Serum proteome profiling identifies novel and powerful markers of cystic fibrosis liver disease.

Cystic Fibrosis associated liver disease (CFLD) develops in approximately 30% of CF patients. However, routine sensitive diagnostic tools for CFLD are lacking. Within this study, we aimed to identify new experimental biomarkers for the detection of CFLD. 45 CF patients were included in the study and received transient elastography. Differential regulation of 220 different serum proteins was assessed in a subgroup of patients with and without CFLD. Most interesting candidate proteins were further quantified and validated by ELISA in the whole patient cohort. To assess a potential relation of biomarker expression to the degree of hepatic fibrosis, serum biomarkers were further determined in 18 HCV patients where liver histology was available. 43 serum proteins differed at least 2-fold in patients with CFLD compared to those without liver disease as identified in proteome profiling. In ELISA quantifications, TIMP-4 and Endoglin were significantly up-regulated in patients with CFLD as diagnosed by clinical guidelines or increased liver stiffness. Pentraxin-3 was significantly decreased in patients with CFLD. Serum TIMP-4 and Endoglin showed highest values in HCV patients with liver cirrhosis compared to those with fibrosis but without cirrhosis. At a cut-off value of 6.3 kPa, transient elastography compassed a very high diagnostic accuracy and specificity for the detection of CFLD. Among the biomarkers, TIMP-4 and Endoglin exhibited a high diagnostic accuracy for CFLD. Diagnostic sensitivities and negative predictive values were increased when elastography and TIMP-4 and Endoglin were combined for the detection of CFLD. Serum TIMP-4 and Endoglin are increased in CFLD and their expression correlates with hepatic staging. Determination of TIMP-4 and Endoglin together with transient elastography can increase the sensitivity for the non-invasive diagnosis of CFLD

Incidence of SARS-CoV-2 in people with cystic fibrosis in Europe between February and June 2020

Funding Information: We thank the people with CF, and their families, for consenting to their data being included in the ECFSPR. We thank the centers and individual country representatives for allowing the use of the anonymized patient data. This work was supported by an unrestricted grant from Chiesi Farmaceutici SpA, Parma, Italy. The funder had no role in the design, conduct or reporting of this study. Datasets for the general population were provided by the European Centre for Disease Prevention and Control (ECDC) based on data provided by WHO and Ministries of Health from the affected countries. The views and opinions of the authors expressed herein do not necessarily state or reflect those of the ECDC. The accuracy of the authors' statistical analysis and the findings they report are not the responsibility of ECDC. ECDC is not responsible for conclusions or opinions drawn from the data provided. ECDC is not responsible for the correctness of the data and for data management, data merging and data collation after provision of the data. ECDC shall not be held liable for improper or incorrect use of the data. Funding Information: This work was supported by an unrestricted grant from Chiesi Farmaceutici SpA, Parma, Italy. The funder had no role in the design, conduct or reporting of this study. Publisher Copyright: © 2021Background: Viral infections can cause significant morbidity in cystic fibrosis (CF). The current Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic could therefore have a serious impact on the health of people with CF (pwCF). Methods: We used the 38-country European Cystic Fibrosis Society Patient Registry (ECFSPR) to collect case data about pwCF and SARS-CoV-2 infection. Results: Up to 30 June 2020, 16 countries reported 130 SARS-CoV-2 cases in people with CF, yielding an incidence of 2.70/1000 pwCF. Incidence was higher in lung-transplanted patients (n=23) versus non-transplanted patients (n=107) (8.43 versus 2.36 cases/1000). Incidence was higher in pwCF versus the age-matched general population in the age groups <15, 15-24, and 25-49 years (p<0.001), with similar trends for pwCF with and without lung transplant. Compared to the general population, pwCF (regardless of transplantation status) had significantly higher rates of admission to hospital for all age groups with available data, and higher rates of intensive care, although not statistically significant. Most pwCF recovered (96.2%), however 5 died, of whom 3 were lung transplant recipients. The case fatality rate for pwCF (3.85%, 95% CI: 1.26-8.75) was non-significantly lower than that of the general population (7.46%; p=0.133). Conclusions: SARS-CoV-2 infection can result in severe illness and death for pwCF, even for younger patients and especially for lung transplant recipients. PwCF should continue to shield from infection and should be prioritized for vaccination.publishersversionPeer reviewe

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-&gt;G, E831X, S945L, S977F, F1052 V, K1060 T, A1067 T, R1070W, F1074L, D1152H, D1270N, 2789+5G-&gt;A, 3272-26A-&gt;G, 3849+10kbC-&gt;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

Impact of COVID-19 on people with cystic fibrosis

International audienc

Effects of Lumacaftor/Ivacaftor on Cystic Fibrosis Disease Progression in Children 2 through 5 Years of Age Homozygous for F508del-CFTR: A Phase 2 Placebo-controlled Clinical Trial.

RATIONALE Lumacaftor/ivacaftor (LUM/IVA) was shown to be safe and well tolerated in children 2 through 5 years of age with cystic fibrosis (CF) homozygous for F508del-CFTR in a phase 3 open-label study. Improvements in sweat chloride concentration, markers of pancreatic function, and lung clearance index2.5 (LCI2.5), along with increases in growth parameters, suggested the potential for early disease modification with LUM/IVA treatment. OBJECTIVE To further assess the effects of LUM/IVA on CF disease progression in children 2 through 5 years of age using chest magnetic resonance imaging (MRI). METHODS This phase 2 study had two parts: a 48-week, randomized, double-blind, placebo-controlled treatment period in which children 2 through 5 years of age with CF homozygous for F508del-CFTR received either LUM/IVA or placebo (Part 1) followed by an open-label period in which all children received LUM/IVA for an additional 48 weeks (Part 2). We report results from Part 1. The primary endpoint was absolute change from baseline in chest MRI global score at Week 48. Secondary endpoints included absolute change in LCI2.5 through Week 48 and absolute changes in weight-for-age, stature-for-age, and body mass index-for-age z-scores at Week 48. Additional endpoints included absolute changes in sweat chloride concentration, fecal elastase-1 levels, serum immunoreactive trypsinogen, and fecal calprotectin through Week 48. The primary endpoint was analyzed using Bayesian methods, where the actual Bayesian posterior probability of LUM/IVA being superior to placebo in the MRI global chest score at Week 48 was calculated using a vague normal prior distribution; secondary and additional endpoints were analyzed using descriptive summary statistics. RESULTS Fifty-one children were enrolled and received LUM/IVA (n=35) or placebo (n=16). For the change in MRI global chest score at Week 48, the Bayesian posterior probability of LUM/IVA being better than placebo (treatment difference <0; higher score indicating greater abnormality) was 76%; the mean treatment difference was -1.5 (95% credible interval, -5.5 to 2.6). Treatment with LUM/IVA also led to within-group numerical improvements in LCI2.5, growth parameters, and biomarkers of pancreatic function as well as greater decreases in sweat chloride concentration compared with placebo from baseline through Week 48. Safety data were consistent with the established safety profile of LUM/IVA. CONCLUSIONS This placebo-controlled study suggests the potential for early disease modification with LUM/IVA treatment, including that assessed by chest MRI, in children as young as 2 years. Clinical trial registered with ClinicalTrials.gov (NCT03625466)

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

Data accuracy, consistency and completeness of the national Swiss cystic fibrosis patient registry: Lessons from an ECFSPR data quality project.

BACKGROUND Good data quality is essential when rare disease registries are used as a data source for pharmacovigilance studies. This study investigated data quality of the Swiss cystic fibrosis (CF) registry in the frame of a European Cystic Fibrosis Society Patient Registry (ECFSPR) project aiming to implement measures to increase data reliability for registry-based research. METHODS All 20 pediatric and adult Swiss CF centers participated in a data quality audit between 2018 and 2020, and in a re-audit in 2022. Accuracy, consistency and completeness of variables and definitions were evaluated, and missing source data and informed consents (ICs) were assessed. RESULTS The first audit included 601 out of 997 Swiss people with CF (60.3 %). Data quality, as defined by data correctness ≥95 %, was high for most of the variables. Inconsistencies of specific variables were observed because of an incorrect application of the variable definition. The proportion of missing data was low with 5 % of missing documents). After providing feedback to the centers, availability of genetic source data and ICs improved. CONCLUSIONS Data audits demonstrated an overall good data quality in the Swiss CF registry. Specific measures such as support of the participating sites, training of data managers and centralized data collection should be implemented in rare disease registries to optimize data quality and provide robust data for registry-based scientific research

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