Scoring Abdominal Symptoms in People with Cystic Fibrosis.

(1) Background: The introduction of highly effective CFTR-modulating therapies (HEMT) has changed the course of the disease for many people with Cystic Fibrosis (pwCF). Attention previously focused on life-threatening conditions of the respiratory system has broadened, bringing the involvement of the digestive system into the clinical and scientific focus. This emphasized the need for sensitive tools to capture and quantify changes in abdominal symptoms (AS), ideally applying patient-reported outcome measures (PROMs). (2) Methods: The present review focuses on studies addressing AS assessment deriving from the multi-organic abdominal involvement in pwCF. Among 5224 publications retrieved until Nov. 2022, 88 were eligible, and 39 were finally included. (3) Results: The review reveals that for a long time, especially before HEMT availability, AS in pwCF were assessed by single questions on abdominal complaints or non-validated questionnaires. PROMs focusing on quality of life (QOL) including a few GI-related questions were applied. Likewise, PROMs developed and partially validated for other non-CF GI pathologies, such as chronic inflammatory bowel diseases, irritable bowel syndrome, gastroesophageal reflux, constipation, or pancreatitis, were implemented. (4) Conclusions: Only lately, CF-specific GI-PROMs have been developed and validated following FDA guidelines, showing high sensitivity to changes and capturing marked and statistically significant reductions in the burden of AS achieved with HEMT implementation.

[CF Lung Disease - a German S3 Guideline: Pseudomonas aeruginosa]. / S3-Leitlinie: Lungenerkrankung bei Mukoviszidose ­ Pseudomonas aeruginosa.

Cystic Fibrosis (CF) is the most common autosomal recessive genetic multisystemic disease. In Germany, it affects at least 8000 people. The disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene leading to dysfunction of CFTR, a transmembrane chloride channel. This defect causes insufficient hydration of the airway epithelial lining fluid which leads to reduction of the mucociliary clearance.Even if highly effective, CFTR modulator therapy has been available for some years and people with CF are getting much older than before, recurrent and chronic infections of the airways as well as pulmonary exacerbations still occur. In adult CF life, Pseudomonas aeruginosa (PA) is the most relevant pathogen in colonisation and chronic infection of the lung, leading to further loss of lung function. There are many possibilities to treat PA-infection.This is a S3-clinical guideline which implements a definition for chronic PA-infection and demonstrates evidence-based diagnostic methods and medical treatment in order to give guidance for individual treatment options.

ESPEN-ESPGHAN-ECFS guideline on nutrition care for cystic fibrosis.

BACKGROUND: Nutritional status is paramount in Cystic Fibrosis (CF) and is directly correlated with morbidity and mortality. The first ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with CF were published in 2016. An update to these guidelines is presented. METHODS: The study was developed by an international multidisciplinary working group in accordance with officially accepted standards. Literature since 2016 was reviewed, PICO questions were discussed and the GRADE system was utilized. Statements were discussed and submitted for on-line voting by the Working Group and by all ESPEN members. RESULTS: The Working Group updated the nutritional guidelines including assessment and management at all ages. Supplementation of vitamins and pancreatic enzymes remains largely the same. There are expanded chapters on pregnancy, CF-related liver disease, and CF-related diabetes, bone disease, nutritional and mineral supplements, and probiotics. There are new chapters on nutrition with highly effective modulator therapies and nutrition after organ transplantation.

Dynamics of abdominal symptoms during the start of a new therapy with elexacaftor/tezacaftor/ivacaftor using the novel CFAbd-day2day questionnaire.

Background: Elexacaftor-tezacaftor-ivacaftor (ETI) is a novel, highly effective CFTR modulator combination proven to enhance lung function and body weight in people with cystic fibrosis (pwCF) carrying a F508del mutation. Recently, we revealed significant reductions in abdominal symptoms (AS) in German, British, and Irish pwCF after 24-26 weeks of ETI using the CFAbd-Score, the first patient-reported outcome measure (PROM) specifically developed and validated for pwCF following FDA guidelines. Notably, many pwCF reported marked changes in their AS during the first days of the new treatment. To capture these immediate effects, we developed the CFAbd-day2day, a CF-specific GI-diary, following FDA and COSMIN guidelines. Aim: To prospectively capture the immediate dynamics of AS using the CFAbd-day2day 14 days before and 14-28 days after ETI initiation. In addition, we aim to provide validation steps of the novel PROM concerning sensitivity to changes. Methods: To develop the CFAbd-day2day, focus groups (community voice = pwCF and their proxies and CF specialists from different fields) were repeatedly consulted. Before and during the new ETI therapy, pwCF prospectively scored AS on a daily basis with the CFAbd-day2day. Results: Altogether, 45 pwCF attended in five CF centers prospectively completed the CFAbd-day2day before (mean ± sd:14 ± 7 days) and after (mean ± sd: 28 ± 23 days) ETI initiation. On the one hand, cumulative scores significantly decreased during the 3-4-week time frame after ETI initiation, compared to 2 weeks prior to therapy. On the other hand, many patients who revealed a relatively stable level of AS before ETI reported changes during the first days of treatment with the highly effective CFTR modulators. Factors like pain and flatulence increased in up to 21% of patients during the first 14 days of therapy, but they improved during days 15-27. Conclusion: The CFAbd-day2day, specifically developed and in the process of validation to prospectively capture GI symptoms in pwCF, provides new substantial insights into the dynamics of AS in pwCF receiving a new treatment with ETI. This novel tool is also helpful in prospectively monitoring patients with specific GI problems. International implementation and further validation steps of the diary are ongoing.

Reduction in abdominal symptoms (CFAbd-Score), faecal M2-pyruvate-kinase and Calprotectin over one year of treatment with Elexacaftor-Tezacaftor-Ivacaftor in people with CF aged ≥12 years - The RECOVER study.

BACKGROUND: RECOVER is a multicentre post-approval study of Elexacaftor/Tezacaftor/Ivacaftor (ETI) in pwCF in Ireland and the UK. The CFAbd-Score is the first validated CF-specific patient reported outcome measure (PROM) focusing on gastrointestinal symptoms; it comprises 28 items in 5 domains. In a preliminary study, we previously reported reductions in abdominal symptoms (AS) in pwCF after 26 weeks of ETI-therapy using the CFAbd-Score. AIM: to assess changes in AS in a second, large cohort and explore novel GI-biomarkers of gut inflammation and cell-proliferation in pwCF over one year of ETI-therapy. METHODS: Participants were recruited as part of the RECOVER study at 8 sites (Ireland&UK). The CFAbd-Score was administered prior to ETI-initiation, and subsequently at 1,2,6 and 12 months on treatment. Faecal M2-pyruvate kinase (M2-PK) and calprotectin (FC) were quantified in samples collected at baseline, 1 and 6 months. RESULTS: 108 CFAbd-Scores and 73 stool samples were collected at baseline. After 12 months of ETI-therapy, total CFAbd-Scores had significantly declined (15.0±1.4→9.8±1.2pts/p<0.001), and so had all its five domains of "pain" (16.9±2.0pts→9.9±1.8pts/p<0.01), "GERD" (14.4±1.8→9.9±1.6/p<0.05), "disorders of bowel movements" (19.2±1.4→14.1±1.5/p<0.01), "appetite" (7.0±1.1→4.6±1.2/p<0.01) and "impaired-QoL" (13.3±1.9→7.5±1.5/p<0.001). Levels of M2-PK and FC significantly decreased during ETI-therapy. DISCUSSION: In-depth analysis of AS with the CFAbd-Score reveals a statistically significant, clinically relevant and sustained improvement with ETI. We attribute this to high sensitivity of the implemented CF-specific PROM, developed and validated following FDA-guidelines. Furthermore, for the first time during ETI-therapy a significant decline in faecal M2-PK, a marker of inflammation and cell-proliferation, was found, in parallel to FC.

Proliferative activity of antigen-specific CD154+ T cells against bacterial and fungal respiratory pathogens in cystic fibrosis decreases after initiation of highly effective CFTR modulator therapy.

Background: Together with impaired mucociliary clearance, lung disease in cystic fibrosis (CF) is driven by dysregulation of innate and adaptive immunity caused by dysfunctional CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), leading to airway infection and hyperinflamma-tion. The highly effective CFTR modulator therapy (HEMT) elexacaftor/tezacaftor/ivacaftor (ETI) generates substantial improvements in clinical outcomes of people with CF (pwCF) by restoration of CFTR activity. Aberrant immune responses of lymphocytes due to CFTR dysfunction has been described in the past, but not the effects of CFTR restoration by HEMT on these cells. We aimed to examine the effect of ETI on the proliferative activity of antigen-specific CD154 (+) T cells against bacterial and fungal species relevant in CF and on total IgG and IgE as markers of B cell adaptive immunity. Methods: We performed ex vivo analyses of Ki-67 expression in antigen-specific CD154 (+) T cells against Pseudomonas aeruginosa, Staphylococcus aureus, Aspergillus fumigatus, Scedosporium apiospermum and Candida albicans from 21 pwCF by cytometric assay based on antigen-reactive T cell enrichment (ARTE), and analysis of total serum IgE and IgG before and after initiation of ETI. Results: Mean Ki-67 expression in antigen-specific CD154 (+) T cells against P. aeruginosa, A. fumigatus, S. apiospermum and C. albicans, but not S. aureus, mean total serum IgG and mean total serum IgE decreased significantly after initiation of ETI. No correlation was found to change in sputum microbiology of the examined pathogens. Mean BMI and FEV1 increased significantly. Conclusion: HEMT is associated with decreased antigen-specific CD154 (+) T cell proliferation activity in our cohort, independent of findings in sputum microbiology of the examined pathogens. Together with the observed clinical improvement and the decrease in total IgE and IgG, this indicates effects due to CFTR restoration on CD154 (+) T cells by ETI and a reduction of B cell activation with subsequent lower immunoglobulin synthesis under HEMT therapy. These results endorse earlier evidence of CFTR dysfunction in T and B cells leading directly to aberrant immune responses with hyperinflammation.

Corrigendum: Elexacaftor-Tezacaftor-Ivacaftor treatment reduces abdominal symptoms in cystic fibrosis-early results obtained with the CF-specific CFAbd-Score.

[This corrects the article DOI: 10.3389/fphar.2022.877118.].

The Cystic Fibrosis Upper and Lower Airway Metagenome.

The microbial metagenome in cystic fibrosis (CF) airways was investigated by whole-genome shotgun sequencing of total DNA isolated from nasal lavage samples, oropharyngeal swabs, and induced sputum samples collected from 65 individuals with CF aged 7 to 50 years. Each patient harbored a personalized microbial metagenome unique in microbial load and composition, the exception being monocultures of the most common CF pathogens Staphylococcus aureus and Pseudomonas aeruginosa from patients with advanced lung disease. The sampling of the upper airways by nasal lavage uncovered the fungus Malassezia restricta and the bacterium Staphylococcus epidermidis as prominent species. Healthy and CF donors harbored qualitatively and quantitatively different spectra of commensal bacteria in their sputa, even in the absence of any typical CF pathogen. If P. aeruginosa, S. aureus, or Stenotrophomonas maltophilia belonged to the trio of the most abundant species in the CF sputum metagenome, common inhabitants of the respiratory tract of healthy subjects, i.e., Eubacterium sulci, Fusobacterium periodonticum, and Neisseria subflava, were present only in low numbers or not detectable. Random forest analysis identified the numerical ecological parameters of the bacterial community, such as Shannon and Simpson diversity, as the key parameters that globally distinguish sputum samples from CF and healthy donors. IMPORTANCE Cystic fibrosis (CF) is the most common life-limiting monogenetic disease in European populations and is caused by mutations in the CFTR gene. Chronic airway infections with opportunistic pathogens are the major morbidity that determines prognosis and quality of life in most people with CF. We examined the composition of the microbial communities of the oral cavity and upper and lower airways in CF patients across all age groups. From early on, the spectrum of commensals is different in health and CF. Later on, when the common CF pathogens take up residence in the lungs, we observed differential modes of depletion of the commensal microbiota in the presence of S. aureus, P. aeruginosa, S. maltophilia, or combinations thereof. It remains to be seen whether the implementation of lifelong CFTR (cystic fibrosis transmembrane conductance regulator) modulation will change the temporal evolution of the CF airway metagenome.

Antigen specificity and cross-reactivity drive functionally diverse anti-Aspergillus fumigatus T cell responses in cystic fibrosis.

BACKGROUNDThe fungus Aspergillus fumigatus causes a variety of clinical phenotypes in patients with cystic fibrosis (pwCF). Th cells orchestrate immune responses against fungi, but the types of A. fumigatus-specific Th cells in pwCF and their contribution to protective immunity or inflammation remain poorly characterized.METHODSWe used antigen-reactive T cell enrichment (ARTE) to investigate fungus-reactive Th cells in peripheral blood of pwCF and healthy controls.RESULTSWe show that clonally expanded, high-avidity A. fumigatus-specific effector Th cells, which were absent in healthy donors, developed in pwCF. Individual patients were characterized by distinct Th1-, Th2-, or Th17-dominated responses that remained stable over several years. These different Th subsets target different A. fumigatus proteins, indicating that differential antigen uptake and presentation directs Th cell subset development. Patients with allergic bronchopulmonary aspergillosis (ABPA) are characterized by high frequencies of Th2 cells that cross-recognize various filamentous fungi.CONCLUSIONOur data highlight the development of heterogenous Th responses targeting different protein fractions of a single fungal pathogen and identify the development of multispecies cross-reactive Th2 cells as a potential risk factor for ABPA.FUNDINGGerman Research Foundation (DFG), under Germany's Excellence Strategy (EXC 2167-390884018 "Precision Medicine in Chronic Inflammation" and EXC 2051-390713860 "Balance of the Microverse"); Oskar Helene Heim Stiftung; Christiane Herzog Stiftung; Mukoviszidose Institut gGmb; German Cystic Fibrosis Association Mukoviszidose e.V; German Federal Ministry of Education and Science (BMBF) InfectControl 2020 Projects AnDiPath (BMBF 03ZZ0838A+B).

Divergent dynamics of inflammatory mediators and multiplex PCRs during airway infection in cystic fibrosis patients and healthy controls: Serial upper airway sampling by nasal lavage.

Background: In cystic fibrosis (CF), acute respiratory exacerbations critically enhance pulmonary destruction. Since these mainly occur outside regular appointments, they remain unexplored. We previously elaborated a protocol for home-based upper airway (UAW) sampling obtaining nasal-lavage fluid (NLF), which, in contrast to sputum, does not require immediate processing. The aim of this study was to compare UAW inflammation and pathogen colonization during stable phases and exacerbations in CF patients and healthy controls. Methods: Initially, we obtained NLF by rinsing 10 ml of isotonic saline/nostril during stable phases. During exacerbations, subjects regularly collected NLF at home. CF patients directly submitted one aliquot for microbiological cultures. The remaining samples were immediately frozen until transfer on ice to our clinic, where PCR analyses were performed and interleukin (IL)-1ß/IL-6/IL-8, neutrophil elastase (NE), matrix metalloproteinase (MMP)-9, and tissue inhibitor of metalloproteinase (TIMP)-1 were assessed. Results: Altogether, 49 CF patients and 38 healthy controls (HCs) completed the study, and 214 NLF samples were analyzed. Of the 49 CF patients, 20 were at least intermittently colonized with P. aeruginosa and received azithromycin and/or inhaled antibiotics as standard therapy. At baseline, IL-6 and IL-8 tended to be elevated in CF compared to controls. During infection, inflammatory mediators increased in both cohorts, reaching significance only for IL-6 in controls (p=0.047). Inflammatory responses tended to be higher in controls [1.6-fold (NE) to 4.4-fold (MMP-9)], while in CF, mediators increased only moderately [1.2-1.5-fold (IL-6/IL-8/NE/TIMP-1/MMP-9)]. Patients receiving inhalative antibiotics or azithromycin (n=20 and n=15, respectively) revealed lower levels of IL-1ß/IL-6/IL-8 and NE during exacerbation compared to CF patients not receiving those antibiotics. In addition, CF patients receiving azithromycin showed MMP-9 levels significantly lower than CF patients not receiving azithromycin at stable phase and exacerbation. Altogether, rhinoviruses were the most frequently detected virus, detected at least once in n=24 (49.0%) of the 49 included pwCF and in n=26 (68.4%) of the 38 healthy controls over the 13-month duration of the study. Remarkably, during exacerbation, rhinovirus detection rates were significantly higher in the HC group compared to those in CF patients (65.8% vs. 22.4%; p<0.0001). Conclusion: Non-invasive and partially home-based UAW sampling opens new windows for the assessment of inflammation and pathogen colonization in the unified airway system.

Elevated Levels of Toxic Bile Acids in Serum of Cystic Fibrosis Patients with CFTR Mutations Causing Pancreatic Insufficiency.

Hepatobiliary involvement is a hallmark in cystic fibrosis (CF), as the causative CF Transmembrane Conductance Regulator (CFTR) defect is expressed in the biliary tree. However, bile acid (BA) compositions in regard to pancreatic insufficiency, which is present at an early stage in about 85% of CF patients, have not been satisfactorily understood. We assess the pattern of serum BAs in people with CF (pwCF) without CFTR modulator therapy in regard to pancreatic insufficiency and the CFTR genotype. In 47 pwCF, 10 free and 12 taurine- and glycine-conjugated BAs in serum were prospectively assessed. Findings were related to genotype, pancreatic insufficiency prevalence (PIP)-score, and hepatic involvement indicated by serum liver enzymes, as well as clinical and ultrasound criteria for CF-related liver disease. Serum concentrations of total primary BAs and free cholic acid (CA) were significantly higher in pwCF with higher PIP-scores (p = 0.025, p = 0.009, respectively). Higher total BAs were seen in pwCF with PIP-scores ≥0.88 (p = 0.033) and with pancreatic insufficiency (p = 0.034). Free CA was higher in patients with CF-related liver involvement without cirrhosis, compared to pwCF without liver disease (2.3-fold, p = 0.036). pwCF with severe CFTR genotypes, as assessed by the PIP-score, reveals more toxic BA compositions in serum. Subsequent studies assessing changes in BA homeostasis during new highly effective CFTR-modulating therapies are of high interest.

The potential of volatile organic compound analysis for pathogen detection and disease monitoring in patients with cystic fibrosis.

INTRODUCTION: Airway infection with pathogens and its associated pulmonary exacerbations (PEX) are the major causes of morbidity and premature death in cystic fibrosis (CF). Preventing or postponing chronic infections requires early diagnosis. However, limitations of conventional microbiology-based methods can hamper identification of exacerbations and specific pathogen detection. Analyzing volatile organic compounds (VOCs) in breath samples may be an interesting tool in this regard, as VOC-biomarkers can characterize specific airway infections in CF. AREAS COVERED: We address the current achievements in VOC-analysis and discuss studies assessing VOC-biomarkers and fingerprints, i.e. a combination of multiple VOCs, in breath samples aiming at pathogen and PEX detection in people with CF (pwCF). We aim to provide bases for further research in this interesting field. EXPERT OPINION: Overall, VOC-based analysis is a promising tool for diagnosis of infection and inflammation with potential to monitor disease progression in pwCF. Advantages over conventional diagnostic methods, including easy and non-invasive sampling procedures, may help to drive prompt, suitable therapeutic approaches in the future. Our review shall encourage further research, including validation of VOC-based methods. Specifically, longitudinal validation under standardized conditions is of interest in order to ensure repeatability and enable inclusion in CF diagnostic routine.

Elexacaftor-Tezacaftor-Ivacaftor Treatment Reduces Abdominal Symptoms in Cystic Fibrosis-Early results Obtained With the CF-Specific CFAbd-Score.

Background: The novel and highly effective CFTR modulator combination of elexacaftor-tezacaftor-ivacaftor (ETI) has been shown to improve lung function and body weight in people with Cystic Fibrosis (pwCF) carrying a F508del mutation. However, the impact of these modulators on gastrointestinal (GI) symptoms is relatively unknown. Therefore, the CFAbd-Score was developed and validated following FDA recommendations for development of a PROM including focus groups, multidisciplinary CF specialists, people with CF and their families. The aim of this study was to assess effects of ETI on GI symptoms using the CFAbd-Score. Methods: Gastrointestinal symptoms were prospectively assessed in pwCF using the CFAbd-Score before and up to 26 weeks during therapy. The CFAbd-Score was also administered to a healthy control (HC) group. The one-sided questionnaire includes 28 items grouped in five domains. Data analysis included calculation of scores with a weighting tool, developed according to FDA recommendations. Results: A total of 107 pwCF attended in four CF centres in Germany and four centres in the UK completed the CFAbd-Score on at least two occasions. Results were compared to those obtained from the questionnaire of 45 HCs. Despite differences in demographics, age and proportion of pancreatic insufficiency between German and UK patients, analyses based on linear mixed-effects models at week 24 of ETI therapy revealed that estimated marginal means (EMMs) of total CFAbd-Scores significantly reduced (mean ± SE: 14.9 ± 1.2→10.6 ± 1.4; p < 0.01). Also EMMs of all five domains significantly declined ("pain" 16.3 ± 1.6→10.2 ± 2.3, "GERD" 15.8 ± 1.8→8.2 ± 1.9, "disorders of bowel movement" 20.9 ± 1.5→16.0 ± 1.7, "disorders of appetite" 7.9 ± 1.1→2.6 ± 1.1 and "quality of life impairment" 10.1 ± 1.92→3.9 ± 1.9). However, during 24 weeks, CF participants' symptoms mostly still did not reach the reference levels of HCs. Discussion: Using the CFAbd-Score, the first PROM specifically developed for assessment of CF-related abdominal symptoms, we demonstrate comprehensive improvements in GI symptoms after initiation of the highly effective modulator therapy ETI.

Abdominal Symptoms Assessed With the CFAbd-Score are Associated With Intestinal Inflammation in Patients With Cystic Fibrosis.

OBJECTIVES: This prospective study evaluated the relationship between fecal markers of intestinal inflammation and cystic fibrosis (CF)-associated abdominal symptoms. These were assessed using the CFAbd-Score, a CF-specific patient-related outcome measure developed and validated, following FDA guidelines. METHODS: In feces from patients with CF (n = 41) and healthy volunteers (n = 27), concentrations of fecal calprotectin (FC), M2-pyruvate kinase (M2-PK), interleukins IL-1ß, IL-6, IL-8, and neutrophilic elastase (NE) were measured. Abdominal symptoms during the 2 preceding weeks were recorded using the CFAbd-Score. This patient-reported outcome measure (PROM) for assessment of the multi-organic abdominal involvement in CF includes 28 items in five domains. RESULTS: Inflammatory parameters FC, IL-1ß, M2-PK, and NE in feces, as well as CFAbd-Scores resulted significantly higher in CF patients than in healthy controls (all P < 0.01). Furthermore, significant differences between both groups were found for pain-symptoms, disorders of bowel movement, impaired quality of life, as well as disorders of eating and appetite. With 83% sensitivity and 74% specificity, FC was the most reliable measure for CF-related intestinal inflammation, which, in the CFAbd-Score, was associated to significantly higher rates of abdominal pain, as well as to general quality of life items such as gastrointestinal-related impaired sleep and frustration. CONCLUSION: Using the CFAbd-Score as a CF-specific PROM for identification and quantification of abdominal symptoms revealed that abdominal pain and impaired quality of life are associated with intestinal inflammation in CF.

Ultrashort echo time MRI of the lung in children and adolescents: comparison with non-enhanced computed tomography and standard post-contrast T1w MRI sequences.

OBJECTIVES: To compare the diagnostic value of ultrashort echo time (UTE) magnetic resonance imaging (MRI) for the lung versus the gold standard computed tomography (CT) and two T1-weighted MRI sequences in children. METHODS: Twenty-three patients with proven oncologic disease (14 male, 9 female; mean age 9.0 + / - 5.4 years) received 35 low-dose CT and MRI examinations of the lung. The MRI protocol (1.5-T) included the following post-contrast sequences: two-dimensional (2D) incoherent gradient echo (GRE; acquisition with breath-hold), 3D volume interpolated GRE (breath-hold), and 3D high-resolution radial UTE sequences (performed during free-breathing). Images were evaluated by considering image quality as well as distinct diagnosis of pulmonary nodules and parenchymal areal opacities with consideration of sizes and characterisations. RESULTS: The UTE technique showed significantly higher overall image quality, better sharpness, and fewer artefacts than both other sequences. On CT, 110 pulmonary nodules with a mean diameter of 4.9 + / - 2.9 mm were detected. UTE imaging resulted in a significantly higher detection rate compared to both other sequences (p < 0.01): 76.4% (84 of 110 nodules) for UTE versus 60.9% (67 of 110) for incoherent GRE and 62.7% (69 of 110) for volume interpolated GRE sequences. The detection of parenchymal areal opacities by the UTE technique was also significantly higher with a rate of 93.3% (42 of 45 opacities) versus 77.8% (35 of 45) for 2D GRE and 80.0% (36 of 45) for 3D GRE sequences (p < 0.05). CONCLUSION: The UTE technique for lung MRI is favourable in children with generally high diagnostic performance compared to standard T1-weighted sequences as well as CT. Key Points • Due to the possible acquisition during free-breathing of the patients, the UTE MRI sequence for the lung is favourable in children. • The UTE technique reaches higher overall image quality, better sharpness, and lower artefacts, but not higher contrast compared to standard post-contrast T1-weighted sequences. • In comparison to the gold standard chest CT, the detection rate of small pulmonary nodules small nodules ≤ 4 mm and subtle parenchymal areal opacities is higher with the UTE imaging than standard T1-weighted sequences.

Impact of timing of PERT on gastrointestinal symptoms in Danish children and adolescents with CF.

AIM: Gastrointestinal (GI) symptoms are often reported by CF patients. Despite a proven relation to exocrine pancreatic insufficiency (PI), it remains unclear whether GI symptoms are related to the timing of pancreatic enzyme replacement therapy (PERT). Whereas most international recommendations suggest administration of PERT at the beginning of meals, it has not been studied whether such a proceeding is associated with lower burden of symptoms. METHODS: Thirty CF patients aged 0-17 years of age with PI were randomised to four weeks of PERT prior to meals followed by four weeks of PERT after meals or vice versa. Using the CF-specific validated CFAbd-Score, abdominal pain, dysfunctional bowel habits and Quality of Life (QoL) related to GI symptoms were assessed in relation to the timing of PERT. Data were analysed using a linear mixed model. RESULTS: There was no significant difference regarding abdominal pain, bowel habits or QoL related to GI symptoms when timing of PERT was changed from prior to after meals. CONCLUSION: No significant difference was found when administration mode of PERT changed from prior to after meals or vice versa. However, after an individual assessment, some patients may profit from changing administration mode of PERT from prior to after meals.

Would it have happened without Christmas? Thoracic emphysema and allergic bronchopulmonary aspergillosis in a juvenile cystic fibrosis patient with the G551D mutation receiving ivacaftor.

Potent CFTR modulators improve CF manifestations far beyond expectations, including reduction of risk of typical complications. This is the first report of a patient who developed life-threatening ABPA and emphysema after overwhelming improvement. https://bit.ly/2P96PTy.