Background Inhaled antibiotics have achieved or stabilised the clinical condition of patients with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa infection. We aimed to determine the effectiveness of aztreonam lysine inhaled solution (AZLI) in patients with CF and chronic P. aeruginosa infection.Methods A retrospective observational study was conducted on patients with CF and chronic P. aeruginosa infection who received AZLI between July 2012 and September 2018 inclusive in three Spanish hospitals in a routine clinical practice setting. The primary endpoint was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) compared with the previous 12 months, at the start of AZLI treatment and 12 months after starting the drug. Other variables analysed were exacerbations, hospitalisations, type and route of antibiotics prescribed, weight and body mass index (BMI) and adverse drug reactions.Results In a cohort of 52 patients, AZLI treatment led to stabilisation of FEV1, changing from a mean (SD) value of 55.60 (21.3)% at the start of treatment to 56.8 (20.4)% after 12 months of treatment (p=0.5296) in patients who had not previously received the drug. In addition, it significantly reduced exacerbations from a median (P25; P75) of 2.0 (1.0; 3.0) in the 12 months prior to AZLI to 1.0 (1.0; 2.0) in the 12 months after treatment initiation (p=0.0350). AZLI also reduced the need for other antibiotics and prevented a decrease in BMI, with an adequate safety profile.Conclusions AZLI achieved stabilisation of lung function measured by FEV1 in patients with CF and chronic P. aeruginosa infection, along with an adequate safety profile.

This is the third 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 recognising and addressing CF health issues. The guidance was produced with wide stakeholder engagement, including people from the CF community, using an evidence-based framework. Authors contributed sections, and summary statements which were reviewed by a Delphi consultation. Monitoring and treating airway infection, inflammation and pulmonary exacerbations remains important, despite the widespread availability of CFTR modulators and their accompanying health improvements. Extrapulmonary CF-specific health issues persist, such as diabetes, liver disease, bone disease, stones and other renal issues, and intestinal obstruction. These health issues require multidisciplinary care with input from the relevant specialists. Cancer is more common in people with CF compared to the general population, and requires regular screening. The CF life journey requires mental and emotional adaptation to psychosocial and physical challenges, with support from the CF team and the CF psychologist. This is particularly important when life gets challenging, with disease progression requiring increased treatments, breathing support and potentially transplantation. Planning for end of life remains a necessary aspect of care and should be discussed openly, honestly, with sensitivity and compassion for the person with CF and their family. CF teams should proactively recognise and address CF-specific health issues, and support mental and emotional wellbeing while accompanying people with CF and their families on their life journey.

Background: Previous studies found high but very variable levels of tetranor-PGEM and PGDM (urine metabolites of prostaglandin (PG) E2 and PGD2, respectively) in persons with cystic fibrosis (pwCF). This study aims to assess the role of cyclooxygenase COX-1 and COX-2 genetic polymorphisms in PG production and of PG metabolites as potential markers of symptoms’ severity and imaging findings. Methods: A total of 30 healthy subjects and 103 pwCF were included in this study. Clinical and radiological CF severity was evaluated using clinical scoring methods and chest computed tomography (CT), respectively. Urine metabolites were measured using liquid chromatography/tandem mass spectrometry. Variants in the COX-1 gene (PTGS1 639 C>A, PTGS1 762+14delA and COX-2 gene: PTGS2-899G>C (-765G>C) and PTGS2 (8473T>C) were also analyzed. Results: PGE-M and PGD-M urine concentrations were significantly higher in pwCF than in controls. There were also statistically significant differences between clinically mild and moderate disease and severe disease. Patients with bronchiectasis and/or air trapping had higher PGE-M levels than patients without these complications. The four polymorphisms did not associate with clinical severity, air trapping, bronchiectasis, or urinary PG levels. Conclusions: These results suggest that urinary PG level testing can be used as a biomarker of CF severity. COX genetic polymorphisms are not involved in the variability of PG production.

This is the final of four papers updating standards for the care of people with CF. That this paper “Planning a longer life” was considered necessary, highlights how much CF care has progressed over the past decade. Several factors underpin this progress, notably increased numbers of people with CF with access to CFTR modulator therapy.As the landscape for CF changes, so do the hopes and aspirations of people with CF and their families. This paper reflects the need to consider people with CF not as a “problem” to be solved, but as a success, a potential and a voice to be heard. People with CF and the wider CF community have driven this approach, reflecting many of the topics in this paper. This exercise involved wide stakeholder engagement. People with CF are keen to contribute to research priorities and be involved in all stages of research. People with CF want healthcare professionals to respect them as individuals and consider the impact of our actions on the world around us.Navigating life presents challenges to all, but for people with CF these challenges are heightened and complex. In this paper we highlight the concerns and life moments that impact people with CF, and events that the CF team should aim to support, including the challenges around having a family.People with CF and their care teams must embrace the updated standards outlined in these four papers to enjoy the full potential for a healthier life.

Background: Antibiotic eradication therapies recommended for newly isolated Pseudomonas aeruginosa ( Pa ) in people with cystic fibrosis (pwCF) can be burdensome. ALPINE2 compared the efficacy and safety of a shortened 14-day course of aztreonam for inhalation solution (AZLI) with 28-day AZLI in paediatric pwCF. Methods: ALPINE2 (a double-blind, phase 3b study) included children aged 3 months to < 18 years with CF and new-onset Pa infection. Participants were randomized to receive 75 mg AZLI three times daily for either 28 or 14 days followed by 14 days' matched placebo. The primary endpoint was rate of primary Pa eradication (no Pa detected during the 4 weeks post AZLI treatment). Non-inferiority was achieved if the lower 95% CI bound of the treatment difference between the two arms was above -20%. Secondary endpoints included assessments of Pa recurrence during 108 weeks of follow-up after primary eradication. Safety endpoints included treatment-emergent adverse events (TEAEs). Results: In total, 149 participants were randomized (14-day AZLI, n = 74; 28-day AZLI, n = 75) and 142 (95.3%) completed treatment. Median age: 6.0 years (range: 0.3-17.0). Baseline characteristics were similar between treatment arms. Primary Pa eradication rates: 14-day AZLI, 55.9%; 28-day AZLI, 63.4%; treatment difference (CI), -8.0% (-24.6, 8.6%). Pa recurrence rates at follow-up end: 14-day AZLI, 54.1% ( n = 20/37); 28-day AZLI, 41.9% ( n = 18/43). TEAEs were similar between treatment arms. No new safety signals were observed. Conclusions: Non-inferiority of 14-day AZLI versus 28-day AZLI was not demonstrated. Both courses were well tolerated, further supporting AZLI short-term safety in paediatric and adolescent pwCF. (c) 2023 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society.

Introduction Viral infections are associated with pulmonary exacerbations in children with Cystic Fibrosis (cwCF), but after 3 years of SARS-CoV-2 pandemic, whether cwCF are at higher risk of developing COVID-19 or its adverse consequences remains controversial. Methods We conducted an observational, multicenter, cross-sectional study of cwCF infected by SARS-CoV-2 between March 2020 and June 2022, (1 to 6 COVID-19 pandemic waves) in Spain. The study aimed to describe patients’ basal characteristics, SARS-CoV-2 clinical manifestations and outcomes, and whether there were differences across the pandemic waves. Results During study time, 351 SARS-CoV2 infections were reported among 341 cwCF. Median age was 8.5 years (range 0-17) and 51% were female. Cases were unevenly distributed across the pandemic, with most cases (82%) clustered between November 2021 and June 2022 (6 wave, also known as Omicron Wave due to the higher prevalence of this strain in that period in Spain). Most cwCF were asymptomatic (24.8%) or presented with mild Covid-19 symptoms (72.9%). Among symptomatic, most prevalent symptoms were fever (62%) and increased cough (53%). No multisystem inflammatory syndrome (MIS-C), persisting symptoms, long-term sequelae or deaths were reported. Conclusions Spanish current data indicate that cwCF do not experience higher risks of SARS-CoV-2 infection nor worse health outcomes or sequelae. Changes in patients’ basal characteristics, clinical courses and outcomes were detected across waves. While the pandemic continues, and new SARS-CoV-2 variants are being identified, a worldwide monitoring of COVID-19 in pediatric CF patients is needed.

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. Authors provided a narrative description of their topic and statements, which were more directive. These statements were reviewed by a Delphi exercise, achieving good levels of agreement from a wide group for all statements. This guidance reinforces the importance of a multi-disciplinary CF team, but also describes developing models of care including virtual consultations. The framework for health is reinforced, including the need for a physically active lifestyle and the strict avoidance of all recreational inhalations, including e-cigarettes. Progress with cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy is reviewed, including emerging adverse events and advice for dose reduction and interruption. This paper contains guidance that is pertinent to all people with CF regardless of age and eligibility for and access to modulator therapy.

BACKGROUND:Cystic fibrosis (CF) is a chronic life-threatening disease. In patients who suffer from chronic disease, Attention Deficit Hyperactivity Disorder (ADHD) is associated with functional impairment that can affect adherence to treatment and consequently influence prognosis.METHODS:CF patients filled in the ADHD Rating Scale (ADHD-RS) adapted to the DSM5 and were assessed on a continuous performance task (MOXO-CPT), a standardized-computerized test designed to evaluate several domains of attention.RESULTS:Of the 175 patients (99 males), 18% presented ADHD symptoms, according to ADHD-RS; 16% in the younger group (<18years), and 18.9% in the adult group. The male to female ratio was 3:1 in children and 1:1 in adults.CONCLUSIONS:The occurrence of ADHD symptoms in patients with CF is substantially higher than in the general population and should be recognized as a co-morbidity of CF. As ADHD can impair adherence to therapy, further research is needed to investigate the effect of ADHD therapy on adherence.

Repeated European surveys of newborn bloodspot screening (NBS) have shown varied strategies for collecting missed cases, and information on data collection differs among countries/regions, hampering data comparison. The ECFS Neonatal Screening Working Group defined missed cases by NBS as either false negatives, protocol-related, concerning analytical issues, or non-protocol-related, concerning pre- and post-analytical issues. A questionnaire has been designed and sent to all key workers identified in each NBS programme to assess the feasibility of collecting data on missed cases, the stage of the NBS programme when the system failed, and individual patient data on each missed case.

Children on long-term home mechanical ventilation are a growing population due to clinical and technological advances and the benefit for the child's quality of life. Invasive home ventilation is one of the most complex therapies offered in the home setting, requiring adequate home environment and appropriate equipment and supplies before discharge. The transition from hospital to home represents a vulnerable period that can be facilitated with an established transition plan with multidisciplinary team involvement. Readiness for home care is achieved when the patient is stable and has been transitioned from a critical care ventilator to a home mechanical ventilator. In parallel, comprehensive competency-based training regarding the knowledge and skills needed to help families use the equipment confidently and safely. Before discharge, families should be counseled on an adequate home environment to ensure a safe transition. The residence arrangement may include physical space modifications, verifying electrical installation, or moving to another home. Durable medical equipment and supplies must be ordered, and community healthcare support arranged. Parents should receive practical advice on setting up the equipment at home and on preventive measures to minimize complications related to tracheostomy and ventilator dependence, including regular maintenance and replacement of necessary equipment. Given the overall impact of invasive ventilation on home life, a structured home care action package is essential to alleviate the burdens involved.

The association between viral infections and pulmonary exacerbations in children with cystic fibrosis (cwCF) is well established. However, the question of whether cwCF are at a higher risk of COVID‐19 or its adverse consequences remains controversial.

Cystic fibrosis (CF) has entered the era of variant-specific therapy, tailored to the genetic variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CFTR modulators, the first variant-specific therapy available, have transformed the management of CF. The latest standards of care from the European CF Society (2018) did not include guidance on variant-specific therapy, as CFTR modulators were becoming established as a novel therapy. We have produced interim standards to guide healthcare professionals in the provision of variant-specific therapy for people with CF. Here we provide evidence-based guidance covering the spectrum of care, established using evidence from systematic reviews and expert opinion. Statements were reviewed by key stakeholders using Delphi methodology, with agreement (≥80%) achieved for all statements after one round of consultation. Issues around accessibility are discussed and there is clear consensus that all eligible people with CF should have access to variant-specific therapy.

Background: The aim of this study was to record the current status of newborn bloodspot screening (NBS) for CF across Europe and assess performance.Methods: Survey of representatives of NBS for CF programmes across Europe. Performance was assessed through a framework developed in a previous exercise.Results: In 2022, we identified 22 national and 34 regional programmes in Europe. Barriers to estab-lishing NBS included cost and political inertia. Performance was assessed from 2019 data reported by 21 national and 21 regional programmes. All programmes employed different protocols, with IRT-DNA the most common strategy. Six national and 11 regional programmes did not use DNA analysis.Conclusions: Integrating DNA analysis into the NBS protocol improves PPV, but at the expense of in-creased carrier and CFSPID recognition. Some programmes employ strategies to mitigate these outcomes. Programmes should constantly strive to improve performance but large datasets are needed to assess outcomes reliably.& COPY; 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

In an issue of CHEST (February 2022), Maisonneuve and Lowenfels1Maisonneuve P, Lowenfels AB. Cancer in cystic fibrosis: a narrative review of prevalence, risk factors, screening, and treatment challenges. Chest. 2022;161(2):356-364.Google Scholar reviewed the studies that demonstrate the relationship between cystic fibrosis transmembrane conductance regulator (CFTR) mutations and the development of various types of cancer, particularly colon cancer. Although not yet proven, they indicate various alterations, such as dysregulation of Wnt/β-catenin signaling, intestinal inflammation, and disruption of intestinal integrity, that may explain the link between CF and cancer.1Maisonneuve P, Lowenfels AB. Cancer in cystic fibrosis: a narrative review of prevalence, risk factors, screening, and treatment challenges. Chest. 2022;161(2):356-364.Google Scholar In our opinion, the review overlooks the potential role that prostaglandin E2 (PGE2) may play in predisposing patients with CF to develop cancers, especially of the digestive tract. Various CFTR-related arachidonic acid metabolism abnormalities have been reported in CF, including an enhanced production of PGE2.2Jabr S. Gartner S. Milne G.L. et al.Quantification of major urinary metabolites of PGE2 and PGD2 in cystic fibrosis: correlation with disease severity.Prostaglandins Leukot Essent Fatty Acids. 2013; 89: 121-126Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Cyclooxygenase (COX) enzymes are involved in the conversion of arachidonic acid into PGE2. There are two COX enzymes: COX-1 and COX-2. COX-1 is constitutively expressed in most cells and is involved in the regulation of physiologic functions, whereas COX-2 expression is induced under inflammatory conditions.3Picado C. Roca-Ferrer J. Role of the cyclooxygenase pathway in the association of obstructive sleep apnea and cancer.J Clin Med. 2020; 9: 3237Crossref Scopus (2) Google Scholar An increased expression of COX-2 has been found in CF airways,4Roca-Ferrer J. Pujols L. Gartner S. et al.Upregulation of COX-1 and COX-2 in nasal polyps in cystic fibrosis.Thorax. 2006; 61: 592-596Crossref PubMed Scopus (34) Google Scholar a finding that can account for the reported increased production of PGE2 in these patients.2Jabr S. Gartner S. Milne G.L. et al.Quantification of major urinary metabolites of PGE2 and PGD2 in cystic fibrosis: correlation with disease severity.Prostaglandins Leukot Essent Fatty Acids. 2013; 89: 121-126Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Interestingly, Chen et al5Chen J. Jiang X.H. Chen H. et al.CFTR negatively regulates cyclooxygenase-2-PGE2 positive feedback loop in inflammation.J Cell Physiol. 2012; 227: 2759-2766Crossref PubMed Scopus (38) Google Scholar demonstrated that the enhanced expression of COX-2 and increased PGE2 production found in CF are directly related to mutated CFTR. Numerous studies have reported that COX-2 is overexpressed in many human cancers.3Picado C. Roca-Ferrer J. Role of the cyclooxygenase pathway in the association of obstructive sleep apnea and cancer.J Clin Med. 2020; 9: 3237Crossref Scopus (2) Google Scholar Scientific evidence supports the key role played by the COX-2/PGE2 axis in oncogenesis.3Picado C. Roca-Ferrer J. Role of the cyclooxygenase pathway in the association of obstructive sleep apnea and cancer.J Clin Med. 2020; 9: 3237Crossref Scopus (2) Google Scholar PGE2 modulates the function of multiple cells that are involved in the “immune escape” mechanism by which the cancer cells efficiently evade the immune system, which allows the tumor to grow, invade, and metastasize.3Picado C. Roca-Ferrer J. Role of the cyclooxygenase pathway in the association of obstructive sleep apnea and cancer.J Clin Med. 2020; 9: 3237Crossref Scopus (2) Google Scholar Increased COX-2 expression has been reported in colon cancer tissue and correlates with the prognosis of the tumor, a finding suggesting that the excessive production of PGE2 by COX-2 promotes tumorigenesis in colon tissue.3Picado C. Roca-Ferrer J. Role of the cyclooxygenase pathway in the association of obstructive sleep apnea and cancer.J Clin Med. 2020; 9: 3237Crossref Scopus (2) Google Scholar Inhibition of PGE2 synthesis by aspirin significantly reduces the risk of developing colorectal cancer.3Picado C. Roca-Ferrer J. Role of the cyclooxygenase pathway in the association of obstructive sleep apnea and cancer.J Clin Med. 2020; 9: 3237Crossref Scopus (2) Google Scholar Taken together, all these findings support the hypothesis that the COX-2/PGE2 axis activated by the mutated CFTR can contribute to the reported high risk to develop colon cancer in patients with CF. Given the close relationship between alteration in CFTR function and activation of the COX-2/PGE2 axis,5Chen J. Jiang X.H. Chen H. et al.CFTR negatively regulates cyclooxygenase-2-PGE2 positive feedback loop in inflammation.J Cell Physiol. 2012; 227: 2759-2766Crossref PubMed Scopus (38) Google Scholar it is expected that new treatments that improve the function of the mutated gene will reduce the production of PGE2 and thus significantly diminish the risk of malignancies in patients with CF. Cancer in Cystic Fibrosis: A Narrative Review of Prevalence, Risk Factors, Screening, and Treatment Challenges: Adult Cystic Fibrosis SeriesCHESTVol. 161Issue 2PreviewCystic fibrosis (CF) is a progressive monogenetic disorder that causes persistent pulmonary disease, but also affects other organ systems, including the digestive tract. Recent advances in treatment and care of patients with CF, including the use of new and highly effective CF transmembrane conductance regulator modulators, have led to a dramatic increase in survival. Young patients with CF now can expect to live to or beyond middle age, when cancer is more frequent. Patients with CF now are known to face an increased risk of digestive tract cancer, particularly cancer of the colon. Full-Text PDF ResponseCHESTVol. 161Issue 5PreviewWe thank Drs Picado and Gartner for their interest in our review.1 Although there is now strong evidence of an increased risk of bowel cancer in patients with cystic fibrosis (CF), the exact mechanisms involved in this association are neither well defined nor yet proven. Among the multiple potential factors listed in our article we briefly mentioned dysregulation of Wnt/β-catenin signaling, intestinal inflammation, and disruption of intestinal integrity.1 In a broad review, Scott et al2 reported that loss of the cystic fibrosis transmembrane conductance regulator (CFTR) promotes nuclear factor-κB (NF-κB) proinflammatory signaling, with elevation of tumor necrosis factor-α, IL-6, and IL-1β-induced secretion of IL-8, cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2), along with enhanced activities of extracellular signal-related kinases 1/2, mitogen-activated protein kinase, NF-κB inhibitor α, and NF-κB. Full-Text PDF

Consensus on the optimal management of asymptomatic congenital pulmonary airway malformation (CPAM) is lacking, and comparison between studies remains difficult due to a large variety in outcome measures. We aimed to define a core outcome set (COS) for pediatric patients with an asymptomatic CPAM. An online, three-round Delphi survey was conducted in two stakeholder groups of specialized caregivers (surgeons and non-surgeons) in various European centers. Proposed outcome parameters were scored according to level of importance, and the final COS was established through consensus. A total of 55 participants (33 surgeons, 22 non-surgeons) from 28 centers in 13 European countries completed the three rounds and rated 43 outcome parameters. The final COS comprises seven outcome parameters: respiratory insufficiency, surgical complications, mass effect/mediastinal shift (at three time-points) and multifocal disease (at two time-points). The seven outcome parameters included in the final COS reflect the diversity in priorities among this large group of European participants. However, we recommend the incorporation of these outcome parameters in the design of future studies, as they describe measurable and validated outcomes as well as the accepted age at measurement.