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Background: A 21-year-old woman diagnosed with cystic fibrosis developed cirrhosis, exocrine pancreatic insufficiency, and insulin-dependent diabetes mellitus. The patient qualified for double organ liver-pancreas transplantation beyond typical indications. The respiratory symptoms of cystic fibrosis were moderate and well-treated. The patient was endangered mainly by liver insufficiency and recurrent hypoglycemia, which was due to the treatment of diabetes with high doses of insulin. Computed tomography showed mild bronchiectasis, cirrhotic liver, splenomegaly, and atrophy of the pancreas. Pseudomonas aeruginosa colonized the upper respiratory tract. Gastrointestinal complications were sufficient for the patient to be qualified for combined liver-pancreas transplantation., Methods: First, a standard hepatectomy was performed. The liver was transplanted orthotopically. Subsequently, the team performed pancreas transplantation through a separate incision. The donor's duodenum was anastomosed to the recipient's jejunum, close to the ligament of Treitz., Results: No serious complications were noted during the postoperative period. Transplanted organs started functioning without delay. The patient was discharged after 6 weeks in general good condition. Twenty months later, the patient felt well, and the grafts kept functioning properly., Conclusion: Combined liver-pancreas transplantation in patients with CF restores exocrine and endocrine pancreatic function and minimizes the risk of life-threatening complications associated with liver insufficiency. Improvement of life quality coincides with the possibility of discontinuing insulin and pancreatic enzyme supplementation. The combination of liver and pancreas transplantation may prevent advanced pulmonary complications, extend the prognosis of survival, and improve the long-term life quality., Competing Interests: Declaration of competing interest All the authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflict of interest The author declares that he has no conflicts of interest with the contents of this article.

Introduction: Inflammation appears early in cystic fibrosis (CF) pathogenesis, with specific elevated inflammatory markers in bronchoalveolar lavage fluid (BALF) correlating with structural lung disease. Our aim was to identify markers of airway inflammation able to predict bronchiectasis progression over two years with high sensitivity and specificity., Methods: Children with CF with two chest computed tomography (CT) scans and bronchoscopies at a two-year interval were included (n= 10 at 1 and 3 years and n= 27 at 3 and 5 years). Chest CTs were scored for increase in bronchiectasis (Δ%Bx), using the PRAGMA-CF score. BALF collected with the first CT scan were analyzed for neutrophil% (n= 36), myeloperoxidase (MPO) (n= 25), neutrophil elastase (NE) (n= 26), and with a protein array for inflammatory and fibrotic markers (n= 26)., Results: MPO, neutrophil%, and inducible T-cell costimulator ligand (ICOSLG), but not clinical characteristics, correlated significantly with Δ%Bx. Evaluation of neutrophil%, NE, MPO, interleukin-8 (IL-8), ICOSLG, and hepatocyte growth factor (HGF), for predicting an increase of > 0.5% of Δ%Bx in two years, showed that IL-8 had the best sensitivity (82%) and specificity (73%). Neutrophil%, ICOSLG and HGF had sensitivities of 85, 82, and 82% and specificities of 59, 67 and 60%, respectively. The odds ratio for risk of >0.5% Δ%Bx was higher for IL-8 (12.4) than for neutrophil%, ICOSLG, and HGF (5.9, 5.3, and 6.7, respectively). Sensitivity and specificity were lower for NE and MPO)., Conclusions: High levels of IL-8, neutrophil%, ICOSGL and HGF in BALF may be good predictors for progression of bronchiectasis in young children with CF., Competing Interests: Declaration of competing interest There is no conflict of interest associated with this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: In cystic fibrosis (CF), coughing is associated with a risk of pelvic floor dysfunction. However, data on the prevalence of symptoms (stress urinary incontinence, bladder overactivity, dysuria, and faecal incontinence) are lacking in males and females with CF. The impact of incontinence on adherence to respiratory care has not been studied., Methods: We conducted a multicentre study in adults with CF followed in the North-West French CF network. Urinary disorders and their severity were assessed using the Urinary Symptom Profile (USP) self-report questionnaire; the impact of urinary disorders on general quality of life was measured using the SF-Qualiveen questionnaire; faecal incontinence was assessed using the Wexner self-report questionnaire; and the CFQ-R14+ questionnaire was used to assess quality of life. A self-administered questionnaire developed for the study assessed the impact of symptoms on respiratory care., Results: Of the 178 people with CF included, 34 % reported stress urinary incontinence, with a large female predominance (63.5 % of females vs. 7.5 % of males), 65 % bladder overactivity (including 16 % urge incontinence) and 50 % faecal incontinence, also with a female predominance. Neither urinary nor faecal incontinence were related to the severity of the respiratory impairment (FEV1). Quality of life was particularly affected in women. Stress urinary Incontinence symptoms affected respiratory care in both sexes., Conclusion: The prevalence of functional urinary and faecal disorders was high in adults with CF and impacted on quality of life and respiratory care. Therefore, multidisciplinary teams must have knowledge of symptoms, the diagnostic tools and management strategies to provide specific treatment., Competing Interests: Declaration of Competing Interest None, (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Cystic fibrosis (CF) may cause a spectrum of hepatobiliary complications, including portal hypertension, multilobular cirrhosis, and liver failure. Current guidelines on the detection and monitoring of hepatobiliary complications in CF were published in 1999. The CF Foundation assembled a committee to evaluate research advances and formulate revised guidelines for CF-associated liver disease. A committee of hepatologists, gastroenterologists, pulmonologists, pharmacists, nurses, dietitians, individuals with CF, and the parents of a child with CF devised "population, intervention, comparison, and outcome" questions regarding hepatobiliary disease in CF. PubMed literature searches were performed for each population, intervention, comparison, and outcome question. Recommendations were voted on with 80% agreement required to approve a recommendation. Public comment on initial recommendations was solicited prior to the formulation of final recommendations. Thirty-one population, intervention, comparison, and outcome questions were assembled, 6401 manuscripts were title screened for relevance, with 1053 manuscripts undergoing detailed full-text review. Seven recommendations were approved for screening, 13 for monitoring of existing disease, and 14 for treatment of CF-associated hepatobiliary involvement or advanced liver disease. One recommendation on liver biopsy did not meet the 80% threshold. One recommendation on screening ultrasound was revised and re-voted on. Through a multidisciplinary committee and public engagement, we have assembled updated recommendations and guidance on screening, monitoring, and treatment of CF-associated hepatobiliary involvement and advanced liver disease. While research gaps remain, we anticipate that these recommendations will lead to improvements in CF outcomes through earlier detection and increased evidence-based approaches to monitoring and treatment., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Our work aims to add evidence on the effectiveness of Elexacaftor-Tezacaftor-Ivacaftor on chronic rhinosinusitis in cystic fibrosis., Materials and Methods: We conducted an observational retrospective cohort study at the Cystic Fibrosis Center of a tertiary care hospital to investigate the effect of Elexacaftor-Tezacaftor-Ivacaftor on chronic rhinosinusitis in cystic fibrosis patients, aged 12 or older. The study's endpoints were the change in the occurrence of acute exacerbations of chronic rhinosinusitis, and the variation of the endoscopic and radiologic findings scored using the Lund-Kennedy endoscopic scale, Lund-Mackay, and modified Lund-Mackay radiologic scales, in patients who underwent both pre-treatment and post-treatment examinations., Results: The study population comprised 136 patients, of which 28 underwent both pre-treatment and post-treatment nasal endoscopy and 15 had pre- and post-treatment CT scans. Elexacaftor-Tezacaftor-Ivacaftor provided a significant improvement in chronic rhinosinusitis. The mean number of acute exacerbations of chronic rhinosinusitis per year in the pre-treatment time was 0.55 versus 0.35 during the treatment (p < 0.0021). The Lund-Kennedy scale had a pre-treatment average score of 4.21 points versus 1.5 points after the start of Elexacaftor-Tezacaftor-Ivacaftor (p < 0.0001). The average Lund-Mackay and modified Lund-Mackay scores in the pre-treatment time were respectively 14.6 and 16.45 points; and after the start of the therapy, they became 5.87 and 6.73 (p < 0.0001)., Conclusion: Elexacaftor-Tezacaftor-Ivacaftor was associated with fewer acute exacerbations of chronic rhinosinusitis, and a significant improvement of chronic rhinosinusitis evaluated endoscopically and radiologically. To our knowledge, this is the first study investigating the change in the occurrence of acute exacerbation of chronic rhinosinusitis in patients affected by cystic fibrosis in therapy with Elexacaftor-Tezacaftor-Ivacaftor., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Rationale: Pulmonary exacerbations (PEx) remain the most common cause of morbidity, recurrent hospitalization, and diminished survival in people with cystic fibrosis (PWCF) and are characterized by excess inflammation. Corticosteroids are potent, widely available antiinflammatory drugs. However, corticosteroid efficacy data from randomized controlled trials in PWCF are limited. Objectives: To determine whether adjunctive systemic corticosteroid therapy is associated with improved outcomes in acute CF PEx. Methods: We performed a secondary analysis of Standardized Treatment of Pulmonary Exacerbations 2 (STOP2), a large multicenter randomized controlled trial of antimicrobial treatment durations for adult PWCF presenting with PEx, that included the use of corticosteroids as a stratification criterion in its randomization protocol. Corticosteroid treatment effects were determined after propensity score matching for covariates including age, sex, baseline forced expiratory volume in 1 second (FEV 1 ), genotype, and randomization arm. The primary outcome measure was the change in percentage predicted FEV 1 (ppFEV 1 ). Symptoms, time to next PEx, and the incidence of adverse events (AEs) and serious adverse events (SAEs) were assessed as secondary endpoints. Phenotypic factors associated with the clinical decision to prescribe steroids were also investigated. Results: Corticosteroids were prescribed for 168 of 982 PEx events in STOP2 (17%). Steroid prescription was associated with decreased baseline ppFEV 1 , increased age, and female sex. Cotreatment with corticosteroids was independent of treatment arm allocation and did not result in greater mean ppFEV 1 response, longer median time to next PEx, or more substantial symptomatic improvement compared with propensity-matched PWCF receiving antibiotics alone. AEs were not increased in corticosteroid-treated PWCF. The total number of SAEs-but not the number of corticosteroid-related or PEx-related SAEs-was higher among patients receiving corticosteroids. Conclusions: Empiric, physician-directed treatment with systemic corticosteroids, although common, is not associated with improved clinical outcomes in PWCF receiving antibiotics for PEx. Clinical trial registered with www.clinicaltrials.gov (NCT02781610).

Objectives: Cystic Fibrosis is an autosomal recessive condition. It is a multisystem disease treated with a broad range of pharmacological therapies, diet and nutrition, and physiotherapy. Previous studies suggest that people with cystic fibrosis have a higher prevalence of developmental defects of enamel which may place this population at a greater risk of developing oral diseases such as caries. The aim of this study was to assess a cohort of people with cystic fibrosis (PwCF) for the presence of developmental defects of enamel and compare the results with a control group of people without cystic fibrosis., Methods: A cross sectional study involving 92 participants with cystic fibrosis and 92 controls was conducted in Cork University Dental School & Hospital. All participants completed a detailed questionnaire prior to undergoing a full clinical examination. The Developmental Defect of Enamel Index was used as a measurement index. All data was statistically analysed with the help of statisticians from Cystic Fibrosis Registry of Ireland., Results: 64 % (n = 59) of PwCF had enamel defects compared to just 30 % (n = 28) of people without cystic fibrosis. The median number of teeth affected by enamel defects in the study group was 1.5, compared to 0 in the control group., Conclusion: In this study the cohort of PwCF had more enamel defects than people without CF. Further research is required to investigate the aetiology of these findings., Clinical Significance: Clinicians should be vigilant after teeth have erupted in PwCF as they may have an increased susceptibility to developmental defects of enamel., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Children with advanced pulmonary disease due to cystic fibrosis (CF) are at risk of acute respiratory failure due to pulmonary exacerbations leading to their admission to pediatric intensive care units (PICU). The objectives of this study were to determine short and medium-term outcomes of children with CF admitted to PICU for acute respiratory failure due to pulmonary exacerbation and to identify prognosis factors., Methods: This retrospective monocentric study included patients less than 18 years old admitted to the PICU of a French university hospital between 2000 and 2020. Cox proportional hazard regression methods were used to determine prognosis factors of mortality or lung transplant., Results: Prior to PICU admission, the 29 patients included (median age 13.5 years) had a severe lung disease (median Forced Expiratory Volume in 1 s percentage predicted at 29%). Mortality rates were respectively 17%, 31%, 34%, 41% at discharge and at 3, 12 and 36 months post-discharge. Survival rates free of lung transplant were 34%, 32%, 24% and 17% respectively. Risk factors associated with mortality or lung transplant using the univariate analysis were female sex and higher pCO2 and chloride levels at PICU admission, and following pre admission characteristics: home respiratory and nutritional support, registration on lung transplant list and Stenotrophomonas Maltophilia bronchial colonization., Conclusion: Children with CF admitted to PICU for acute respiratory failure secondary to pulmonary exacerbations are at high risk of death, both in the short and medium terms. Lung transplant is their main chance of survival and should be considered early., (© 2024. The Author(s).)

The impact of evolving treatment regimens, airway clearance strategies, and antibiotic combinations on the incidence and prevalence of respiratory infection in cystic fibrosis (CF) in children and adolescents remains unclear. The incidence, prevalence, and prescription trends from 2002 to 2019 with 18,339 airway samples were analysed. Staphylococcus aureus [- 3.86% (95% CI - 5.28-2.43)] showed the largest annual decline in incidence, followed by Haemophilus influenzae [- 3.46% (95% CI - 4.95-1.96)] and Pseudomonas aeruginosa [- 2.80%95% CI (- 4.26-1.34)]. Non-tuberculous mycobacteria and Burkholderia cepacia showed a non-significant increase in incidence. A similar pattern of change in prevalence was observed. No change in trend was observed in infants < 2 years of age. The mean age of the first isolation of S. aureus (p < 0.001), P. aeruginosa (p < 0.001), H. influenza (p < 0.001), Serratia marcescens (p = 0.006) and Aspergillus fumigatus (p = 0.02) have increased. Nebulised amikacin (+ 3.09 ± 2.24 prescription/year, p = 0.003) and colistin (+ 1.95 ± 0.3 prescriptions/year, p = 0.032) were increasingly prescribed, while tobramycin (- 8.46 ± 4.7 prescriptions/year, p < 0.001) showed a decrease in prescription. Dornase alfa and hypertonic saline nebulisation prescription increased by 16.74 ± 4.1 prescriptions/year and 24 ± 4.6 prescriptions/year (p < 0.001). There is a shift in CF among respiratory pathogens and prescriptions which reflects the evolution of cystic fibrosis treatment strategies over time., (© 2024. Crown.)

Background: Oral health impacts systemic health, individual well-being, and quality of life. It is important to identify conditions that may exacerbate oral disease to aid public health and policy development and promote targeted patient treatment strategies. Developmental defects can increase an individual's risk of dental caries, hypersensitivity, premature tooth wear, erosion, and poor aesthetics. As part of an ongoing study assessing oral health in adults with cystic fibrosis at Cork University Dental School and Hospital, a systematic review of available literature was conducted to assess the prevalence of enamel defects in people with cystic fibrosis., Aims: To critically evaluate the literature to determine if the prevalence of developmental defects of enamel is higher in people with cystic fibrosis (PwCF)., Methods: Data Sources: Three online databases were searched Embase, Scopus, and Web of Science Core Collection. Studies that examined an association between cystic fibrosis and developmental defects of enamel were included in this systematic review., Results: The initial search identified 116 publications from the following databases Embase, Web of Science Core Collection, and Scopus. Eleven studies were included for qualitative analysis. Nine studies concluded that PwCF had a higher prevalence of enamel defects than control people and one study found no difference in cystic fibrosis (CF) status. All studies had a risk of bias that may influence study results and their interpretation., Conclusions: The results of the systematic review show a consistent pattern that PwCF have a higher prevalence of DDE than people without CF. Genetic dysfunction, chronic systemic infections, and long-term antibiotic use are possible aetiological causes. This review highlights the need for future studies to investigate if DDEs are caused by the underlying CFTR mutation or as a consequence of disease manifestations and/or management., (© 2024. The Author(s).)

Background: Microbiological diagnosis of mycobacteriosis is often difficult, as it is necessary to differentiate between transient colonization and active infection., Methods: We studied the cultural properties of Mycobacterium abscessus complex (MABSc) strains obtained from cystic fibrosis patients, and also analyzed composite correlation index (CCI) values in patients with repeated MABSc inoculation and their correlation with the presence of clinical and radiological manifestations of mycobacteriosis., Results: As a result, MABSc more often grew in S-form colonies in patients without clinical manifestations of chronic infection, while R-form colonies were characteristic of patients with chronic infection and clinical symptoms. At the same time, in patients examined once, no growth of colonies in the R-form was recorded, and all strains produced growth in the form of either S-colonies or in the S- and R-forms simultaneously. Statistically significant results were obtained for the relationship of the CCI with the clinical and radiological picture. In addition, a heterogeneous MABSc population with low CCI score values correlated with the development of mycobacteriosis in patients. In patients with high CCI score values (homogeneity of isolated strains), on the contrary, there were no radiological or clinical signs of the disease., Conclusion: These data make it possible to build a strategy for monitoring patients depending on changes in CCI score values. The use of CCI matrix to evaluate microorganisms' identification results is a potentially new method that expands the use of matrix-assisted laser desorption ionization time-of-flight mass spectrometry., (Copyright © 2024 Copyright: © 2024 International Journal of Mycobacteriology.)

Nine people with cystic fibrosis (pwCF) were found to have isolated elevations in serum total bilirubin after starting elexacaftor/tezacaftor/ivacaftor (ETI) that were associated with Gilbert's Syndrome. In longitudinal examination, total bilirubin levels increased substantially after initiation of ETI without elevations in liver transaminases in those with this syndrome. Because elevated bilirubin levels in Gilbert's Syndrome are benign, ETI was able to be continued in these individuals. Genetic testing for this relatively common syndrome should be strongly considered for pwCF experiencing isolated hyperbilirubinemia after starting ETI, since appropriate diagnosis may help pwCF avoid unnecessary interruption in this therapy with significant health benefits in CF., (© 2024 Wiley Periodicals LLC.)

Cystic fibrosis (CF) is a progressive, genetic, multi-organ disease affecting the respiratory, digestive, endocrine, and reproductive systems. CF can affect any aspect of the gastrointestinal (GI) tract, including the esophagus, stomach, small intestine, colon, pancreas, liver, and gall bladder. GI pathophysiology associated with CF results from CF membrane conductance regulator (CFTR) dysfunction. The majority of people with CF (pwCF) experience exocrine pancreatic insufficiency resulting in malabsorption of nutrients and malnutrition. Additionally, other factors can cause or worsen fat malabsorption, including the potential for short gut syndrome with a history of meconium ileus, hepatobiliary diseases, and disrupted intraluminal factors, such as inadequate bile salts, abnormal pH, intestinal microbiome changes, and small intestinal bacterial overgrowth. Signs and symptoms associated with fat malabsorption, such as abdominal pain, bloating, malodorous flatus, gastroesophageal reflux, nausea, anorexia, steatorrhea, constipation, and distal intestinal obstruction syndrome, are seen in pwCF despite the use of pancreatic enzyme replacement therapy. Given the association of poor nutrition status with lung function decline and increased mortality, aggressive nutrition support is essential in CF care to optimize growth in children and to achieve and maintain a healthy body mass index in adults. The introduction of highly effective CFTR modulator therapy and other advances in CF care have profoundly changed the course of CF management. However, GI symptoms in some pwCF may persist. The use of current knowledge of the pathophysiology of the CF GI tract as well as appropriate, individualized management of GI symptoms continue to be integral components of care for pwCF., (© 2024 American Society for Parenteral and Enteral Nutrition.)

Rationale: Diagnosing cystic fibrosis (CF) pulmonary exacerbations (PEx) in very young people with CF <3 years (VY-PwCF) is challenging because of the frequency of respiratory viral infections in this age group, and there are limited data on the clinical features associated with the diagnosis of PEx in this age group. The goal of this study was to identify clinical features associated with the diagnosis of PEx in VY-PwCF., Methods: We reviewed the medical records of VY-PwCF followed at the Children's Hospital of Philadelphia born between 2013 and 2019. We collected data from all encounters with respiratory symptoms. PEx was defined by treatment with oral or intravenous antibiotics. Clinical features of PEx and non-PEx encounters were compared using descriptive statistics, and odds ratios of PEx diagnosis were calculated., Results: A total of 78 patients were included in the analysis. The mean (SD) number of PEx per patient was 6.17 (5.88). The presence of a wet or nighttime cough and symptoms >3 days in duration were significantly associated with PEx diagnosis (p < .001). In contrast, symptoms such as sore throat or rhinorrhea were not associated with a higher likelihood of PEx., Conclusions: The presence of a wet or night-time cough and longer symptom duration are common features of PEx in VY-PwCF, whereas symptoms suggestive of upper respiratory viral infection are not. Our results will be helpful in counseling families of VY-PwCF in the signs and symptoms of PEx and in planning future research in PEx in this age group., (© 2023 Wiley Periodicals LLC.)

Cystic fibrosis (CF) care in Denmark has been characterized by close monitoring and pre-emptive treatment of lung disease and other CF-related complications. Continuous evaluation through data collection and commitment to clinical research has incrementally improved outcomes. This approach has been in line with best practices set forth by European Standards of Care but has also gone beyond Society standards particularly pertaining to early treatment with high-dose combination antimicrobial therapy. Despite a high prevalence of severe CF variants, lung function has been among the best in Europe. In this review, the Danish approach to management of CF prior to the introduction of new CF modulator treatment is explained and benchmarked. Downsides to the Danish approach are discussed and include increased burden of treatment, risk of antimicrobial resistance, side-effects and costs., (© 2024 The Authors. APMIS published by John Wiley & Sons Ltd on behalf of Scandinavian Societies for Pathology, Medical Microbiology and Immunology.)

Introduction: Patients with cystic fibrosis (CF) are living longer and may be considered for total hip arthroplasty (THA) or total knee arthroplasty (TKA). Perioperative outcomes and implant survival after these procedures performed for those with CF have not been previously described., Methods: Using the M151 PearlDiver database, a large, national, administrative database, THA and TKA patients with and without CF were identified and matched 1:10 based on age, sex, and Elixhauser Comorbidity Index. Ninety-day perioperative outcomes and 2-year revision rates were assessed and compared with multivariable logistic regression., Results: For THA, 185 patients with CF were matched with 1,846 control subjects without CF. Patients with CF were at significantly increased odds of 90-day postoperative events including sepsis (odd radio [OR] 4.15), pneumonia (OR 3.40), pleural effusion (OR 2.77), minor events (OR 1.73), any adverse event (OR 1.64), urinary tract infection (UTI) (OR 1.63), and severe events (OR 1.60) ( P < 0.05 for each). For TKA, 505 patients with CF were matched with 5,047 control subjects without CF. Patients with CF were at significantly increased odds of 90-day postoperative events including pneumonia (OR 4.95), respiratory failure (OR 4.31), cardiac event (OR 2.29), minor events (OR 2.16), pleural effusion (OR 2.35), severe events (OR 2.06), urinary tract infection (OR 2.06), any adverse event (OR 1.96), atelectasis (OR 1.94), and acute kidney injury (OR 1.61) ( P < 0.05 for each). For both THA and TKA, those with CF were not at greater odds of 2-year rates of revision., Discussion: After THA and TKA, those with CF were found to be at increased odds of multiple defined postoperative events (predominantly infectious/pulmonary), but not 2-year revision rates. These findings help define areas in need of focused optimization and are reassuring regarding risks of surgery., (Copyright © 2023 by the American Academy of Orthopaedic Surgeons.)

There is a lack of research that has focused on attention-deficit hyperactivity disorder (ADHD) in people with cystic fibrosis (pwCF). Given ADHD is associated with executive functioning impairments, exploring ADHD in the context of living with cystic fibrosis (CF) is of great importance. The purpose of the current systematic review was to examine ADHD in pwCF across the lifespan in terms of its prevalence, its impact on various health outcomes, and treatments for managing ADHD. This systematic review followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Articles reporting studies of any design that focused on ADHD in pwCF were included. Studies were excluded if they did not meet this criterion and if they were written in languages other than English. PsycINFO, MEDLINE, EMBASE, and CINAHL databases were searched. Search items were based on three concepts: (1) terms related to CF, (2) terms related to ADHD, and (3) terms related to age. Ten studies were included in this systematic review. Reported prevalence rates of ADHD in pwCF ranged from 5.26% to 21.9%. The reported relationships between ADHD and CF and other health outcomes is inconsistent. In terms of treatment considerations, pharmacological interventions and behavioural strategies for managing ADHD in the context of living with CF have been reported as being successful. Additional research is needed to further explore ADHD in the CF population and health variables that may be associated with CF prognosis., (© 2024 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background and Purpose: Olfactory dysfunction (OD) commonly occurs in patients with sinonasal dysfunction, but the prevalence and severity of olfactory issues in adolescents with cystic fibrosis (AwCF) is unclear. OD may contribute to dietary deficiencies and exacerbate nutritional challenges. We sought to review literature on the effectiveness of medical and surgical management of sinonasal symptoms in AwCF and the associated impact on olfactory function., Methods: We performed a systematic literature search of PubMed, Embase, Web of Science, and Ebsco CINAHL from 1980 to 2022 per PRISMA-ScR protocols to conduct a scoping review in an effort to compile data on study design, patient demographics, clinical characteristics and outcomes, along with risk of bias., Results: Of 368 abstracts, 3 articles exclusively evaluated AwCF for a total of 34 patients. Two studies evaluated endoscopic sinus surgery (ESS) and dornase alfa. An additional 6 articles were included for mixed pediatric and adult CF populations totaling 313 patients. Interventions included ESS, elexacaftor-tezacaftor-ivacaftor (ETI), ivacaftor, saline, dornase alfa, hyaluronic acid, and hyaluronic acid-tobramycin combination. Outcome measures included subjective assessment of OD using non-validated (4/9) and validated (4/9) surveys, and psychophysical (1/9) smell testing. Studies evaluating ESS, FESS, dornase alfa, ivacaftor, and both hypertonic and isotonic saline reported statistically significant improvement in OD, whereas ETI failed to improve OD despite improvement in other quality of life measures., Conclusions: There is limited data regarding the impact of medical and surgical interventions on olfaction for AwCF. Assessment of olfaction was often limited to subjective and qualitative self-report. We suggest that tracking of olfactory outcomes with psychophysical testing is critical in this population with dietary challenges and weight management issues., Competing Interests: Declaration of Competing Interest Proceed as no conflict., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Cystic fibrosis related diabetes (CFRD) is commonly associated with declining lung function and nutritional status. We aimed to evaluate the pulmonary impact of early glucose abnormalities by using 2-h standard oral glucose tolerance testing (OGTT) and continuous glucose monitoring (CGM) in people with cystic fibrosis (PwCF)., Methods: PwCF aged ≥10 years old without known CFRD were included in a five-year prospective multicentre study. Annual evaluation of nutritional status, lung function, OGTT and CGM was set up. Associations between annual rate changes (Δ) in lung function, ΔFEV1 (forced expiratory volume in 1 s) percentage predicted (pp) and ΔFVC (forced vital capacity) pp., and annual rate changes in OGTT or CGM variables were estimated with a mixed model with a random effect for subject., Results: From 2009 to 2016, 112 PwCF (age: 21 ± 11 years, BMI (body mass index) z-score: -0.55 ± 1.09, FEV1pp: 77 ± 24 %, 2-h OGTT glucose: 122 ± 44 mg/dL, AUC (area under curve) >140 mg/dL: 1 mg/dL/day (0.2, 3.0) were included. A total of 428 OGTTs and 480 CGMs were collected. The participants presented annual decline of FVCpp and FEV1pp at -1.0 % per year (-1.6, -0.4), p < 0.001 and - 1.9 % per year (-2.5, -1.3), p < 0.001 respectively without change in BMI z-score during the study. Variation of two-hour OGTT glucose was not associated with declining lung function, as measured by ΔFEV1pp (p = 0.94) and ΔFVCpp (p = 0.90). Among CGM variables, only increase in AUC >140 mg/dL between two annual visits was associated with a decrease in ΔFVCpp (p < 0.05) and ΔFEV1pp (p < 0.05)., Conclusions: This prospective study supports the fact that early glucose abnormalities revealed by CGM predict pulmonary function decline in PwCF, while 2-h standard OGTT glucose is not associated with pulmonary impairment., Competing Interests: Declaration of competing interest No potential conflicts of interest relevant to this article were reported., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Rationale: Rates of viral respiratory infection (VRI) are similar in people with cystic fibrosis (CF) and the general population; however, the associations between VRI and CF pulmonary exacerbations (PEx) require further elucidation. Objectives: To determine VRI prevalence during CF PEx and evaluate associations between VRI, clinical presentation, and treatment response. Methods: The STOP2 (Standardized Treatment of Pulmonary Exacerbations II) study was a multicenter randomized trial to evaluate different durations of intravenous antibiotic therapy for PEx. In this ancillary study, participant sputum samples from up to three study visits were tested for respiratory viruses using multiplex polymerase chain reactions. Baselines and treatment-associated changes in mean lung function (percent predicted forced expiratory volume in 1 s) , respiratory symptoms (Chronic Respiratory Infection Symptom Score), weight, and C-reactive protein were compared as a function of virus detection. Odds of PEx retreatment within 30 days and future PEx hazard were modeled by logistic and Cox proportional hazards regression, respectively. Results: A total of 1,254 sputum samples from 621 study participants were analyzed. One or more respiratory viruses were detected in sputum samples from 245 participants (39.5%). Virus-positive participants were more likely to be receiving CF transmembrane conductance regulator modulator therapy (45% vs. 34%) and/or chronic azithromycin therapy (54% vs. 44%) and more likely to have received treatment for nontuberculous Mycobacterium infection in the preceding 2 years (7% vs. 3%). At study visit 1, virus-positive participants were more symptomatic (mean Chronic Respiratory Infection Symptom Score, 53.8 vs. 51.1), had evidence of greater systemic inflammation (log 10 C-reactive protein concentration, 1.32 log 10 mg/L vs. 1.23 log 10 mg/L), and had a greater drop in percent predicted forced expiratory volume in 1 second from the prior 6-month baseline (5.8 vs. 3.6). Virus positivity was associated with reduced risk of future PEx (hazard ratio, 0.82; 95% confidence interval, 0.69-0.99; P  = 0.034) and longer median time to next PEx (255 d vs. 172 d; P  = 0.021) compared with virus negativity. Conclusions: More than one-third of STOP2 participants treated for a PEx had a positive test result for a respiratory virus with more symptomatic initial presentation compared with virus-negative participants, but favorable long-term outcomes. More refined phenotyping of PEx, taking VRIs into account, may aid in optimizing personalized management of PEx.Clinical trial registered with www.clinicaltrials.gov (NCT02781610).

The interaction between extracellular vesicles (EVs) and SARS-CoV-2, the virus causing COVID-19, especially in people with cystic fibrosis (PwCF) is insufficiently studied. EVs are small membrane-bound particles involved in cell-cell communications in different physiological and pathological conditions, including inflammation and infection. The CF airway cells release EVs that differ from those released by healthy cells and may play an intriguing role in regulating the inflammatory response to SARS-CoV-2. On the one hand, EVs may activate neutrophils and exacerbate inflammation. On the other hand, EVs may block IL-6, a pro-inflammatory cytokine associated with severe COVID-19, and protect PwCF from adverse outcomes. EVs are regulated by TGF-β signaling, essential in different disease states, including COVID-19. Here, we review the knowledge, identify the gaps in understanding, and suggest future research directions to elucidate the role of EVs in PwCF during COVID-19.

Objectives: To investigate the nutritional status of children with cystic fibrosis (CF) and understand the correlation between malnutrition and clinical characteristics as well as lung function., Methods: A retrospective analysis was performed on clinical data of CF children admitted from January 2016 to June 2023. Clinical characteristics of CF children with different nutritional statuses were compared, and the correlation between malnutrition and lung function was analyzed., Results: A total of 52 CF children were included, comprising 25 boys (48%) and 27 girls (52%), aged between 7 months and 17 years. Respiratory symptoms were the predominant clinical manifestations (96%, 50/52). The prevalence of malnutrition was 65% (34/52), with moderate/severe malnutrition being the most common (65%, 22/34). The malnutrition group had a longer duration of illness, higher proportion of digestive system symptoms, and lower levels of serum albumin ( P <0.05). Pulmonary function parameters, including forced expiratory volume in one second as a percentage of the predicted value, ratio of forced expiratory volume in one second to forced vital capacity, forced expiratory flow at 25% of forced vital capacity exhaled, forced expiratory flow at 50% of forced vital capacity exhaled, forced expiratory flow at 75% of forced vital capacity exhaled, and maximum mid-expiratory flow as a percentage of the predicted value, were lower in the malnutrition group compared to the normal nutrition group ( P <0.05). Correlation analysis showed body mass index Z-score was positively correlated with the above six pulmonary function parameters ( P <0.05)., Conclusions: The prevalence of malnutrition is high in CF children and is associated with decreased lung function. CF children with higher body mass index have better lung function. Therefore, screening and evaluation of nutritional status as well as appropriate nutritional intervention should be emphasized in CF children.

Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity in patients with cystic fibrosis (CF). CFRD has been correlated with important clinical outcomes, including poor nutrition, reduced pulmonary function, and earlier mortality. However, clinical decline due to abnormalities of blood glucose (dysglycemia) begins early in CF, before the diagnosis of CFRD by the gold-standard oral glucose tolerance test (OGTT). Continuous glucose monitoring (CGM) has been validated in patients with CF and has been recognized as a valuable tool in detecting early glucose abnormalities in patients with CF. Several CGM parameters have been used to predict CFRD in some but not all studies, and there is no consensus regarding CGM use for diagnostic purposes. Thus, it remains a complementary test to OGTT in CFRD diagnosis. The aim of this review is to provide an update on the pathophysiological mechanisms of CFRD, recent advances in the use of CGM for CFRD screening, and the association between CGM measures and CF-related clinical outcomes.

Background: Gut dysbiosis is implicated in colorectal cancer (CRC) pathogenesis. Cystic fibrosis (CF) is associated with both gut dysbiosis and increased CRC risk. We therefore compared the faecal microbiota from individuals with CF to CRC and screening samples. We also assessed changes in CRC-associated taxa before and after triple CF transmembrane conductance regulator (CFTR) modulator therapy., Methods: Bacterial DNA amplification comprising V4 16S rRNA analysis was conducted on 84 baseline and 53 matched follow-up stool samples from adults with CF. These data were compared to an existing cohort of 430 CRC and 491 control gFOBT samples from the NHS Bowel Cancer Screening Programme. Data were also compared to 26 previously identified CRC-associated taxa from a published meta-analysis., Results: Faecal CF samples had a lower alpha diversity and clustered distinctly from both CRC and control samples, with no clear clinical variables explaining the variation. Compared to controls, CF samples had an increased relative abundance in 6 of the 20 enriched CRC-associated taxa and depletion of 2 of the 6 taxa which have been reported as reduced in CRC. Commencing triple modulator therapy had subtle influence on the relative abundance of CRC-associated microbiota (n = 23 paired CF samples)., Conclusions: CF stool samples were clearly dysbiotic, clustering distinctly from both CRC and control samples. Several bacterial shifts in CF samples resembled those observed in CRC. Studies assessing the impact of dietary or other interventions and the longer-term use of CFTR modulators on reducing this potentially pro-oncogenic milieu are needed., Competing Interests: Declaration of Competing Interest D.G.P speaker/board honoraria from Vertex. H.W: Received previous funding from Gilead, which was not directly related to this research project and from Health Education England for simulated placement delivery funding. L.R.C, H.M.W, D.B, A.F.B, L.W., J.D., C.Y., S.B., M.B., P.Q and declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Allergic bronchopulmonary aspergillosis (ABPA) is a regular occurrence in everyday pneumology. ABPA should be considered in patients with severe asthma, in mould allergic patients with very high serum IgE levels and in patients with cystic fibrosis. The aim should be to make the diagnosis as early as possible in the course of the disease to avoid late complications such as bronchiectasis and fibrotic lung remodelling. Symptoms are highly variable and rather non-specific, overlapping with those of the underlying primary disease. However, clearly defined diagnostic criteria exist, so that the diagnosis can be made relatively easily if one thinks of it. In therapy, systemic steroids and antifungals (mainly azoles) play the leading role. However, biologics have been gaining in importance in recent years, especially in cases of insufficient therapy response or occurrence of side effects to standard therapies, as well as an alternative in permanently steroid-dependent patients., Competing Interests: Erklärung zu finanziellen Interessen Forschungsförderung erhalten: ja, von einem/den Sponsor(en) dieser Fortbildungseinheit; Honorar/geldwerten Vorteil für Referententätigkeit erhalten: ja, von einem/den Sponsor(en) dieser Fortbildungseinheit; Bezahlter Berater/interner Schulungsreferent/Gehaltsempfänger: ja, von einem/den Sponsor(en) dieser Fortbildungseinheit; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an im Bereich der Medizin aktiven Firma: nein; Patent/Geschäftsanteile/Aktien (Autor/Partner, Ehepartner, Kinder) an zu Sponsoren dieser Fortbildung bzw. durch die Fortbildung in ihren Geschäftsinteressen berührten Firma: nein Erklärung zu nichtfinanziellen Interessen Joest: Mitgliedschaft DGP, ERS, AeDA, DGAKI, EAACI, BDP, WDGP. Kütting: Mitgliedschaft DRG, ESR, DEGIR, ESIR, RSNA, ESTI, SCMR. Skowasch: Mitgliedschaft DGP, ERS, DGU, ESC., (Thieme. All rights reserved.)

Objective: This study examined whether bronchoscopy leads to clinicoradiological improvement in cystic fibrosis (CF) and the predictive factors. The study also investigated whether pulmonary atelectasis is a poor prognostic factor in CF., Methods: This multicenter, case-control, observational, retrospective study included two groups of patients with CF: a case group (patients with persistent atelectasis who were followed-up at least for 2 years) and a control group (patients without atelectasis matched 1:1 by sex and age [±3 years]). We recorded demographic data, lung function test results, pulmonary complications, comorbidities, treatments (including bronchoscopies, surgery and transplantation), and deaths., Results: Each group included 55 patients (case group: 20 men, mean age 25.4 ± 10.4 years; control group: 20 men, mean age 26.1 ± 11.4 years). Bronchoscopy did not lead to clinicoradiological improvement. Allergic bronchopulmonary aspergillosis (ABPA) was more frequent in the case group. Patients in the case group more frequently used inhaled steroids, their pre-atelectasis lung function was statistically worse, and they had more exacerbations during follow-up., Conclusion: Moderate-to-severe pulmonary disease and ABPA can favor atelectasis. Pulmonary atelectasis can be a poor prognostic factor in CF because it increases exacerbations. Despite our results, we recommend enhancing treatment, including bronchoscopy, to prevent persistent atelectasis., Competing Interests: Declaration of conflicting interestThe authors declare that there are no conflicts of interest.

Background: Aspergillus infection is known to be associated with worse respiratory outcomes in people with CF (pwCF) and is a well-recognised complication of severe SARS-CoV-2 infection. The aim of this observational cross-sectional study was to examine the association of pre-existing Aspergillus infection and/or allergic bronchopulmonary aspergillosis (ABPA) in pwCF and severity of COVID-19., Methods: Data on SARS-CoV-2 infections in pwCF from January 2020 to June 2021 were collected by the European Cystic Fibrosis Society Patient Registry. The primary outcome was COVID-19 severity measured by hospitalisation comparing those with Aspergillus infection and/or ABPA in the 12 months preceding COVID-19 and those without., Results: In total, 1095 pwCF were diagnosed with SARS-CoV-2 and information on pre-existing Aspergillus/ABPA status was available from 807. PwCF and SARS-CoV-2 in the Aspergillus/ABPA group (n = 153), in comparison to the non-Aspergillus/ABPA group (n = 654), were more likely to be hospitalised (adjusted OR 1.79 (1.19 to 2.85); p = 0.005) and their disease course was more likely to be complicated by sepsis (adjusted OR 7.78 (1.78 to 49.43); p = 0.008). The association with hospital admission was no longer significant after excluding patients with ABPA. Secondary analysis comparing pwCF who received antifungal treatment (n = 18), versus those who did not (n = 474) during COVID-19, showed a higher rate of hospitalisation (p < 0.001); intensive care unit admission (p < 0.001), and requirement for invasive ventilation (p < 0.001) in the antifungal treated group., Conclusion: We show that pre-existing Aspergillus/ABPA is associated with increased rates of hospitalisation and sepsis during COVID-19 in pwCF., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: Iron deficiency is highly prevalent in people with cystic fibrosis (PwCF). While elexacaftor/tezacaftor/ivacaftor (ETI) has shown remarkable improvements in respiratory symptoms in PwCF, the effect of ETI on iron status remains unknown. This study aims to identify the effect of ETI on iron status in PwCF., Methods: A single-center retrospective cohort study of 127 adult PwCF was conducted to assess the impact of ETI on iron, ferritin, transferrin levels, and percent saturation of transferrin (PSAT). Data were collected from the electronic medical record from January 2017 to September 2022, encompassing 2 years before and after ETI initiation. The primary outcome was serum iron parameters: iron, ferritin, transferrin, and PSAT levels following ETI treatment. Secondary outcomes analyzed iron supplementation. Univariate and multivariate mixed-effects models were used for the analysis of ETI., Results: After adjusting for covariates, following ETI initiation, the mean iron level increased by 20.24 μg/dL (p < .001), ferritin levels were 31.4% (p < .001) higher, PSAT showed a 5.09 percentage point increase (p < .001), and transferrin levels increased by 2.71 mg/dL (p = .439). Patients with and without iron supplementation experienced a significant increase in iron after ETI (p < .001)., Conclusions: ETI is associated with a significant increase in iron, ferritin, and PSAT levels. Patients with and without iron supplementation demonstrated a significant increase in iron. This study shows the benefits of ETI on iron status in PwCF. However, further translational studies are required to understand the impact of ETI on iron absorption and metabolism in PwCF., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Objectives: Gram-negative pathogens causing respiratory infection in people with cystic fibrosis and bronchiectasis are becoming progressively more resistant to conventional antibiotics. Although cefiderocol is licenced for the treatment of infections due to Gram-negative organisms, there are limited data on the activity of cefiderocol against pathogens associated with chronic respiratory diseases. The aim of this study was to determine the susceptibility of Gram-negative pathogens from cystic fibrosis and bronchiectasis to cefiderocol and comparator antibiotics., Methods: Minimal inhibitory concentrations (MICs) of cefiderocol and 15 comparator antibiotics were determined by broth microdilution against 300 respiratory isolates: Burkholderia spp., Stenotrophomonas spp., Achromobacter spp., Ralstonia spp. and Pandoraea spp., and used to calculate the MIC of each antibiotic required to inhibit 50% (MIC 50 ) and 90% (MIC 90 ) of isolates., Results: The MIC 50 and MIC 90 of cefiderocol for all 300 isolates tested was 0.25 and 32 mg/L, with 232 (77.3%) isolates having an MIC value ≤2 mg/L. In addition, cefiderocol demonstrated excellent activity against Stenotrophomonas spp. and Achromobacter spp. isolates, with 86.7% and 87.2%, respectively, exhibiting an MIC of 2 mg/L. Tigecycline also demonstrated good activity against all isolates with an MIC 50 of <0.5 mg/L., Conclusions: These in vitro data demonstrated that cefiderocol had greater activity than most comparator antibiotics and could be an alternative treatment option for respiratory infection caused by these pathogens that has not responded to first-line therapy., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rationale: Primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) are characterized by inherited impaired mucociliary clearance leading to chronic progressive lung disease as well as chronic rhinosinusitis (CRS). The diseases share morphological and functional commonalities on magnetic resonance imaging (MRI) of the lungs and paranasal sinuses, but comparative MRI studies are lacking. Objectives: To determine whether PCD shows different associations of pulmonary and paranasal sinus abnormalities on MRI and lung function test results in children (infants to adolescents) compared with children with CF. Methods: Eighteen children with PCD (median age, 9.5 [IQR, 3.4-12.7] yr; range, 0-18 yr) and 36 age-matched CF transmembrane conductance regulator modulator-naive children with CF (median age, 9.4 [3.4-13.2] yr; range, 0-18 yr) underwent same-session chest and paranasal sinus MRI as well as spirometry (to determine forced expiratory volume in 1 s percent predicted) and multiple-breath washout (to determine lung clearance index z -score). Pulmonary and paranasal sinus abnormalities were assessed using previously validated chest MRI and CRS-MRI scoring systems. Results: Mean chest MRI global score was similar in children with PCD and CF (15.0 [13.5-20.8] vs. 15.0 [9.0-15.0]; P  = 0.601). Consolidations were more prevalent and severe in children with PCD (56% vs. 25% and 1.0 [0.0-2.8] vs. 0.0 [0.0-0.3], respectively; P  < 0.05). The chest MRI global score correlated moderately with forced expiratory volume in 1 second percent predicted in children with PCD and children with CF ( r  = -0.523 and -0.687; P  < 0.01) and with lung clearance index in children with CF ( r  = 0.650; P  < 0.001) but not in PCD ( r  = 0.353; P  = 0.196). CRS-MRI sum score and mucopyocele subscore were lower in children with PCD than in children with CF (27.5 [26.3-32.0] vs. 37.0 [37.8-40.0] and 2.0 [0.0-2.0] vs. 7.5 [4.8-9.0], respectively; P  < 0.01). CRS-MRI sum score did not correlate with chest MRI score in PCD ( r  = 0.075-0.157; P  = 0.557-0.788) but correlated moderately with MRI morphology score in CF ( r  = 0.437; P  < 0.01). Conclusions: MRI detects differences in lung and paranasal sinus abnormalities between children with PCD and those with CF. Lung disease does not correlate with CRS in PCD but correlates in CF.

Background: High frequency chest wall oscillation (HFCWO) is a form of airway clearance therapy that has been available since the mid-1990s and is routinely used by patients suffering from retained pulmonary secretions. Patients with cystic fibrosis (CF), neuromuscular disease (NMD), and other disorders, including bronchiectasis (BE) and COPD (without BE), are commonly prescribed this therapy. Limited evidence exists describing HFCWO use in the BE population, its impact on long-term management of disease, and the specific patient populations most likely to benefit from this therapy. This study sought to characterize the clinical characteristics of patients with BE who have documented use of HFCWO at baseline and 1-year follow-up., Methods: An analysis from a large national database registry of patients with BE was performed. Demographic and clinical characteristics of all patients receiving HFCWO therapy at baseline are reported. Patients were stratified into two groups based on continued or discontinued use of HFCWO therapy at 1-year follow-up., Results: Over half (54.8 %) of patients who reported using HFCWO therapy had a Modified Bronchiectasis Severity Index (m-BSI) classified as severe, and the majority (81.4 %) experienced an exacerbation in the prior two years. Of patients with 1-year follow-up data, 73 % reported continued use of HFCWO. Compared to patients who discontinued therapy, these patients were more severe at baseline and at follow-up suggesting that patients with more severe disease are more likely to continue HFCWO therapy., Conclusions: Patients who have more severe disease and continue to experience exacerbations and hospitalizations are more likely to continue HFCWO therapy., Clinical Trial Registration: NA., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ashwin Basavaraj reports writing assistance was provided by LeeAnn Phipps. AB - Consultant and Advisory Board for Baxter, Insmed, Physio-Assist, Dymedso, Zambon. Medical education consulting for Tactile Medical. Principal investigator on clinical trial sponsored by Baxter with funding to institution. Educational grant funding received from Insmed to institution. RC - No disclosures to report. BB – Employee relationship with Baxter. MM - Grant funding from Insmed and COPD foundation. Consulting fees from Insmed, Boehringer-Ingelheim, and Tactile Medical. Payment/honoraria for presentations/lectures from Insmed. Participation on data safety monitoring/advisory board for AN2, Renovion. TA - Support as medical director of the Bronchiectasis and NTM research registry. Has participated in clinical trials sponsored by Bayer, Aradigm, Zambon., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Pulmonary exacerbations (PEx) are strong predictors of respiratory disease progression in children with cystic fibrosis (CwCF) and may be associated with persistent decreased lung function after acute management. Telemonitoring devices can be used for early detection and monitoring of PEx, but its utility is debated., Research Question: Which symptoms and telemonitoring spirometry characterics are related to outcome dynamics following initial PEx management?, Methods: This retrospective study included CwCF followed at Bordeaux University Hospital, France. All severe PEx episodes treated with intravenous (IV) antibiotics (ATB) between 1 January 2017 and 31 December 2021 in CwCF using home telemonitoring were analyzed. Symptoms and home spirometry data were collected 45 days before and up to 60 days after each IV ATB course. We defined three response profiles based on terciles of baseline forced expiratory volume in 1 s (FEV 1 ) recovery., Results: A total of 346 IV ATB courses for PEx were administered to 65 CwCF during the study period. The drop in FEV 1 became significant 8 days before IV ATB initiation. Forty-one percent of IV ATB courses failed to restore baseline FEV 1 . The magnitude of FEV 1 drop and a greater delay in the initiation of treatment correlated with a low response level. On the 14th day of the IV treatment, a FEV 1 recovery less than 94% of baseline was associated with a nonresponder profile., Interpretation: Home spirometry may facilitate the early recognition of PEx to implement earlier interventions. This study also provides an outcome lung function threshold which identifies low responders to IV ATB., (© 2023 Wiley Periodicals LLC.)

Patients with cystic fibrosis (CF) often develop respiratory tract infections with pathogenic multidrug-resistant organisms (MDROs) such as methicillin-resistant Staphylococcus aureus, and a variety of gram-negative organisms that include Pseudomonas aeruginosa, Burkholderia sp., Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and nontuberculous mycobacteria (NTM). Despite the introduction of new therapies to address underlying cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction, MDRO infections remain a problem and novel antimicrobial interventions are still needed. Therapeutic approaches include improving the efficacy of existing drugs by adjusting the dose based on differences in CF patient pharmacokinetics/pharmacodynamics, the development of inhaled formulations to reduce systemic adverse events, and the use of newer beta-lactam/beta-lactamase combinations. Alternative innovative therapeutic approaches include the use of gallium and bacteriophages to treat MDRO pulmonary infections including those with extreme antibiotic resistance. However, additional clinical trials are required to determine the optimal dosing and efficacy of these different strategies and to identify patients with CF most likely to benefit from these new treatment options., Competing Interests: Disclosure T.S. Murray-none. J.L. Koff is the PI for bacteriophage clinical trial NCT04684641 and a national Co-PI for bacteriophage clinical trial NCT05010577. J.L. Koff & G.L. Stanley: Colleagues at Yale University have licensed intellectual property related to bacteriophage therapy to a company although neither J.L. Koff nor G.L. Stanley has a financial interest in this process., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Many people with cystic fibrosis (PwCF) have chronic rhinosinusitis (CRS). CRS requires additional management beyond that of pulmonary disease and leads to increased utilization of healthcare resources. Elexacaftor/tezacaftor/ivacaftor (ETI) is a highly effective modulator therapy that has been shown to improve CRS in PwCF. However, the impact of ETI on rhinologic healthcare utilization is understudied., Objective: To compare rates of rhinologic healthcare utilization and procedures among PwCF prior to and after initiating ETI therapy., Methods: A single-center, cohort study investigating adult PwCF was performed in January 2023. Demographics, clinical characteristics, and data related to CF treatment were retrospectively abstracted. Characteristics of the cohort were compared over 2 periods: the 12-months prior to ETI initiation and the 12-months after ETI initiation. Post-ETI data were linearly extrapolated if a subject had not yet completed the full 12 months of ETI. Paired t-testing, Wilcoxon signed rank testing, and regression analysis were performed., Results: Of 126 PwCF, 98 (77.8%) were on ETI therapy and 35 (27.7%) were both on ETI and concurrently followed by the rhinology service (ETI-ENT). Rhinology clinic visits ( P  = .007) and frequency of obtaining nasal cultures ( P  = .046) decreased for the ETI-ENT cohort after initiating ETI treatment. There were no significant changes in the number of endoscopic sinus surgeries ( P  = .452) performed. Beyond ETI use, regression analysis did not identify any factors associated with changes in utilization., Conclusion: Aspects of rhinology healthcare utilization by PwCF decreased after initiation of ETI therapy. Additional studies are needed to determine rhinologic healthcare requirements for PwCF who remain on ETI for the long-term and to evaluate larger cohorts of PwCF on ETI., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: D.M.B.: In the last 24 months, D.M.B. has received grant support unrelated to this work from the CF Foundation and International Society of Inflammation and Allergy of the Nose consultant for Garner Health (equity); received honorarium from Rockpointe.J. L.T-C.: In the last 36 months, J.L.T-C. has received grants to her institution unrelated to this work from Vertex Pharmaceuticals Incorporated, Eloxx, and 4DMT; has received fees from Vertex Pharmaceuticals Incorporated related to consultation on clinical research design, participation on advisory boards, and speaking engagements; and has served on advisory boards and/or provided clinical trial design consultation for Insmed, 4DMT, and AbbVie. She serves on a DMC for AbbVie. She serves as the adult patient care representative to the CFF Board of Trustees, and on the CF Foundation’s Clinical Research Executive Committee, Clinical Research Advisory Board, Racial Justice Working Group and as immediate past chair of the CF TDN’s Sexual Health, Reproduction and Gender Research Working Group, on the scientific advisory board for Emily’s Entourage, and on the ATS Respiratory Health Awards, Scientific Grant Review and Clinical Problems Assembly Programming Committees.

Background: Cystic fibrosis (CF) is characterized by highly viscous mucus obstructing the lower and upper airways, chronic neutrophil inflammation and infection resulting not only in lung destruction but also in paranasal sinus involvement. The pathogenesis of CF-associated chronic rhinosinusitis (CRS) is still not well understood, and it remains unclear how the microbiome in the upper airways (UAW) influences paranasal sinus inflammation., Methods: In a cross-sectional study in pediatric patients with CF under stable disease conditions, we examined the microbiome in relation to inflammation by comparing nasal swabs (NS) and nasal lavage (NL) as two UAW sampling methods. The microbiota structure of both NS and NL was determined by 16S rRNA gene amplicon sequencing. In addition, pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and proteases (SLPI, TIMP-1, NE/A1-AT complex) as well as neutrophil elastase activity were measured in NL., Results: Simultaneous NS and NL samples were collected from 36 patients with CF (age range: 7 - 19 years). The microbiome of NS samples was shown to be significantly lower in α-diversity and evenness compared to NL samples. NS samples were particularly found to be colonized with Staphylococcus species. NL microbiome was shown to correlate much better with the sinonasal inflammation status than NS microbiome. Especially the detection of Moraxella in NL was associated with increased inflammatory response., Conclusion: Our results show that the NL microbiome reflects sinonasal inflammation better than NS and support NL as a promising tool for simultaneous assessment of the UAW microbiome and inflammation in children with CF., Competing Interests: Declaration of competing interest M.A.M. reports grants from Vertex Pharmaceuticals; fees for advisory board participation or consulting from Abbvie, Antabio, Arrowhead Pharmaceuticals, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotech, Pari, Prieris, Recode, Santhera, Splisense, Vertex Pharmaceuticals; lecture honoraria from Vertex Pharmaceuticals; travel support from Boehringer Ingelheim and Vertex Pharmaceuticals outside the submitted work. The other authors have nothing to declare., (Copyright © 2023. Published by Elsevier B.V.)

Background: There are limited studies to date on the effects of elexacaftor/tezacaftor/ivacaftor (E/T/I) on markers of liver fibrosis in adults with cystic fibrosis (CF). This study aims to analyse changes in makers of liver fibrosis before and after initiation of E/T/I in CF adults., Methods: Outcome measures of liver fibrosis, including liver stiffness measurement (LSM) using FibroScan, AST-to-platelet-ratio index (APRI) and gamma-GT-to-platelet-ratio (GPR) were available in 74 CF adults following initiation of E/T/I. This was compared to historical data collected in 2018 prior to UK availability of E/T/I., Results: The median duration of E/T/I therapy at the time liver fibrosis markers were repeated was 21 (IQR: 17-25) months. There was an increase in APRI from historical measurement to follow-up but no change in LSM or GPR. There were no differences in change in fibrosis markers according to CF liver disease (CFLD) status, although those with a raised LSM at baseline (>6.8 kPa) (n = 14) had a significant reduction in LSM from historical measurement to follow-up versus those with a normal historical value (-3.3 kPa vs 0.25 kPa, p < 0.01)., Conclusions: Apart from APRI, we found no changes in liver fibrosis outcomes after initiation of E/T/I in adults with CF. Those with a historical diagnosis of CFLD had no significant worsening or improvement of liver fibrosis markers. We did observe a reduction in LSM in those with liver nodularity, with an initial highest result suggesting a potential positive treatment effect of E/T/I in this category of those with severe CFLD., Competing Interests: Declaration of Competing Interest DT, JS, RBT, KPH and AJ have no conflicts of interest to disclose. PB has accepted speaking fees and honoraria from Vertex pharmaceuticals and advisory board fees from INSMED. VA has accepted speaking fees and honoraria from Vertex pharmaceuticals and Roche diagnostics., (Copyright © 2023. Published by Elsevier B.V.)

When cultured together under standard laboratory conditions Pseudomonas aeruginosa has been shown to be an effective inhibitor of Staphylococcus aureus . However, P. aeruginosa and S. aureus are commonly observed in coinfections of individuals with cystic fibrosis (CF) and in chronic wounds. Previous work from our group revealed that S. aureus isolates from CF infections are able to persist in the presence of P. aeruginosa strain PAO1 with a range of tolerances with some isolates being eliminated entirely and others maintaining large populations. In this study, we designed a serial transfer, evolution experiment to identify mutations that allow S. aureus to survive in the presence of P. aeruginosa . Using S. aureus USA300 JE2 as our ancestral strain, populations of S. aureus were repeatedly cocultured with fresh P. aeruginosa PAO1. After eight coculture periods, S. aureus populations that survived better in the presence of PAO1 were observed. We found two independent mutations in the highly conserved S. aureus aspartate transporter, gltT , that were unique to evolved P. aeruginosa -tolerant isolates. Subsequent phenotypic testing demonstrated that gltT mutants have reduced uptake of glutamate and outcompeted wild-type S. aureus when glutamate was absent from chemically defined media. These findings together demonstrate that the presence of P. aeruginosa exerts selective pressure on S. aureus to alter its uptake and metabolism of key amino acids when the two are cultured together.

Background: No evidence exists to guide the frequency of obtaining bacterial respiratory cultures during inpatient treatment of pediatric cystic fibrosis (CF) pulmonary exacerbations (PEx). At our institution, admission and weekly respiratory cultures are routinely collected to guide antimicrobial selection. This study evaluates the extent that this practice informs clinical management and the healthcare-related costs associated with routinely repeating cultures., Methods: All children with CF with at least one hospital admission for IV antibiotics from January 2015 to December 2019 were included. Data collected included patient demographics, culture results, and antibiotic history. Respiratory cultures were numbered from the last clinic culture (`Culture 1'), culture on admission (`Culture 2'), and so on (`Cultures 3-6'). Outcomes assessed were microbiological results, frequency and timing of antibiotic change, and total microbiological laboratory costs., Results: Seventy-eight children with 224 admissions and 695 bacterial cultures were analyzed. Repeated microbiology sampling revealed 118 new bacterial species in 82 admissions.  Culture 2 was most likely to identify a new bacterial species (91/115, 79.1 %) and most likely to be followed by a change in antibiotic (33/37; 89.2 %). The total cost of all cultures was $18,264.79. Eliminating Cultures 3-6 from routine practice could represent a 51 % cost-savings ($9,362.89), without significant impact on identification of new clinically relevant isolates., Conclusion: Ongoing bacterial surveillance during a CF PEx beyond admission culture provides minimal information, rarely impacts clinical management, and can increase healthcare costs. An optimized approach would be to routinely obtain admission cultures and to obtain further cultures only if clinically indicated., Competing Interests: Declaration of Competing Interest JHR reports unrestricted research funding and travel support from Vertex Pharmaceuticals and medical advisory board fees from Sanofi. The other authors have no financial disclosures to report., (Copyright © 2023. Published by Elsevier B.V.)

Previous studies indicate that hospital rather than home treatment of pulmonary exacerbations (PEx) in people with cystic fibrosis (CF) can improve outcomes. We evaluated characteristics of adult participants from the Standardized Treatment of Pulmonary Exacerbations (STOP2) trial with two separate comparisons: (1) those who were treated initially in hospital (N = 768) to those treated initially at home (N = 214) and (2) those treated only in hospital (N = 328) to those who were treated only at home or both at home and in hospital (N = 654). Participants who had Medicaid insurance, were treated for shorter duration, and traveled longer to reach treatment centers were more likely to have been treated initially in the hospital. Having Medicaid insurance, being treated for a shorter duration, and being male were associated with being treated only in the hospital. This analysis suggests decisions about the location of treatment are based on pragmatic factors rather than on clinical characteristics., Competing Interests: Declaration of Competing Interest Grants from the Cystic Fibrosis Foundation in part supported the salaries of LSG, RNH, SLH, PAF, CHG, NEW, DBS, and LK. Grants from the NIH in part supported the salaries of SLH, PAF, and CHG. DBS received payments for committee work from the Cystic Fibrosis foundation. DBS's institution also grant support payments from Gilead Sciences and the CHEST Foundation. DBS received personal payment for participation on an advisory board for Vertex Pharmaceuticals., (Copyright © 2023. Published by Elsevier B.V.)

Chronic rhinosinusitis is a common manifestation of CF that is associated with impaired quality of life and can be difficult to treat. CFTR modulator therapy has resulted in significant improvements in lower respiratory and nutritional outcomes for people with CF however their impact on chronic rhinosinusitis has received less attention. We review the literature in relation to chronic rhinosinusitis in CF and examine the impact of CFTR modulator therapy on symptoms, imaging, endoscopic appearances, and olfactory outcomes in the treatment of chronic rhinosinusitis. While an overall improvement in symptoms, imaging and endoscopic appearances is seen in response to treatment, limited impact is documented on olfaction. Outcome measures employed were heterogenous, limiting comparison of findings. There is a need for well powered prospective real-world studies with standardised outcome measures., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: Rates of venous thromboembolism (VTE) are increasing in people with cystic fibrosis (PwCF). Providers treating VTE in PwCF have reported low confidence concerning anticoagulant drug selection, dose, duration, and drug-drug interactions. As there are currently no published reports regarding management of VTE in PwCF, our objective was to describe the management of VTE in PwCF., Methods: PwCF and VTE at the University of Utah Health were identified through electronic medical record searches. Patients were categorized into one of three treatment groups: warfarin, direct oral anticoagulant (DOAC), and low molecular weight heparin (LMWH). The primary outcome was episodes of major bleeding. Secondary outcomes included clinically relevant nonmajor (CRNM) bleeding., Results: Nine PwCF with a total of 12 unique VTE episodes were included in the study, with all but one episode associated with a peripherally inserted central catheter (PICC). Of the 12 VTE cases, 25% were treated with warfarin, 50% with a DOAC, and 25% with LMWH. There were no episodes of major bleeding and only one episode of CRNM bleeding (Hemoptysis) in the LMWH group. All anticoagulant doses and durations generally followed guidelines for persons without CF. DOACs were the most common VTE treatment, at doses and duration consistent with guidelines for persons without CF, with no major or CRNM bleeding., Conclusion: VTE treatment in PwCF is generally consistent with guidelines for persons without CF with low rates of bleeding. DOACs are a potential option for treatment of VTE in PwCF, but more research is needed., (© 2023 Wiley Periodicals LLC.)