Spirometric and anthropometric improvements in response to elexacaftor/tezacaftor/ivacaftor depending on age and lung disease severity.

Introduction: Triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) was introduced in August 2020 in Germany for people with CF (pwCF) ≥12 years (yrs.) of age and in June 2021 for pwCF ≥6 yrs of age. In this single-center study, we analyzed longitudinal data on the percent-predicted forced expiratory volume (ppFEV1) and body-mass-index (BMI) for 12 months (mo.) after initiation of ETI by linear mixed models and regression analyses to identify age- and severity-dependent determinants of response to ETI. Methods: We obtained data on 42 children ≥6-11 yrs, 41 adolescents ≥12-17 yrs, and 143 adults by spirometry and anthropometry prior to ETI, and 3 and 12 mo. after ETI initiation. Data were stratified by the age group and further sub-divided into age-specific ppFEV1 impairment. To achieve this, the age strata were divided into three groups, each according to their baseline ppFEV1: lowest 25%, middle 50%, and top 25% of ppFEV1. Results: Adolescents and children with more severe lung disease prior to ETI (within the lowest 25% of age-specific ppFEV1) showed higher improvements in lung function than adults in this severity group (+18.5 vs. +7.5; p = 0.002 after 3 mo. and +13.8 vs. +7.2; p = 0.012 after 12 mo. of ETI therapy for ≥12-17 years and +19.8 vs. +7.5; p = 0.007 after 3 mo. for children ≥6-11 yrs). In all age groups, participants with more severe lung disease showed higher BMI gains than those with medium or good lung function (within the middle 50% or top 25% of age-specific ppFEV1). Regression analyses identified age as a predictive factor for FEV1 increase at 3 mo. after ETI initiation, and age and ppFEV1 at ETI initiation as predictive factors for FEV1 increase 12 mo. after ETI initiation. Discussion: We report initial data, which suggest that clinical response toward ETI depends on age and lung disease severity prior to ETI initiation, which argue for early initiation of ETI.

Differential effects of ELX/TEZ/IVA on organ-specific CFTR function in two patients with the rare CFTR splice mutations c.273+1G>A and c.165-2A>G.

Introduction: Evidence for the efficiency of highly-effective triple-CFTR-modulatory therapy with elexacaftor/tezacaftor/ivacaftor (ETI), either demonstrated in clinical trials or by in vitro testing, is lacking for about 10% of people with cystic fibrosis (pwCF) with rare mutations. Comprehensive assessment of CFTR function can provide critical information on the impact of ETI on CFTR function gains for such rare mutations, lending argument of the prescription of ETI. The mutation c.165-2A>G is a rare acceptor splice mutation that has not yet been functionally characterized. We here describe the functional changes induced by ETI in two brothers who are compound heterozygous for the splice mutations c.273+1G>C and c.165-2A>G. Methods: We assessed the effects of ETI on CFTR function by quantitative pilocarpine iontophoresis (QPIT), nasal potential difference measurements (nPD), intestinal current measurements (ICM), ß-adrenergic sweat secretion tests (SST) and multiple breath washout (MBW) prior to and 4 months after the initiation of ETI. Results: Functional CFTR analysis prior to ETI showed no CFTR function in the respiratory and intestinal epithelia and in the sweat gland reabsorptive duct in either brother. In contrast, ß-adrenergic stimulated, CFTR-mediated sweat secretion was detectable in the CF range. Under ETI, both brothers continued to exhibit high sweat chloride concentration in QPIT, evidence of low residual CFTR function in the respiratory epithelia, but normalized ß-adrenergically stimulated production of primary sweat. Discussion: Our results are the first to demonstrate that the c.165-2A>G/c.273+1G>C mutation genotype permits mutant CFTR protein expression. We showed organ-specific differences in the expression of CFTR and consecutive responses to ETI of the c.165-2A>G/c.273+1G>C CFTR mutants that are probably accomplished by non-canonical CFTR mRNA isoforms. This showcase tells us that the individual response of rare CFTR mutations to highly-effective CFTR modulation cannot be predicted from assays in standard cell cultures, but requires the personalized multi-organ assessment by CFTR biomarkers.

Comparison of Three Eradication Treatment Protocols for Pseudomonas Aeruginosa in Children and Adolescents with Cystic Fibrosis.

BACKGROUND: Pseudomonas aeruginosa (Pa) continues to affect disease progression in cystic fibrosis (CF). However, the best eradication regimen remains unclear. This work compares three different antibiotic eradication regimens in pediatric CF: an administration according to a standard-operating procedure (SOP) order vs. administration outside of this order (ooSOP). METHODS: This observational study includes all CF patients<18 years who received one of three Pa eradication treatments in the past eight years at our center: 1) inhaled high-dose tobramycin (Hi-TOBI), 2) inhaled colistin+oral ciprofloxacin (COL/Cip), 3) inhaled low-dose tobramycin+4 intravenous 14-day Pa active antibiotic treatments (lo-Tobra/IV). We compared eradication rates of the three treatment regimens performed according to the SOP-based order vs. ooSOP. Logistic regression analysis was performed to identify risk factors for eradication failure. RESULTS: Performed according to SOP order, Hi-TOBI showed the greatest efficacy, followed by lo-Tobra/IV and finally COL/Cip, while ooSOP lo-Tobra/IV was most successful, followed by COL/Cip and Hi-TOBI. Previous Pa-infections and Pa-therapies along with age at CF diagnosis were risk factors for eradication failure. CONCLUSION: Antibiotic treatment in SOP-based pre-defined order leads to significantly better eradication rates than individual modifications of the order of administration. A short course of inhalational high-dose Tobramycin is most successful at the first attempt. Prolonged antibiotic therapy seems to improve eradication after failed initial attempts.

Pulmonary Alveolar Microlithiasis: A novel patient and brief review of the literature.

Pulmonary Alveolar Microlithiasis (PAM) is a rare hereditary lung disease caused by biallelic pathogenic variants (pV) in the solute family 34 member 2 gene (SLC34A2; Izumi et al., Am J Respir Crit Care Med 2007; 175: 263-268). pVs in this sodium phosphate co-transporter gene lead to accumulation of calcium phosphate crystals within pulmonary alveoli. More than 1000 cases of PAM were thus far reported, with high variance in disease courses (Stamatis et al., Ann Thorac Surg 1993; 56: 972-975). Frequently, asymptomatic cases are observed, and often times slow disease progression until respiratory insufficiency in middle age occurs (Kosciuk, Eur Respir Rev 2020; 29: 200024). Treatment options for PAM are scarce and largely ineffective, and lung transplantation is the only effective therapy in end-stage disease (Stamatis et al., Ann Thorac Surg 1993; 56: 972-975). Here, we report a novel PAM case in an adolescent migrant from East Africa and discuss current diagnostic and therapeutic options.

The First 4 Years - Outcome of Children Identified by Newborn Screening for CF in Germany.

BACKGROUND: Newborn screening (NBS) has been shown to improve cystic fibrosis (CF) disease course and has been widely implemented worldwide. This monocentric study compared children diagnosed by NBS vs. a cohort preceding the implementation of NBS in Germany in 2016 to evaluate ascribed benefits of NBS. METHODS: We compared all children with confirmed CF diagnosis (n=19, "NBS group") out of all children presenting with positive NBS at our center after implementation of NBS (n=100) to children diagnosed with CF at our center within 4 years before NBS implementation (n=29, "pre-NBS group") for outcomes of anthropometry, gastrointestinal and pulmonary disease manifestations and respiratory microbiology. RESULTS: Children diagnosed by NBS had a lower incidence of initial difficulty to thrive (15 vs. 41%) and showed higher mean z-scores for Body-Mass-Index (BMI), weight and length at diagnosis and during study period. Children in the pre-NBS group displayed higher proportions of oxygen-dependent pulmonary exacerbations (10 vs. 0%). They show a significantly lower amount of normal bacterial flora (p=0.005) along with a significantly higher number of throat swab cultures positive for Pseudomonas aeruginosa (p=0.0154) in the first year of life. Yet, pulmonary imaging did not reveal less pulmonary morbidity in the NBS group. CONCLUSIONS: Our results confirm that NBS for CF leads to earlier diagnosis and improves nutritional outcomes in early childhood. Although trajectories of structural lung damage at early age were unaffected by NBS, NBS positive CF patients at preschool age displayed less pulmonary exacerbations and pathological bacteria in throat swabs.

Intestinal current measurement and nasal potential difference to make a diagnosis of cases with inconclusive CFTR genetics and sweat test.

BACKGROUND: Nasal potential difference (NPD) and intestinal current measurements (ICM) are cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers recommended to make a diagnosis in individuals with inconclusive sweat test and CFTR genetics and a clinical suspicion for cystic fibrosis (CF) or CFTR-related disorder (CFTR-RD). METHODS: NPD and ICM were measured according to standard operating procedures of the European Cystic Fibrosis Society Diagnostic Network Working Group. RESULTS: We assessed 219 individuals by NPD or ICM who had been referred to our laboratory due to clinical symptoms suggestive of CF, but inconclusive sweat test and CFTR genetics (median age: 16.3 years, range 0.4 to 76 years). CF or CFTR-related disorder was diagnosed in 22 of 29 patients (76%) with a CFTR genotype of unknown or variable clinical significance and in 51 of 190 carriers (27%) of one (35/42) or no (16/148) identified CFTR mutation. If two CFTR sequence variants had been identified, the outcome of NPD and ICM was consistent with the classification of the CFTR2 database. Moreover, a suspected false-positive diagnosis of CF was confirmed in seven and withdrawn in eight patients. Of 26 individuals assessed by both NPD and ICM, eleven individuals exhibited discordant tracings of ICM and NPD, with one measurement being in the CF range and the other in the normal range. CONCLUSION: The majority of patients whom we diagnosed with CF or CFTR-RD by extended electrophysiology are carriers of the wild-type CFTR coding sequence on at least one of their CF alleles. The disease-causing genetic lesions should reside in the non-coding region of CFTR or elsewhere in the genome, affecting the regulation of CFTR expression in a tissue-depending fashion which may explain the large within-group variability of CFTR activity in the respiratory and intestinal epithelium seen in this group.

An apple a day won't keep the doctor away: presentation, treatment, and outcome in pediatric apple aspirations.

INTRODUCTION: Foreign body (FB) aspiration is a frequent and preventable source of morbidity and mortality, especially in children under 4 years of age. Few comprehensive studies exist on presentation and outcome of apple aspirations in children. METHODS: In a retrospective analysis of bronchoscopy records of a tertiary medical care center from January 2007 to August 2019, we identified pediatric cases of suspected apple aspirations. RESULTS: A total of 11 suspected apple aspirations were identified (observation time 12.7 years, n = 5858 bronchoscopies, n = 226 interventions due to suspected FB aspirations in total). The mean age of patients was 24 months (standard error mean, 7 months; range, 8-83 months), and 6 out of 11 cases (55%) were male. Bronchoscopy confirmed apple aspiration in n = 6/11 cases (55%). In n = 2/11 cases (18%), a bite of the apple was located in the esophagus causing significant tracheal narrowing, and in n = 3/11 cases (27%), no FB was found. In all cases of airway FB identification, extraction was successful. Hypersalivation was associated with esophageal FB location, whereas persistent cough, stridor, or dyspnea were associated with airway FB location. Outcomes ranged from complete reconstitution 1 day after bronchoscopy in most cases to hypoxemia with severe brain damage in one patient. DISCUSSION: This analysis shows that apple aspirations are not entirely uncommon in children and may lead to disastrous complications. Typical signs of airway location are persistent cough, stridor or dyspnea, whereas hypersalivation may point toward an esophageal location. In each case of suspected apple aspiration, timely bronchoscopy with possible FB extraction should be performed by an experienced team.

Glucose Tolerance in Patients with Cystic Fibrosis - Results from the German Cystic Fibrosis Registry.

BACKGROUND: Oral glucose tolerance (OGT) deteriorates progressively in cystic fibrosis (CF). Clinical registries provide a unique basis to study real-world data. PATIENTS & METHODS: OGT tests (OGTTs) documented in the German CF-registry in 2016 were classified according WHO, modified by ADA: normal glucose tolerance (NGT), indeterminate glycaemia (INDET), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG+IGT, diabetes mellitus (DM). To study the association with lung function, multivariable regression adjusted for age, sex, and CFTR mutation was performed. RESULTS: Overall, OGTT screening was done in 35% of CF patients ≧10 years. Of the 996 patients (46.4% females; median age (IQR): 19 (14-27) years) with evaluable OGTTs, 56.2% had either NGT or INDET, whereas 34% had a pre-diabetic OGTT (IFG; IGT; IFG+IGT) and 9.8% a diabetic OGTT. 7 patients had glucose tolerance abnormalities <10 years. DM was more common in females or patients with F508del homozygote mutation, whereas IFG was more frequent in males (all p<0.05). Nearly 75% of patients after transplantation and about half with enteral/parental nutrition and/or steroid use had either a pre-diabetic or diabetic glucose tolerance. In the adjusted model, age (p<0.001) and OGTT category (p=0.013) had both a significant impact on %FEV1. CONCLUSION: Our data of the German CF-registry highlights incidence of glucose tolerance abnormalities in second decade of life in CF patients. However, it also underlines the need for improvement of the documentation and/or performance of OGTT screening in real-world CF care. HINTERGRUND: Bei Mukoviszidose (zystischer Fibrose: CF) verschlechtert sich die orale Glukosetoleranz (OGT) im Krankheitsverlauf. PATIENTEN & METHODEN: OGT Tests (OGTTs), die 2016 im Deutschen CF-Register dokumentiert waren, wurden gemäß WHO (modifiziert nach ADA) kategorisiert: Normale Glukosetoleranz (NGT), intermittierende Glykämie (INDET), eingeschränkte Nüchternglukosetoleranz (IFG), gestörte Glukosetoleranz (IGT), IFG+IGT, Diabetes Mellitus (DM). Um den Zusammenhang mit der Lungenfunktion zu analysieren, wurde eine multivariable Regressionsanalyse adjustiert für Alter, Geschlecht und CFTR Mutation durchgeführt. ERGEBNISSE: Insgesamt wurden 35% der CF-Patienten ≥10 Jahre mittels OGTT gescreent. Von den 996 Patienten (46,4% weiblich, medianes Alter (IQR): 19 (14-27) Jahre) mit auswertbaren OGTTs hatten 56,2% entweder NGT oder INDET, wohingegen bei 34% ein prädiabetischer (IFG; IGT; IFG+IGT) und bei 9,8% ein diabetischer OGTT beobachtet wurde. Bei 7 Patienten zeigten sich vor dem 10. LJ Abnormalitäten im Glukosestoffwechsel. DM war häufiger bei Frauen und Patienten mit homozygoter F508del Mutation, wobei IFG öfters bei Männern vorlag (alle p<0,05). Ca. 75% der Patienten mit Transplantation und etwa die Hälfte der Patienten mit künstlicher Ernährung und/oder Steroidgabe hatten eine prädiabetische oder diabetische Glukosetoleranz. Das Alter (p<0,001) und die OGTT Kategorie (p=0,013) zeigten im adjustierten Modell eine signifikante Assoziation mit %FEV1. SCHLUSSFOLGERUNG: Unsere Daten unterstreichen das Auftreten von Abnormalitäten im Glukosestoffwechsel bei CF im 2. Lebensjahrzehnt. Jedoch weißt es auf die Notwendigkeit eines regelmäßigen Diabetesscreenings und/oder Dokumentation von OGTTs bei CF hin.

Assessment of a Mobile App by Adolescents and Young Adults With Cystic Fibrosis: Pilot Evaluation.

BACKGROUND: Cystic fibrosis (CF) continues to be the most common life-limiting chronic pulmonary disease in adolescents and young adults. Treatment of CF demands a high treatment time investment to slow the progression of lung function decline, the most important contributor to morbidity and mortality. Adherence is challenging in CF due to the high treatment burden and the lack of immediate health consequences in case of nonadherence. Lung function decline is particularly pronounced in the transition phase between 12 and 24 years of age. The improvement of self-management and self-responsibility and independence from parents and desire for normalcy are conflicting aspects for many adolescents with CF, which influence adherence to the time-consuming pulmonary therapy. Mobile health (mHealth) care apps could help to support self-management and independence and thereby reconcile seemingly conflicting goals to improve adherence, quality of life, and ultimately CF life expectancy. OBJECTIVE: This study aimed to (1) assess user behavior and satisfaction among adolescents and young adults with CF over an observation period of three months using an mHealth app; (2) identify areas of improvement for this mHealth app; and (3) compare overall and disease-specific satisfaction, lung function, and anthropometry before and after using the mHealth app. METHODS: A total of 27 adolescents and young adults with CF (age range 12-24 years, mean age 16 years, SD 3 years; 14 females, 11 males) used a free mHealth app for three months of whom 25 provided questionnaire data for analysis at the end of the study. Data collection was carried out using questionnaires on usage characteristics and life satisfaction, and standardized assessment of lung function and anthropometry. RESULTS: The use of the reminder function for medication declined from 70% (15/21) of the participants at week 4 to 65% (13/20) at week 8 of the observation period. At the end of the study, only 17% (4/23) of the participants wanted to continue using the app. Nevertheless, 56% (14/25) of participants saw the mobile app as a support for everyday life. Potential improvements targeting hedonistic qualities were identified to improve mHealth app adherence. Comparisons of satisfaction with different life aspects hinted at improvements or stabilization for the subitem respiration and the subitem lack of handicap by CF, suggesting that app use might stabilize certain CF-specific aspects of the weighted satisfaction with life. Lung function and anthropometry were not affected consistently. CONCLUSIONS: Most of the patients did not want to continue using the app after the study period. Only a few CF-specific aspects of weighted life satisfaction were possibly stabilized by the mHealth app; clinical parameters were not affected. Adaptation of the functions to adolescent-specific needs could improve the long-term use and thus positively affect the disease course.

Preventive Inhalation of Hypertonic Saline in Infants with Cystic Fibrosis (PRESIS). A Randomized, Double-Blind, Controlled Study.

Rationale: Cystic fibrosis (CF) lung disease starts in early infancy, suggesting that preventive treatment may be most beneficial. Lung clearance index (LCI) and chest magnetic resonance imaging (MRI) have emerged as promising endpoints of early CF lung disease; however, randomized controlled trials testing the safety and efficacy of preventive therapies in infants with CF are lacking. Objectives: To determine the feasibility, safety, and efficacy of preventive inhalation with hypertonic saline (HS) compared with isotonic saline (IS) in infants with CF, including LCI and MRI as outcome measures. Methods: In this randomized, double-blind, controlled trial, 42 infants with CF less than 4 months of age were randomized across five sites to twice-daily inhalation of 6% HS (n = 21) or 0.9% IS (n = 21) for 52 weeks. Measurements and Main Results: Inhalation of HS and IS was generally well tolerated by infants with CF, and the number of adverse events did not differ between groups (P = 0.49). The change in LCI from baseline to Week 52 was larger in infants with CF treated with HS (-0.6) than in those treated with IS (-0.1; P < 0.05). In addition, weight gain was improved in infants with CF treated with HS (P < 0.05), whereas pulmonary exacerbations and chest MRI scores did not differ in the HS group versus the IS group. Conclusions: Preventive inhalation with HS initiated in the first months of life was safe and well tolerated and resulted in improvements in LCI and weight gain in infants with CF. Our results support the feasibility of LCI as an endpoint in randomized controlled trials in infants with CF. Clinical trial registered with www.clinicaltrials.gov (NCT01619657).

Multicentre standardisation of chest MRI as radiation-free outcome measure of lung disease in young children with cystic fibrosis.

BACKGROUND: A recent single-centre study demonstrated that MRI is sensitive to detect early abnormalities in the lung and response to therapy in infants and preschool children with cystic fibrosis (CF) supporting MRI as an outcome measure of early CF lung disease. However, the feasibility of multicentre standardisation remains unknown. OBJECTIVE: To determine the feasibility of multicentre standardisation of chest MRI in infants and preschool children with CF. METHODS: A standardised chest 1.5T MRI protocol was implemented across four specialised CF centres. Following training and initiation visits, 42 infants and preschool children (mean age 3.2±1.5years, range 0-6years) with clinically stable CF underwent MRI and chest X-ray (CXR). Image quality and lung abnormalities were assessed using a standardised questionnaire and an established CF MRI and CXR score. RESULTS: MRI was successfully performed with diagnostic quality in all patients (100%). Incomplete lung coverage was observed in 6% and artefacts also in 6% of sequence acquisitions, but these were compensated by remaining sequences in all patients. The range of the MRI score in CF patients was similar across centres with a mean global MRI score of 13.3±5.8. Cross-validation of the MRI against the CXR score revealed a moderate correlation (r=0.43-0.50, p<0.01). CONCLUSION: Our results demonstrate that multicentre standardisation of chest MRI is feasible and support its use as radiation-free outcome measure of lung disease in infants and preschool children with CF.

Effects of Lumacaftor-Ivacaftor Therapy on Cystic Fibrosis Transmembrane Conductance Regulator Function in Phe508del Homozygous Patients with Cystic Fibrosis.

RATIONALE: The combination of the CFTR (cystic fibrosis transmembrane conductance regulator) corrector lumacaftor with the potentiator ivacaftor has been approved for the treatment of patients with cystic fibrosis homozygous for the Phe508del CFTR mutation. The phase 3 trials examined clinical outcomes but did not evaluate CFTR function in patients. OBJECTIVES: To examine the effect of lumacaftor-ivacaftor on biomarkers of CFTR function in Phe508del homozygous patients with cystic fibrosis aged 12 years and older. METHODS: This prospective observational study assessed clinical outcomes including FEV1% predicted and body mass index, and CFTR biomarkers including sweat chloride concentration, nasal potential difference, and intestinal current measurement before and 8-16 weeks after initiation of lumacaftor-ivacaftor. MEASUREMENTS AND MAIN RESULTS: A total of 53 patients were enrolled in the study, and 52 patients had baseline and follow-up measurements. After initiation of lumacaftor-ivacaftor sweat chloride concentrations were reduced by 17.8 mmol/L (interquartile range [IQR], -25.9 to -6.1; P < 0.001), nasal potential difference showed partial rescue of CFTR function in nasal epithelia to a level of 10.2% (IQR, 0.0-26.1; P < 0.011), and intestinal current measurement showed functional improvement in rectal epithelia to a level of 17.7% of normal (IQR, 10.8-29.0; P < 0.001). All patients improved in at least one CFTR biomarker, but no correlations were found between CFTR biomarker responses and clinical outcomes. CONCLUSIONS: Lumacaftor-ivacaftor results in partial rescue of Phe508del CFTR function to levels comparable to the lower range of CFTR activity found in patients with residual function mutations. Functional improvement was detected even in the absence of short-term improvement of FEV1% predicted and body mass index. Clinical trial registered with www.clinicaltrials.gov (NCT02807415).

Vessel wall contrast enhancement: a diagnostic sign of cerebral vasculitis.

PURPOSE: Inflammatory stenoses of cerebral arteries cause stroke in patients with florid vasculitis. However, diagnosis is often difficult even with digital subtraction angiography (DSA) and biopsy. The purpose of this study was to establish the value of contrast-enhanced MRI, proven to be sensitive to extradural arteritis, for the identification of intracranial vessel wall inflammation. PATIENTS AND METHODS: Twenty-seven patients with a diagnosis of cerebral vasculitis affecting large brain vessels were retrieved from the files: 8 children (2-10 years, 7 female, 1 male) and 19 adults (16-76 years, 10 female, 9 male). Diagnosis was based on histological or serological proof of vasculitis or on clinical and imaging criteria. All MRI examinations included diffusion-weighted imaging, time-of-flight magnetic resonance angiography (TOF-MRA) and contrast-enhanced scans. MRI scans were assessed for the presence of ischemic brain lesions, arterial stenoses, vessel wall thickening and contrast uptake. RESULTS: Ischemic changes of the brain tissue were seen in 24/27 patients and restricted diffusion suggestive of recent ischemia in 17/27; 25/27 patients had uni- or multifocal stenoses of intracranial arteries on TOF-MRA and 5/6 had stenoses on DSA. Vessel wall thickening was identified in 25/27, wall enhancement in 23/27 patients. CONCLUSION: Wall thickening and intramural contrast uptake are frequent findings in patients with active cerebral vasculitis affecting large brain arteries. Further prospective studies are required to determine the specificity of this finding.