Standards for the care of people with cystic fibrosis; establishing and maintaining health.

This is the second in a series of four papers updating the European Cystic Fibrosis Society (ECFS) standards for the care of people with CF. This paper focuses on establishing and maintaining health. The guidance is produced using an evidence-based framework and with wide stakeholder engagement, including people from the CF community.

A Phase 3, open-label, 96-week trial to study the safety, tolerability, and efficacy of tezacaftor/ivacaftor in children ≥ 6 years of age homozygous for F508del or heterozygous for F508del and a residual function CFTR variant.

Background: Two previous Phase 3 studies ("parent studies") showed that tezacaftor/ivacaftor was generally safe and efficacious for up to 24 weeks in children 6 through 11 years of age with cystic fibrosis (CF) and F508del/F508del (F/F) or F508del/residual function (F/RF) genotypes. We assessed the safety and efficacy of tezacaftor/ivacaftor in an open-label, 96-week extension study.

Methods: This was a Phase 3, 2-part, multicenter, open-label, extension study in children 6 through 11 years of age at treatment initiation (Study VX17-661-116; NCT03537651).

Outcomes of Cystic Fibrosis Screening-Positive Infants With Inconclusive Diagnosis at School Age.

Background And Objectives: Cystic fibrosis (CF) screen-positive infants with an inconclusive diagnosis (CFSPID) are infants in whom sweat testing and genetic analysis does not resolve a CF diagnosis. Lack of knowledge about the health outcome of these children who require clinical follow-up challenges effective consultation. Early predictive biomarkers to delineate the CF risk would allow a more targeted approach to these children.

Long-term safety of lumacaftor-ivacaftor in children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation: a multicentre, phase 3, open-label, extension study.

Background: A previous phase 3 study showed that lumacaftor-ivacaftor was generally safe and well tolerated over 24 weeks of treatment in children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation. In this study, we aimed to assess the long-term safety of lumacaftor-ivacaftor in a rollover study of children who participated in this previous phase 3 study.

Methods: In this multicentre, phase 3, open-label, extension study (study 116; VX16-809-116), we assessed safety of lumacaftor-ivacaftor in children included in a previous multicentre, phase 3, open-label study (study 115; VX15-809-115).

Role of transient elastography and APRI in the assessment of pediatric cystic fibrosis liver disease.

Background: Diagnosis and monitoring of cystic fibrosis liver disease (CFLD) is challenging. Transient elastography (TE) is a rapid, non-invasive method for assessing liver fibrosis. Its role in detecting fibrosis in CFLD has only begun to be explored.

Long-term safety and efficacy of lumacaftor-ivacaftor therapy in children aged 6-11 years with cystic fibrosis homozygous for the F508del-CFTR mutation: a phase 3, open-label, extension study.

Background: The safety and efficacy of 24 weeks of lumacaftor-ivacaftor combination therapy in children aged 6-11 years with cystic fibrosis homozygous for the F508del-CFTR mutation was previously shown in two phase 3 studies. Here, we report long-term safety and efficacy data.

Methods: In this phase 3, open-label, multicentre, extension study (study 110), we examined the long-term safety, tolerability, and efficacy of lumacaftor-ivacaftor in children pooled from two phase 3 parent studies (open-label study 011B and randomised, placebo-controlled study 109).

Nasal Brushing Sampling and Processing using Digital High Speed Ciliary Videomicroscopy - Adaptation for the COVID-19 Pandemic.

Primary Ciliary Dyskinesia (PCD) is a genetic motile ciliopathy, leading to significant otosinopulmonary disease. PCD diagnosis is often missed or delayed due to challenges with different diagnostic modalities. Ciliary videomicroscopy, using Digital High-Speed Videomicroscopy (DHSV), one of the diagnostic tools for PCD, is considered the optimal method to perform ciliary functional analysis (CFA), comprising of ciliary beat frequency (CBF) and beat pattern (CBP) analysis.

Performance of a Three-Tier (IRT-DNA-IRT) Cystic Fibrosis Screening Algorithm in British Columbia.

Newborn screening for Cystic Fibrosis has been implemented in most programs worldwide, but the approach used varies, including combinations of immunoreactive trypsinogen (IRT) and CFTR mutation analysis on one or more specimens. The British Columbia (BC) newborn screening program tests ~45,000 infants per year in BC and the Yukon Territory, covering almost 1.5 million km in western Canada.

Epidemiology of Infections in People with Cystic Fibrosis in Canada between 2000 and 2017.

Infections by species bacteria in cystic fibrosis (CF) may be transmissible, necessitating infection control measures, and remain a serious cause of morbidity and mortality. The last major study of epidemiology in Canada included cases up until July 2000 and was marked by the dominance of a limited number of epidemic clones of . Describe the nationwide epidemiology of species infections in people with cystic fibrosis in Canada over the 17-year period since 2000.

Matrix-assisted laser desorption/ionization time-of-flight MS for the accurate identification of complex and in the clinical microbiology laboratory.

complex (Bcc) bacteria, currently consisting of 23 closely related species, and , can cause serious and difficult-to-treat infections in people with cystic fibrosis. Identifying bacteria to the species level is considered important for understanding epidemiology and infection control, and predicting clinical outcomes. Matrix-assisted laser desorption/ionization time-of-flight MS (MALDI-TOF) is a rapid method recently introduced in clinical laboratories for bacterial species-level identification.

Immunoreactive trypsinogen levels in newborn screened infants with an inconclusive diagnosis of cystic fibrosis.

Background: Newborn screening (NBS) for cystic fibrosis (CF) not only identifies infants with a diagnosis of CF, but also those with an uncertain diagnosis of cystic fibrosis (CF), i.e. CF transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS) or CF screen positive inconclusive diagnosis (CFSPID).

An investigation into biomarkers for the diagnosis of ABPA and aspergillus disease in cystic fibrosis.

Background: Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease due to Aspergillus fumigatus (Af) which occurs in 10% of patients with cystic fibrosis (CF). ABPA is associated with increased morbidity and accelerated lung function decline; however, existing diagnostic criteria are nonspecific and diagnosis remains challenging. As ABPA is driven by Th2 inflammation, the aim of this study was to evaluate exhaled nitric oxide (FE ), eosinophilic cationic protein (ECP), peripheral eosinophil count, and bronchodilator response (BDR) in patients with CF.

Ciliary functional analysis: Beating a path towards standardization.

Primary ciliary dyskinesia is an inherited disorder in which respiratory cilia are stationary, or beat in a slow or dyskinetic manner, leading to impaired mucociliary clearance and significant sinopulmonary disease. One diagnostic test is ciliary functional analysis using digital high-speed video microscopy (DHSV), which allows real-time analysis of complete ciliary function, comprising ciliary beat frequency (CBF) and ciliary beat pattern (CBP). However, DHSV lacks standardization.

A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 through 11 years with cystic fibrosis.

Background: Tezacaftor/ivacaftor is a new treatment option in many regions for patients aged ≥12 years who are homozygous (F/F) or heterozygous for the F508del-CFTR mutation and a residual function (F/RF) mutation. This Phase 3, 2-part, open-label study evaluated the pharmacokinetics (PK), safety, tolerability, and efficacy of tezacaftor/ivacaftor in children aged 6 through 11 years with these mutations.

Methods: Part A informed weight-based tezacaftor/ivacaftor dosages for part B.

An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5 years (KLIMB).

Background: KIWI (NCT01705145) was a 24-week, single-arm, pharmacokinetics, safety, and efficacy study of ivacaftor in children aged 2 to 5 years with cystic fibrosis (CF) and a CFTR gating mutation. Here, we report the results of KLIMB (NCT01946412), an 84-week, open-label extension of KIWI.

Methods: Children received age- and weight-based ivacaftor dosages for 84 weeks.

To beat, or not to beat, that is question! The spectrum of ciliopathies.

Cilia are widely distributed throughout the human body, and have numerous roles in physiology, development, and disease. Ciliary ultrastructure is complex, consisting of nine parallel microtubules doublets, with or without motor dynein arms and a central pair of microtubules. Classification of cilia has evolved over time, and currently, four main classes are described: motile and non-motile cilia with a "9 + 2" structure, and motile and non-motile cilia with a "9 + 0" structure, which depend on the presence or absence of dynein arms and a central pair.

Diagnosis of Primary Ciliary Dyskinesia. An Official American Thoracic Society Clinical Practice Guideline.

Background: This document presents the American Thoracic Society clinical practice guidelines for the diagnosis of primary ciliary dyskinesia (PCD).

Target Audience: Clinicians investigating adult and pediatric patients for possible PCD.

Methods: Systematic reviews and, when appropriate, meta-analyses were conducted to summarize all available evidence pertinent to our clinical questions.

Adverse events following live-attenuated intranasal influenza vaccination of children with cystic fibrosis: Results from two influenza seasons.

Background: Despite the approved use of live-attenuated intranasal influenza vaccine (LAIV) for seasonal immunization of patients with cystic fibrosis (CF), many questions remain unanswered regarding the timing, duration, and types of adverse events that occur following administration of this vaccine.

Methods: In 2012 and 2013, 264 LAIV doses were administered to 198 patients aged 2-19 with CF. Vaccinees were followed prospectively for 55 days after vaccination (day 0) and information on adverse events was collected.