The European Cystic Fibrosis Society Patient Registry (ECFSPR) data validation programme: accuracy and consistency of data

Background: The ECFSPR database for 2016 contains data of 44,719 patients from 31 countries. Data of high quality is essential for use in annual reports and epidemiological research. Methods: A validation programme was introduced to quantify consistency and accuracy of data-input at source level, with on-site visits to countries entering data directly in the ECFSTracker software. Data fields to verify: demographic, diagnostic and transplantation, anthropometric and best lung function measurement, bacterial infections, medications and complications. Accuracy was defined as the proportion of values entered in ECFSTracker matching the medical record, and definitions used by the ECFSPR (consistency) for randomly selected cases. Results: Ten out of 41 centres (24%) in 4 countries (Austria, Portugal, Slovakia, Switzerland), reporting 6550% of all patients in their countries, were selected. Demographic, diagnostic and transplant data were checked for 489 patients (21%*), clinical data for 463 patients (20%*) (2016 data). Data on birth, gender, and transplantation exceeded 98.8% accuracy. Anomalies on reported mutations was 0.9%; reliable source data based on genetic reports, were available in 3 out of 4 countries in 95,9%- 91,9% of all patients, 55,5% in one country. Antropometry (92,2%), lung function (86,4%), inhaled antibiotics (96.1%), DNase (89.1%), pancreatic enzyme use (97.6%) were accurate and consistent with the ECFSPR definitions, so were chronic Pseudomonas (95.0%), Burkholderia infection (97.0%), and hemoptysis (94.6%). Liver disease was reported inconsistently due to different interpretation of the definition and resulted in an accuracy of 86.8%. Conclusions: The ECFSPR dataset is highly accurate for most data verified at source level. To further optimize we recommend centres to use a reliable source for genetic information, adhere to the definition of best lung function, and the ECFSPR to redefine liver disease. *of the total patients in these countries

Distribution of cystic fibrosis patients not eligible to studied CFTR modulators in Europe

Studied Cystic Fibrosis (CF) modulators have been announced to cover 90% of all CF patients. A genotype-agnostic novel therapy for CF is under development, which will focus on people with CFwho have mutations that are not eligible for the approved small molecule modulators and triple combination therapies. The data in the European Cystic Fibrosis Society Patient Registry (ECFSPR) are used to provide a quantitative overview of eligible patients. Patients who are alive and seen during the 2017, or alive and not seenwere considered (excluding France who delivered the data directly to the sponsor). Not considered were patients F508del homozygotes eligible for elexacaftor/tezacaftor/ivacaftor, tezacaftor/ivacaftor, lumacaftor/ivacaftor, or heterozygotes eligible for elexacaftor/tezacaftor/ivacaftor. Neither were patients with at least one of the following mutations: E56 K, P67L, R74W, D110E, D110H, R117C, E193 K, L206W, R347H, R352Q, A455E, D579G, 711 +3A->G, E831X, S945L, S977F, F1052 V, K1060 T, A1067 T, R1070W, F1074L, D1152H, D1270N, 2789+5G->A, 3272-26A->G, 3849+10kbC->T (eligible for tezacaftor/ivacaftor, ivacaftor) and R117H, G178R, S549N, S549R, G551D, G551S, G1069R, R1070Q, G1244E, S1251N, S1255P, G1349D (eligible for ivacaftor). From the 41,264 patients registered in the ECFSPR for the 2017, 4,798 patients (12%) carry a genotype that is not eligible to the currentlyapproved modulators or the triple combo. The percentage of non-eligible patients varies from 2,3% in Ireland to 71,9% in Armenia. 2,954 of these patients are 11 years or older, 1,561 have a FEV1% of predicted value between 40% and 90%. In Europe approximately 88% of the patients will be eligible for the currently approved modulators or triple combo, in some countries this percentage is below 50%. With the ECFSPR data, a realistic and useful overviewcould be created to support the design of a study for patients that are not eligible to the currently available modulator and triple combination therapies

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

Hermansky-Pudlak syndrome type 2 manifests with fibrosing lung disease early in childhood

Background: Hermansky-Pudlak syndrome (HPS), a hereditary multisystem disorder with oculocutaneous albinism, may be caused by mutations in one of at least 10 separate genes. The HPS-2 subtype is distinguished by the presence of neutropenia and knowledge of its pulmonary phenotype in children is scarce. Methods: Six children with genetically proven HPS-2 presented to the chILD-EU register between 2009 and 2017; the data were collected systematically and imaging studies were scored blinded. Results: Pulmonary symptoms including dyspnea, coughing, need for oxygen, and clubbing started 3.3 years before the diagnosis was made at the mean age of 8.83 years (range 2-15). All children had recurrent pulmonary infections, 3 had a spontaneous pneumothorax, and 4 developed scoliosis. The frequency of pulmonary complaints increased over time. The leading radiographic pattern was ground-glass opacities with a rapid increase in reticular pattern and traction bronchiectasis between initial and follow-up Computer tomography (CT) in all subjects. Honeycombing and cysts were newly detectable in 3 patients. Half of the patients received a lung biopsy for diagnosis; histological patterns were cellular non-specific interstitial pneumonia, usual interstitial pneumonia-like, and desquamative interstitial pneumonia. Conclusions: HPS-2 is characterized by a rapidly fibrosing lung disease during early childhood. Effective treatments are required