Effects of long-term tobramycin inhalation solution (TIS) once daily on exacerbation rate in patients with non-cystic fibrosis bronchiectasis.

BACKGROUND: Use of long-term tobramycin inhalation solution (TIS) has been shown beneficial in cystic fibrosis (CF) and earlier findings also suggest a benefit in non-CF bronchiectasis. We investigated the efficacy and safety of maintenance TIS once daily (OD) in frequent exacerbating bronchiectasis patients chronically infected by different pathogens sensitive for tobramycin. OBJECTIVE: The primary outcome was the frequency of exacerbations during the 12-month study period. Secondary outcomes were time to first exacerbation, change in lung function and quality of life (QoL), bacterial analysis and safety. MATERIALS/PATIENTS: IN THIS MULTICENTER RCT PATIENTS AGED ≥ 18-YEAR-OLD WERE INCLUDED WITH CONFIRMED BRONCHIECTASIS AND ≥ 2 EXACERBATIONS IN THE PRECEDING YEAR. PATIENTS WERE ASSIGNED (1:1) TO RECEIVE TIS OR PLACEBO OD FOR 1-YEAR.: RESULTS: 58 patients were included of which 52 were analyzed in the mITT analysis. TIS reduced exacerbation frequency with a RR of 0.74 (95% CI 0.49-1.14) (p = 0.15). Within the TIS population a decrease in number of exacerbations was found (2; p = 0.00), which was also seen in the placebo-treated patients (1.5; p = 0.00). In the TIS-treated patients the QoL improved (LRTI-VAS p = 0.02 Leicester Cough p = 0.02) without additional safety concerns. No differences were found for the other secondary outcomes. CONCLUSION: Long-term TIS OD is a safe treatment modality and showed a non-significant reduced exacerbation frequency of 0.74 as compared to placebo in bronchiectasis patients chronically infected by tobramycin sensitive pathogens. TIS OD may be a potential therapeutic strategy in selected patients with bronchiectasis suffering from a high burden of disease. TRAIL REGISTRATION NUMBER: The BATTLE study was registered at Clinical trials.gov number: NCT02657473 . Date: 13 august 2016.

ß2-Adrenergic receptor agonists activate CFTR in intestinal organoids and subjects with cystic fibrosis.

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 ß2-adrenergic receptor agonists as the most potent inducers of CFTR function.ß2-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 ß2-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.

Inhibition of Heat-Stable Toxin-Induced Intestinal Salt and Water Secretion by a Novel Class of Guanylyl Cyclase C Inhibitors.

BACKGROUND: Many enterotoxigenic Escherichia coli strains produce the heat-stable toxin, STa, which, by activation of the intestinal receptor-enzyme guanylyl cyclase (GC) C, triggers an acute, watery diarrhea. We set out to identify GCC inhibitors that may be of benefit for the treatment of infectious diarrheal disease. METHODS: Compounds that inhibit STa-induced cyclic guanosine 3',5'-monophosphate (cGMP) production were selected by performing cyclase assays on cells and membranes containing GCC, or the related GCA. The effect of leads on STa/GCC-dependent activation of the cystic fibrosis transmembrane conductance regulator anion channel was investigated in T84 cells, and in porcine and human intestinal tissue. Their effect on STa-provoked fluid transport was assessed in ligated intestinal loops in piglets. RESULTS: Four N-2-(propylamino)-6-phenylpyrimidin-4-one-substituted piperidines were shown to inhibit GCC-mediated cellular cGMP production. The half maximal inhibitory concentrations were ≤ 5 × 10(-7) mol/L, whereas they were >10 times higher for GCA. In T84 monolayers, these leads blocked STa/GCC-dependent, but not forskolin/adenylyl cyclase-dependent, cystic fibrosis transmembrane conductance regulator activity. GCC inhibition reduced STa-provoked anion secretion in pig jejunal tissue, and fluid retention and cGMP levels in STa-exposed loops. These GCC inhibitors blocked STa-provoked anion secretion in rectal biopsy specimens. CONCLUSIONS: We have identified a novel class of GCC inhibitors that may form the basis for development of future therapeutics for (infectious) diarrheal disease.

Influence of perfusate temperature on nasal potential difference.

Nasal potential difference (NPD) quantifies abnormal ion transport in cystic fibrosis. It has gained acceptance as an outcome measure for the investigation of new therapies. To quantify the effect of solution temperature on NPD, we first examined the effect of switching from room temperature (20-25°C) to warmed (32-37°C) solutions and vice versa during each perfusion step. Secondly, standard protocols were repeated at both temperatures in the same subjects. Changing solution temperature did not alter NPD during perfusion with Ringer's solution (<1 mV) (p>0.1). During perfusion with zero chloride solution, changing from room temperature to warmed solutions tended to decrease absolute NPD (i.e. it became less negative) by 0.9 mV (p>0.1); changing from warmed to room temperature increased NPD by 2.1 mV (p<0.05). During isoprenaline perfusion, changing from room temperature to warmed solutions increased NPD by 1.5 mV (p<0.01) and from warmed to room temperature decreased NPD by 1.4 mV (p<0.05). For full protocols at room temperature or warmed in the same subjects, mean values were similar (n = 24). During warmed perfusion, group results for total chloride response had a larger standard deviation. As this increased variability will probably decrease the power of trials, this study suggests that solutions at room temperature should be recommended for the measurement of NPD.

No long-term effect of past Pneumocystis jirovecii pneumonia on pulmonary function in people with HIV.

OBJECTIVE: To assess the impact of past Pneumocystis jirovecii pneumonia (PJP) on the pulmonary diffusion capacity in people with HIV (PWH) with a history of advanced immunodeficiency. DESIGN: Prospective cross-sectional study. METHODS: Adult PWH with past PJP >1 year ago were included as the study group. The control group consisted of PWH with a nadir CD4 + lymphocyte count <200 cells/mm 3 , matched by age, sex, smoking status and time since HIV diagnosis. All PWH completed a pulmonary function test (PFT) consisting of pre-bronchodilation spirometry, body plethysmography and single-breath carbon monoxide transfer factor (TLCO) measurement. TLCO, diffusion impairment (defined as a TLCO Z -score <-1.645), total lung capacity (TLC) and forced expiratory volume in one second/forced vital capacity (FEV1/FVC) Z -scores were assessed. Multivariable regression analyses were conducted with Z -scores and odds of diffusion impairment as outcomes. RESULTS: PFTs of 102 participants were analyzed, 51 of whom had past PJP with a median of 10 years since PJP. Mean TLCO Z -score and diffusion impairment rate did not differ significantly between groups ( P  = 0.790; P  = 0.650). Past PJP was not independently associated with TLCO Z -score [ ß = 0.14; 95% confidence interval (CI) -0.30-0.57], diffusion impairment (odds ratio 1.00; 95% CI 0.36-2.75) nor TLC or FEV1/FVC Z -scores, whereas current (vs. never) smoking was associated with more diffusion impairment and lower TLCO Z -scores. CONCLUSION: In our study, past PJP was not associated with long-term diffusion impairment. Our findings suggest that smoking plays a more important role in persistent pulmonary function impairment whereas PJP-related changes seem to be reversible.

Treatment with inhaled antibiotics in bronchiectasis, side effects, and evaluation of the tolerance test; analysis from the BATTLE randomized controlled trial.

INTRODUCTION: Tobramycin inhalation solution (TIS) is a treatment option for patients with frequent exacerbations of bronchiectasis. A possible side effect of TIS is the development of chronic cough and bronchospasm, whereby the guidelines suggest a (in hospital) tolerance test with the first dose of TIS. However, data on respiratory adverse events are not consistent. In the present analysis from the BATTLE study (NCT02657473), we evaluated the added value of the tolerance test and aimed to observe the development of inhaled treatment related bronchial hyperreactivity. METHODS: Fifty-seven patients from the BATTLE study were analyzed. Patients were randomized to receive TIS or placebo OD for 1 year. A tolerance test was performed with spirometry measurements before and after the first dose and with a bronchodilator in advance. Adverse events were strictly monitored. RESULTS: Fifty-seven patients (100%) passed the tolerance test with no decrease in spirometry measurements or development of local intolerability. During the study treatment, a total of five TIS-treated patients (17.8%) withdrew due to airway hyperresponsiveness after a mean of 9.2 (SD13.9) weeks and one placebo-treated patient (3.5%) after 2 weeks (TIS vs. placebo; p = 0.66). The other TIS-related adverse events were not clinically significant. CONCLUSION: The use of inhaled medication is well tolerated in the heterogenous bronchiectasis population, without signs of airway hyperresponsiveness after the first dose of inhaled medication. From this observation, it can be concluded that there is no additional value for this advised tolerance test. However, closely monitoring on adverse effects during the first weeks after starting TIS is recommended.

Radiological and long-term clinical response to elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis with advanced lung disease.

INTRODUCTION: A triple combination of CFTR modulators ELE/TEZ/IVA (elexacaftor/tezacaftor/ivacaftor, Trikafta™) has been evaluated in clinical trials for people with cystic fibrosis (pwCF) and was approved to the European and US market. During registration and settling reimbursement in Europe, it could be requested on a compassionate use basis, for patients with advanced lung disease (ppFEV1 < 40). AIM: The aim of this study is to evaluate 2 years of experience with the clinical and radiological response of ELE/TEZ/IVA in pwCF in a compassionate use setting. METHODS: pwCF who started ELE/TEZ/IVA in a compassionate use setting were prospectively followed with assessment of spirometry, BMI, chest CT, CFQ-R and sweat chloride concentration (SCC) before start and after 3 months. Furthermore, spirometry, sputum cultures, and BMI were repeated after 1, 6, 12, 18, and 24 months. RESULTS: Eighteen patients were eligible for this evaluation, nine with F508del/F508del genotype (eight of whom were using dual CFTR modulators) and nine with F508del/minimal function mutation. After 3 months, mean change in SCC was -44.9 (p ≤ 0.001), together with significant improvement in CT (change in Brody score: -28.27 p ≤ 0.001) and CFQ-R results (change in respiratory domain: +18.8, p = 0.002). After 24 months, ppFEV1 change was +8.89 (p = 0.002), BMI had improved by +1.53 kg/m2 (p ≤ 0.001) and exacerbation rate declined from 5.94 in 24 months before start to 1.17 (p ≤ 0.001) in the 24 months after. CONCLUSION: pwCF with advanced lung disease experience relevant clinical benefit after 2 years of treatment with ELE/TEZ/IVA in a compassionate use setting. Structural lung damage, quality of life, exacerbation rate, and BMI improved significantly with treatment. Gain in ppFEV1 is lower compared to the phase III trials that included younger patients with moderately affected lung function.

Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation.

BACKGROUND: VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro. METHODS: A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo. RESULTS: The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens. CONCLUSIONS: In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit. CLINICAL TRIAL NUMBER: NCT00865904.

[Dutch guideline to prevent perioperative pulmonal complications: how is the adherence?] / Protocol ter preventie van perioperatieve pulmonale complicaties.

INTRODUCTION: Patients with a history of chronic obstructive pulmonary disease (COPD) or asthma undergoing surgery are at risk for developing postoperative pulmonary complications, associated with morbidity and mortality. A national guideline was composed on preventive strategies in non-thoracic surgery, in which perioperative administration of corticosteroids are a cornerstone. We investigated the implementation in our hospital. METHOD: Patients with a history of asthma and/or COPD who underwent non-thoracic surgery between January 2017 and July 2018 in our hospital, were included. Primary outcome was perioperative administration of intravenous prednisolone or oral prednisone as preventative treatment. The reasons for (non)adherence were investigated as secondary outcome. RESULTS: 1,623 patients qualified for a preventative treatment. Overall, 653 patients (40%) received treatment according to protocol. The other 970 patients received no treatment (79%), another corticosteroid (12%) or received the other strategy (9%). Based on interviews and surveys, several barriers were found: fear of side effects of corticosteroids, indications for other types of corticosteroids, and lack of confidence in the literature. CONCLUSION: The current guideline for prevention of postoperative pulmonary complications has not been implemented thoroughly at our hospital. The lack of adherence appears to be caused by lack in clarity in clinical practice, lack of confidence in the evidence on which the protocol is based, and fear of side effects of corticosteroids. There are also notable differences between the vision of pulmonologists and the anesthesiologists. Further research is needed to solidify the guideline, anticipating aforementioned compliance barriers to achieve better implementation.

The effect of maintenance azithromycin on radiological features in patients with bronchiectasis - Analysis from the BAT randomized controlled trial.

RATIONALE: Bronchiectasis (abnormal dilatation of bronchi) is usually diagnosed by high resolution computed tomography (HRCT) and radiological severity has been found to correspond with clinical outcome. A beneficial effect of macrolides maintenance treatment in frequent exacerbating bronchiectasis patients has been established in randomized trials. This study was undertaken to prospectively evaluate the effect of long-term azithromycin (AZM) on radiological features in patients with bronchiectasis. METHODS: The BAT randomized controlled trial (2008-2010) investigated the effect of 1 year of AZM (250 mg OD) in bronchiectasis with frequent exacerbations. Chest (HR)CT-scans at baseline and after one year of study treatment were obtained and scored by two radiologists according to the Brody - and the Bhalla scoring system. RESULTS: 77 (93%) patients conducted the BAT trial were evaluated in this post-hoc analysis. A significant improvement of the radiological features based on the Brody score was found after one year of AZM therapy as compared to placebo (p = 0.024), with a not significant improvement of the Bhalla score (p=0.071). Especially the consolidation (Bhalla) and parenchymal changes (Brody) sub scores significantly improved (both p=0.030), and even a radiological deterioration was seen on the Brody bronchiectasis sub score for the placebo treated patients (mean 14.5 (11.7) vs.15.7 (11.9)). CONCLUSIONS: The beneficial effect of long-term AZM treatment on radiological features was demonstrated in this randomized controlled trial. (HR)CT's can be used as an objective measure of treatment response in bronchiectasis. CLINICAL TRIAL REGISTRATION NUMBER: NCT00415350.

Diagnostic value of routine chest tube tip culture in surgery for noninfectious lung disease.

BACKGROUND: Evaluation of the diagnostic value of routine chest tube tip culture for detection of postoperative infection after surgery for noninfectious lung disease. METHODS: Included subjects were patients who underwent lung surgery between January 1st 2013 and January 1st 2018 in University Medical Centre Utrecht and of whom a chest tube tip was cultured. Postoperative outcomes included pneumonia, surgical site infection, and empyema within 30 days after surgery. Univariable analysis for diagnostic accuracy of chest tube tip culture results predicting these postoperative outcomes was performed, as well as multivariable analysis using penalized firth logistic regression. RESULTS: Patients developed one or more postoperative infections in 42 out of 210 (20%) lung surgeries. Pneumonia, surgical site infection, and empyema were found in 36 (17%), 8 (4%), and 2 (1%) cases respectively. Chest tube tip culture had a sensitivity of 31%, a specificity of 83%, a positive predictive value of 32%, and a negative predictive value of 83% for postoperative infections. In the subgroup of patients who did not have evidence of postoperative infection at the time of chest tube removal, the drain tip culture's positive and negative predictive value changed to 18% and 92% respectively. Adding additional variables to chest tube tip culture in a prediction model resulting in only limited improvement in diagnostic performance. CONCLUSIONS: We found insufficient diagnostic performance to support the practice of routine chest tube tip culture after surgery for noninfectious lung disease. Therefore, routine chest tube tip culture is not advisable and should be omitted to unburden the healthcare process and prevent low value care together with extra costs.

Management of Individual Patient Expectations When Starting with Highly Effective CFTR Modulators.

Highly effective CFTR modulators such as elexacaftor/tezacaftor/ivacaftor (ELE/TEZ/IVA will become available for an increasing number of people with cystic fibrosis (pwCF) in the near future. Before the start of this therapy, many questions may arise concerning the expected effects. We assembled the currently available data from the literature about ELE/TEZ/IVA that focused on commonly asked questions from patients. Overall, the literature so far presents a very hopeful prospect of effects, not only on lung function, but also on nutritional status, sinonasal symptoms and quality of life. The effects in patients with pwCF with severe lung damage are also favorable. Treatment is generally well tolerated. In some cases, patient-derived cell models can help in predicting the effects for individual patients.

Nasal potential difference in suspected cystic fibrosis patients with 5T polymorphism.

BACKGROUND: 5T polymorphism is a CFTR mutation with unclear clinical consequences: the phenotype varies from healthy individuals to Cystic Fibrosis (CF). The aim of this study was to evaluate if nasal potential difference (NPD) and sweat testing correlate with symptoms and CF diagnosis in 5T patients. METHODS: 86 patients with 5T who had undergone NPD measurement, were included (6 homozygous (5T/5T), 41 with a PI-CF causing mutation in trans (5T/PI-CF), 11 with a PS-CF causing mutation in trans (5T/PS-CF) and 28 without a known mutation in trans (5T/?). Data including age, phenotype, sweat chloride and follow up were collected. RESULTS: 33% of the 5T/5T patients had abnormal NPD results, compared to 70% in 5T/PI-CF; 33% in 5T/PS-CF and 29% in 5T/?. The percentage of high or borderline sweat chloride was highest in 5T/PI-CF, and 5T/?, compared to 5T/5T and 5T/PS-CF (91, 96, 80, and 63%, respectively). TGm (number of TG repeats in intron 8) analysis was performed in 21 5T/PI-CF patients. TG11 was associated with lower sweat chloride, lower percentage of abnormal NPD and less progression of symptoms compared to TG12 and TG13. CONCLUSION: There is much variation in clinical status among 5T patients. All patients in this study with 5T/PS CF, all patients with both normal NPD and sweat test, and most patients with TG11 were stable or improving over time. Therefore, NPD measurement and TGm status aid to assess if a patient is at high risk for developing CF or CFTR-related disease and if specific follow up in a CF center is required.

Standardized Measurement of Nasal Membrane Transepithelial Potential Difference (NPD).

We describe a standardized measurement of nasal potential difference (NPD). In this technique, cystic fibrosis transmembrane conductance regulator (CFTR) and the epithelial sodium channel (ENaC) function are monitored by the change in voltage across the nasal epithelium after the superfusion of solutions that modify ion channel activity. This is enabled by the measurement of the potential difference between the subcutaneous compartment and the airway epithelium in the nostril, utilizing a catheter in contact with the inferior nasal turbinate. The test allows the measurement of the stable baseline voltage and the successive net voltage changes after perfusion of 100 µM amiloride, an inhibitor of Na+ reabsorption in Ringer's solution; a chloride-free solution containing amiloride to drive chloride secretion and 10 µM isoproterenol in a chloride-free solution with amiloride to stimulate the cyclic adenosine monophosphate (cAMP)-dependent chloride conductance related to CFTR. This technique has the advantage of demonstrating the electrophysiological properties of two key components establishing the hydration of the airway surface liquid of the respiratory epithelium, ENaC, and CFTR. Therefore, it is a useful research tool for phase 2 and proof of concept trials of agents that target CFTR and ENaC activity for the treatment of cystic fibrosis (CF) lung disease. It is also a key follow-up procedure to establish CFTR dysfunction when genetic testing and sweat testing are equivocal. Unlike sweat chloride, the test is relatively more time consuming and costly. It also requires operator training and expertise to conduct the test effectively. Inter- and intra-subject variability has been reported in this technique especially in young or uncooperative subjects. To assist with this concern, interpretation has been improved through a recently validated algorithm.

Is sweat chloride predictive of severity of cystic fibrosis lung disease assessed by chest computed tomography?

BACKGROUND: Cystic Fibrosis (CF) lung disease is characterized by a marked heterogeneity. Sweat chloride-level is a functional marker of the CF Transmembrane Regulator (CFTR) protein and could be an important predictor of later disease severity. METHODS: In this retrospective analysis children from the Rotterdam CF clinic with available sweat chloride level at diagnosis and at least one routine spirometry-controlled volumetric chest CT scan in follow-up were included. CT scans were scored using the CF-CT scoring system (% of maximum). Associations between sweat chloride-levels and CF-CT scores were calculated using linear regression models, adjusting for age at sweat test and age at follow-up. Because structural lung damage develops over the course of many years, effect modification by the age at follow-up CT-scan was tested for by age-stratification. RESULTS: In 59 children (30 male) sweat chloride was measured at diagnosis (median age 0.5 years, range 0-13) and later chest CT performed (median age 14 years, range 6-18). Sweat chloride was associated with significantly higher CT-CT total score, bronchiectasis score, and mucus plugging score. Stratification for age at follow-up in tertiles showed this association remained only in the oldest age group (range 15-18 years). In that subgroup associations were found with all but one of the CF-CT subscores, as well as with all tested lung functions parameters. CONCLUSION: Sweat chloride-level is a significant predictor of CF lung disease severity as determined by chest CT and lung function. This association could only be demonstrated in children with follow-up to age 15 years and above.

Potentiator synergy in rectal organoids carrying S1251N, G551D, or F508del CFTR mutations.

The potentiator VX-770 (ivacaftor/KALYDECO™) targets defective gating of CFTR and has been approved for treatment of cystic fibrosis (CF) subjects carrying G551D, S1251N or one of 8 other mutations. Still, the current potentiator treatment does not normalize CFTR-dependent biomarkers, indicating the need for development of more effective potentiator strategies. We have recently pioneered a functional CFTR assay in primary rectal organoids and used this model to characterize interactions between VX-770, genistein and curcumin, the latter 2 being natural food components with established CFTR potentiation capacities. Results indicated that all possible combinations of VX-770, genistein and curcumin synergistically repaired CFTR-dependent forskolin-induced swelling of organoids with CFTR-S1251N or CFTR-G551D, even under suboptimal CFTR activation and compounds concentrations, conditions that may predominate in vivo. Genistein and curcumin also enhanced forskolin-induced swelling of F508del homozygous organoids that were treated with VX-770 and the prototypical CFTR corrector VX-809. These results indicate that VX-770, genistein and curcumin in double or triple combinations can synergize in restoring CFTR-dependent fluid secretion in primary CF cells and support the use of multiple potentiators for treatment of CF.

Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis.

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.

Emphysema Is Common in Lungs of Cystic Fibrosis Lung Transplantation Patients: A Histopathological and Computed Tomography Study.

BACKGROUND: Lung disease in cystic fibrosis (CF) involves excessive inflammation, repetitive infections and development of bronchiectasis. Recently, literature on emphysema in CF has emerged, which might become an increasingly important disease component due to the increased life expectancy. The purpose of this study was to assess the presence and extent of emphysema in endstage CF lungs. METHODS: In explanted lungs of 20 CF patients emphysema was semi-quantitatively assessed on histology specimens. Also, emphysema was automatically quantified on pre-transplantation computed tomography (CT) using the percentage of voxels below -950 Houndfield Units and was visually scored on CT. The relation between emphysema extent, pre-transplantation lung function and age was determined. RESULTS: All CF patients showed emphysema on histological examination: 3/20 (15%) showed mild, 15/20 (75%) moderate and 2/20 (10%) severe emphysema, defined as 0-20% emphysema, 20-50% emphysema and >50% emphysema in residual lung tissue, respectively. Visually upper lobe bullous emphysema was identified in 13/20 and more diffuse non-bullous emphysema in 18/20. Histology showed a significant correlation to quantified CT emphysema (p = 0.03) and visual emphysema score (p = 0.001). CT and visual emphysema extent were positively correlated with age (p = 0.045 and p = 0.04, respectively). CONCLUSIONS: In conclusion, this study both pathologically and radiologically confirms that emphysema is common in end-stage CF lungs, and is age related. Emphysema might become an increasingly important disease component in the aging CF population.

Ex vivo CF diagnosis by intestinal current measurements (ICM) in small aperture, circulating Ussing chambers.

Intestinal current measurements (ICM) on rectal suction biopsies are a tool for the ex vivo diagnosis of classical and atypical cystic fibrosis (CF). We present the basic ICM protocol, typical tracings and their interpretation. The ICM technique allows the registration of CF-induced changes in electrogenic transepithelial ion transport (Cl-, HCO3-, K+) in a Cl- secretory epithelium, and on the basis of pharmacological criteria, is able to discriminate between CFTR-mediated Cl- secretion and secretion through alternative anion channels. ICM is particularly useful for the classification of individuals with CF-like clinical features with equivocal sweat test values and/or no or one identifiable CFTR mutation.