied kidney injury in 186 lung-transplantation patients at the UMC Utrecht between 2001 and 2011. Kidney function and whole-blood tacrolimus trough concentrations were determined from day 1 to 14 and at 1, 3, 6, and 12 months postoperative. Systemic inflammatory response syndrome (SIRS), septic shock, and nephrotoxic medications were evaluated as covariates for AKI. We analyzed liver injury and drug-drug interactions., Results: AKI was present in 85 (46%) patients. Tacrolimus concentrations were supra-therapeutic in 135 of 186 patients (73%). AKI in the first week after transplantation was related to supra-therapeutic tacrolimus concentrations (OR 1.55; 95% CI 1.06-2.27), ≥3 other nephrotoxic drugs (OR 1.96; 95% CI 1.02-3.77), infection (OR 2.48; 95% CI 1.31-4.70), and cystic fibrosis (OR 2.17; 95% CI 1.16-4.06). Recovery rate of AKI was lower than expected (19%), and the cumulative incidence of severe CKD at 1 year was 15%., Conclusions: After lung transplantation, AKI is common and often evolves into severe CKD, which is a known cause of morbidity and mortality. Supra-therapeutic whole-blood tacrolimus trough concentrations are related to the early onset of AKI. Conscientious targeting tacrolimus blood concentrations might be vital in the early phase after lung transplantation. What is known about this subject? • Lung transplant recipients often develop acute kidney injury evolving into chronic kidney disease increasing both morbidity and mortality. • To date, the pathophysiology of kidney injury after lung transplantation has not been fully elucidated. • The immunosuppressant tacrolimus is difficult to dose, especially in the unstable clinical setting, and is nephrotoxic., What This Study Adds: • For the first time, supra-therapeutic whole-blood tacrolimus trough concentrations are related to the emergence of acute kidney injury in the first days after lung transplantation. • Supra-therapeutic whole-blood tacrolimus trough concentrations often occur early after lung transplantation. • AKI after lung transplantation shows low recovery rates.

Antibodies against HLA and non-HLA are associated with transplantation outcome. Recently, pretransplant serum IgG antibody levels against apoptotic cells were found to correlate with kidney allograft loss. We investigated the presence of these antibodies in lung transplantation (LTx) patients and evaluated the correlation of pre-LTx serum levels of IgG antibodies against apoptotic cells with LTx outcome. These cells included donor lung endothelial cells (ECs) obtained from lung perfusion fluid collected during LTx procedure. Cells were isolated, expanded in vitro , and analyzed as targets for antiapoptotic cell reactivity. Cultured cells exhibited EC morphology and were CD31+, CD13+, and vWF+. End-stage lung disease patients showed elevated serum IgG levels against apoptotic lung EC ( p  = 0.0018) compared to healthy controls. Interestingly, the levels of circulating antibodies directed against either apoptotic Jurkat cells or apoptotic lung ECs did not correlate, suggesting a target cell specificity. We observed no correlation between chronic or acute rejection and pre-LTx serum levels of antiapoptotic antibodies. Also, these levels did not differ between matched patients developing chronic rejection or not during follow-up or at the time of diagnosis, as they remained as high as prior to transplantation. Thus, circulating levels of antiapoptotic cell antibodies are elevated in end-stage lung disease patients, but our data do not correlate with outcome after LTx.

Background: Lung transplant recipients have an increased susceptibility to a variety of infections due to immunosuppressive therapy. Current guidelines recommend pneumococcal and other vaccinations, prior to lung transplantation to protect against post-transplant infections, but measurement of the antibody response to vaccination is not advised. Immune status investigation in lung transplant candidates, including the response to pneumococcal polysaccharide vaccination, has not been described., Methods: Immune status investigation, including measurement of immunoglobulins, complement and the response to 23-valent pneumococcal polysaccharide vaccination (23vPPV) was performed in 81 adult lung transplant candidates., Results: Eighteen patients had low IgG levels and 32 patients had low IgG1 and/or IgG2 levels. After vaccination with 23vPPV the median antibody concentration of all serotypes increased significantly. Fifty-two patients had protective IgG-post-vaccination antibody levels to at least 10 serotypes. Twenty-nine patients had an impaired response to 23vPPV., Conclusions: In conclusion, a significant proportion of our cohort of lung transplant candidates had one or more abnormalities in the immune status. It is likely that these patients have an increased risk for infections after transplantation. Revaccination, including measurement of antibody response, and possibly antibody replacement therapy should be considered to minimize infection risk., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Resting energy expenditure (REE) is increased in patients with cystic fibrosis (CF) with end-stage lung disease due to chronic inflammation and pulmonary infections. After lung transplantation (LTx), energy expenditure is expected to be lower because inflammation will decrease. We assessed the agreement between measured and predicted REE in pre-LTx CF and post-LTx patients with CF and differences in REE in pre-LTx CF and post-LTx patients with CF in a cross-sectional study., Methods: Included were 12 pre-LTx patients with CF (9 women; median age 31.6 years; interquartile range [IQR], 23.3-40.0) and 12 patients with CF within 2 years after LTx (6 women; median age 33.5 years; IQR, 22.3-40.3). REE was measured in a fasted state using indirect calorimetry. Values were compared with predicted REE calculated by formulas of Harris-Benedict (1919 and 1984), Schofield, and the World Health Organization (1985). A calculated REE between 90% and 110% of REE measured was considered adequate., Results: Prediction equations underestimate REE in at least 75% of pre-LTx and 33% of post-LTx patients with CF. Mean (SD) REE measured by indirect calorimetry was 1735 (251) kcal pre-LTx and 1650 (235) kcal post-LTx ( P = .40). REE expressed per kilogram of fat-free mass (FFM) was 40.5 kcal/kg in pre-LTx patients with CF, which was higher than the 34.3 kcal/kg in post-LTx patients with CF ( P = .01)., Conclusions: Prediction equations underestimate REE in patients with end-stage CF. REE per kg of FFM is lower post-LTx than pre-LTx in patients with CF. Measurement of REE is recommended for patients with CF, especially pre-LTx, to optimize energy requirements for improving nutrition status.

We hypothesized that people with cystic fibrosis (CF) who express CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations associated with residual function may benefit from G-protein coupled receptor (GPCR)-targeting drugs that can activate and enhance CFTR function.We used intestinal organoids to screen a GPCR-modulating compound library and identified β2-adrenergic receptor agonists as the most potent inducers of CFTR function.β2-Agonist-induced organoid swelling correlated with the CFTR genotype, and could be induced in homozygous CFTR-F508del organoids and highly differentiated primary CF airway epithelial cells after rescue of CFTR trafficking by small molecules. The in vivo response to treatment with an oral or inhaled β2-agonist (salbutamol) in CF patients with residual CFTR function was evaluated in a pilot study. 10 subjects with a R117H or A455E mutation were included and showed changes in the nasal potential difference measurement after treatment with oral salbutamol, including a significant improvement of the baseline potential difference of the nasal mucosa (+6.35 mV, p<0.05), suggesting that this treatment might be effective in vivo Furthermore, plasma that was collected after oral salbutamol treatment induced CFTR activation when administered ex vivo to organoids.This proof-of-concept study suggests that organoids can be used to identify drugs that activate CFTR function in vivo and to select route of administration., (Copyright ©ERS 2016.)

Identifying subjects with cystic fibrosis (CF) who may benefit from cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs is time-consuming, costly, and especially challenging for individuals with rare uncharacterized CFTR mutations. We studied CFTR function and responses to two drugs-the prototypical CFTR potentiator VX-770 (ivacaftor/KALYDECO) and the CFTR corrector VX-809 (lumacaftor)-in organoid cultures derived from the rectal epithelia of subjects with CF, who expressed a broad range of CFTR mutations. We observed that CFTR residual function and responses to drug therapy depended on both the CFTR mutation and the genetic background of the subjects. In vitro drug responses in rectal organoids positively correlated with published outcome data from clinical trials with VX-809 and VX-770, allowing us to predict from preclinical data the potential for CF patients carrying rare CFTR mutations to respond to drug therapy. We demonstrated proof of principle by selecting two subjects expressing an uncharacterized rare CFTR genotype (G1249R/F508del) who showed clinical responses to treatment with ivacaftor and one subject (F508del/R347P) who showed a limited response to drug therapy both in vitro and in vivo. These data suggest that in vitro measurements of CFTR function in patient-derived rectal organoids may be useful for identifying subjects who would benefit from CFTR-correcting treatment, independent of their CFTR mutation., (Copyright © 2016, American Association for the Advancement of Science.)

Aims: Pulmonary infections are more frequent in and associated with higher mortality in Cystic Fibrosis-Related Diabetes (CFRD) patients compared to CF patients without CFRD. Hyperglycaemia can lead to a higher vulnerability for infections. Aim of the study was to test whether the infection rate in well-controlled CFRD patients was similar to that in CF patients without CFRD., Methods: This is a retrospective six-year cohort analysis on a consecutive series of 138 CF patients. They were categorized in two groups with CFRD or without CFRD. Pulmonary infection frequency was defined as the number of intravenous (IV) antibiotic treatments. Clinical factors associated with infection frequency were collected., Results: CFRD was diagnosed in 54 (39%) CF patients of whom 44 (81%) achieved target value for glycaemic control (HbA1c 7.0% (⩽53mmol/mol)). Median frequency of IV antibiotics was 0 without CFRD and 3 episodes in patients with CFRD (rate ratio (RR) 2.9 (95% CI 1.6-5.2)). Multivariate analysis showed that frequency of IV antibiotics was significantly related to Pseudomonas aeruginosa colonization (RR 3.7) and lower lung function at baseline (RR 0.97) but not to CFRD by itself., Conclusions: In this cohort with overall strict glycaemic control, the frequency of IV antibiotics use was related to chronic infection and impaired lung function at baseline, but not to CFRD by itself. Although this study in itself does not prove beneficial effect of strict glycaemic control, it does emphasize the potential role of glycaemic control on infection frequency in CF patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)