Subclinical vascular, hemodynamic and arterial stiffness changes in adults with cystic fibrosis: cross-sectional observational study.

Cardiovascular diseases can be an emerging complication in cystic fibrosis (CF), as the median life expectancy has improved considerably. The objective of this study was to compare vascular, hemodynamic parameters and arterial stiffness in adult CF patients with healthy participants pared by sex and age, and to assess the factors associated with arterial stiffness in the CF group. This is a cross-sectional observational study. The evaluation of cardiovascular parameters was performed non-invasively using Mobil-O-Graph. 36 individuals with CF and 35 controls were evaluated. The mean arterial pressure (96.71 ± 10.98 versus 88.61 ± 7.40 mmHg, p = 0.0005), cardiac output (4.86 ± 0.57 versus 4.48 ± 0.44 L/min, p = 0.002) and systolic volume (64.30 ± 11.91 versus 49.02 ± 9.31 ml, p < 0.0001) were significantly lower in the CF group. The heart rate was higher in the CF when compared to the control (77.18 ± 10.47 versus 93.56 ± 14.57 bpm, p < 0.0001). The augmentation index (AIx@75) was higher in the CF than control (29.94 ± 9.37 versus 16.52 ± 7.179%, p < 0.0001). In the multivariate model controlled by body mass index and Forced Expiratory Volume in the first second, central systolic blood pressure and reflection coefficient directly related to AIx@75. Negatively related to AIx@75 were age and systolic volume. The adjusted determination coefficient was 87.40%. Individuals with CF presented lower arterial blood pressures and changes in cardiac function with lower stroke volume and cardiac output. The AIx@75, an indirect index of arterial stiffness and direct index of left ventricular overload, is increased in this population. The subclinical findings suggest the need for earlier cardiovascular assessment in this population due to increased risks of cardiovascular disease.

Dietary intake and quality among adults with cystic fibrosis: A systematic review.

AIMS: This systematic review aims to describe the dietary quality, dietary intake and related behaviours of adults diagnosed with cystic fibrosis. METHODS: A comprehensive literature search was conducted in four databases (Medline, CINAHL, EMBASE, CENTRAL); studies were included if they addressed dietary intake, diet quality or eating behaviours among adults (≥15 years) living with cystic fibrosis and were published from January 2000 to November 2022. The Mixed Methods Appraisal Tool was used to assess the risk of bias and quality of included studies. Findings were synthesised narratively. RESULTS: Nineteen observational studies (n = 2236) were included and considered high to moderate quality. Most (13/19) studies reported that individuals with cystic fibrosis were consuming high-energy diets; where studies reported energy intake as a proportion of requirements met, energy intake was high, even when using individualised or cystic fibrosis-specific referents. In addition, fat intakes as a proportion of energy appeared high (29%-39% of total energy), particularly as current guidelines recommend macronutrient profile similar to the general population (<30% of total energy). There was considerable variation in the reporting of fatty acid profiles and other nutrients. Five studies reported on concerns regarding diet and eating in this population. CONCLUSION: Findings from the current review suggest dietary intakes of adults with cystic fibrosis appear to be less than optimal and concerns about diet, weight and food may be emerging in this population. Future research utilising consistent measures of dietary assessment and reporting, reporting of medical therapies, and exploring potential concerns about diet and eating is warranted.

Potential drug-drug interactions analysis in Polish pediatric pneumonology units, including cystic fibrosis patients.

The lack of data on drug-drug interactions in pediatrics represents a relevant problem in making appropriate therapeutic decisions. Our study aimed to investigate the incidence and risk factors for potential drug-drug interactions (pDDIs) in pediatric pneumonology units, including cystic fibrosis patients. We performed a 6-month prospective observational study during which clinical pharmacists, using the Lexicomp Drug Interactions checker, screened medical records to identify pDDIs. Spearman's rank coefficient, logistic regression, and the Mann-Whitney U test were used to identify correlations, analyze risk factors for pDDIs, and compare cystic fibrosis patients with the rest, respectively. Recommendations were provided for the D and X pDDIs categories. Within the 218 patients, 428 pDDIs were identified, out of which 237 were classified as clinically significant. Almost 60% of patients were exposed to at least one relevant interaction. The number of pDDIs correlated with the number of; drugs (rs = 0.53, P <  .001), hospitalization length (rs = 0.20, P <  .01), and off-label medicines (rs = 0.25, P <  .001). According to the multivariate analysis, at least 6 administered medications (OR = 4.15; 95% CI = 2.21-7.78), 4 days of hospitalization (OR = 6.41; 95% CI = 2.29-17.97), and off-label therapy (OR = 3.37; 95% CI = 1.69-6.70) were the risk factor for pDDIs. Despite significant differences in the number of medications taken, comorbidities, and off-label drugs, cystic fibrosis patients were not more exposed to pDDI. Given the lack of data on pDDIs in the pediatric population, the need for close cooperation between clinicians and clinical pharmacists to improve the safety and efficacy of pharmacotherapy is highlighted.

Development and validation of a supportive programme for family caregivers of children suffering from cystic fibrosis: protocol for a sequential exploratory mixed-methods study.

INTRODUCTION: Families with children who have cystic fibrosis (CF) face a multitude of challenges. They require complex and time-consuming daily care, various forms of knowledge and intricate care responsibilities. One of the most critical challenges that Iranian families of children with CF face is the lack of adequate support from health teams in the early stages of diagnosis, frequent hospitalisation and the postdischarge process. Unfortunately, limited studies have been conducted in this field, and the Iranian society lacks a comprehensive support programme for these families after leaving treatment centres or home care teams. Therefore, it is necessary to identify and redefine the needs of these families for better care and support in Iran. METHODS AND ANALYSIS: A mixed-method research design with an exploratory sequential approach will be used in this study. The study consists of three stages: stage (1) the qualitative phase (conventional content analysis and scoping review); stage (2) the programme design phase (development of a support programme) and stage (3) the quantitative phase (validation of the programme through the Delphi method). In the first stage, data will be collected through interviews. Key concepts, evidence and gaps in research will also be identified, collected and analysed through a scoping review. In the second stage, a support programme will be designed based on the results of the content analysis of interviews and the findings from the scoping review. In the final phase, the study will aim to validate the designed programme through a Delphi study. ETHICS AND DISSEMINATION: This study formed part of a Ph.D. degree and was approved by the ethics committee of Tabriz University of Medical Sciences (IR.TBZMED.REC.1402.395). Informed consent will be obtained from all study participants. Findings will be published in a peer-reviewed journal.

Monitoring cystic fibrosis airway infections with Pseudomonas aeruginosa with anti-OprF serum antibodies.

BACKGROUND: The management of cystic fibrosis (CF) requires knowledge of the patient's microbiological status. The serology of anti-Pseudomonas aeruginosa antibodies against exoenzymes or water-soluble antigens has gained diagnostic value, particularly to detect the onset of colonization with P. aeruginosa. However, the diversity and variable expression of these antigens, which was unknown when the ELISAs became common diagnostic procedures at CF clinics, prohibits the quantitative evaluation of bacterial antigen load during intermittent and chronic infection. METHODS: An ELISA was developed to measure the serum IgG antibody levels against P. aeruginosa porin OprF, a species-specific, conserved, immunogenic and constitutively expressed protein present in the outer membrane and extracellular vesicles. RESULTS: Serial serum samples were collected from 310 people with CF (pwCF) over a period of up to 15 years. Compared to a reference of P. aeruginosa - negative CF sera set to 1, OprF antibody titers ranged from 0.3 to 13.2 (median: 1.7) in 56 intermittently colonized patients and from 0.5 to 51.2 (median: 11.8) in 176 chronically colonized pwCF showing higher anti-OprF antibody levels during chronic than during intermittent colonization with P. aeruginosa (P = 0, Z = - 21.7, effect size 0.62). Inhalation with twice daily 80 mg tobramycin decreased OprF antibody titers (P = 5 × 10-5), particularly during the third and fourth year of chronic colonization. CONCLUSION: The OprF ELISA should be an appropriate tool to monitor Pseudomonas serology at all stages of infection and disease severity and to study the impact of short- and long-term therapeutic interventions.

The intermittent intrapulmonary deflation technique for airway clearance in patients with cystic fibrosis: A randomized trial.

BACKGROUND: Cystic fibrosis (CF) is a muco-obstructive lung disease characterized by thick sputum with abnormal rheological properties. The intermittent intrapulmonary deflation (IID) is a new instrumental airway clearance technique (ACT) that aims to decrease the sputum viscoelastic properties. This study assessed the benefits of adding the IID technique to a conventional ACT in patients with CF hospitalized for intravenous antibiotic therapy. METHODS: Participants with CF accustomed to autogenic drainage (AD) as their standard ACT received, in a randomized order, a 30-min session of either AD alone or AD combined with IID (AD+IID). Sputum was collected during each ACT regimens and for a 24-hour period following both sessions. Sputum wet weight, dry weight, solids content and rheological properties were analyzed. Cough events occurring during and over 2 h post ACT were compared between both regimens. RESULTS: Seventeen patients with CF (aged 29 ± 11 years; FEV1%: 57.1 ± 20.1) were analysed. The sputum wet weight collected during AD alone was significantly higher than during AD+IID (8.11 ± 6.93 vs 5.40 ± 4.11 respectively, p = 0.01). The sputum rheological properties did not significantly differ between group. There were more cough episodes during AD alone compared to AD+IID (median [IQR]: 8 [5-15.5] vs 5 [3.5-11.0] respectively, p = 0.02). CONCLUSIONS: In participants with CF accustomed to AD, adding the IID technique in combination to AD does not confer a clear benefit on airway clearance in the short term. Clinical Trials register: NCT04157972.

Nebulized hypertonic saline and positive expiratory pressure device use in patients with bronchiectasis: Analysis from the United States Bronchiectasis and NTM research registry.

BACKGROUND: Nebulized Hypertonic saline (HS) and positive expiratory pressure device (PEP) are often used in patients with bronchiectasis. We sought to describe the clinical characteristics in patients using HS and PEP, utilizing a large national database registry. METHODS: Data from the US Bronchiectasis and NTM Research Registry were used in this study. Patients with a diagnosis of bronchiectasis were included. Eligible patients were assigned to one of four mutually exclusive groups: HS only, PEP only, HS & PEP, or no airway clearance or mucoactive agent. Descriptive statistics were computed for the overall study population and stratified by the four groups. One-way ANOVA and chi-square tests were used to test the difference in the means in continuous variables and the association between categorical variables (respectively) across the four groups. RESULTS: A total of 2195 patients were included. Of those with bronchiectasis and a productive cough, a greater number of patients utilized HS only vs PEP only (17.5 % vs 9.1 %, p < 0.001). Similar association was found in those with Pseudomonas aeruginosa (22.3 % HS only vs 6.5 % PEP only, p < 0.001). There was a higher number of patients who used HS and PEP therapy in combination vs PEP therapy alone (25.0 % vs 9.1 %, p = 0.002), in those with a productive cough. CONCLUSIONS: In patients with bronchiectasis and a productive cough or Pseudomonas aeruginosa, HS is used more often than PEP alone. There is a need for further analysis to compare these two modalities and explore the factors influencing their utilization.

The solute carrier family 26 member 9 modifies rapidly progressing cystic fibrosis associated with homozygous F508del CFTR mutation.

BACKGROUND AND AIMS: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations to the CF transmembrane conductance regulator (CFTR). Symptoms and severity of the disease can be quite variable suggesting modifier genes play an important role. MATERIALS AND METHODS: Exome sequencing was performed on six individuals carrying homozygous deltaF508 for CFTR genotype but present with rapidly progressing CF (RPCF). Data was analyzed using an unbiased genome-wide genetic burden test against 3076 controls. Single cell RNA sequencing data from LungMAP was utilized to evaluate unique and co-expression of candidate genes, and structural modeling to evaluate the deleterious effects of identified candidate variants. RESULTS: We have identified solute carrier family 26 member 9 (SLC26A9) as a modifier gene to be associated with RPCF Two rare missense SLC26A9 variants were discovered in three of six individuals deemed to have RPCF: c.229G > A; p.G77S (present in two patients), and c.1885C > T; p.P629S. Co-expression of SLC26A9 and CFTR mRNA is limited across different lung cell types, with the highest level of co-expression seen in human (6.3 %) and mouse (9.0 %) alveolar type 2 (AT2) cells. Structural modeling suggests deleterious effects of these mutations as they are in critical protein domains which might affect the anion transport capability of SLC26A9. CONCLUSION: The enrichment of rare and potentially deleterious SLC26A9 mutations in patients with RPCF suggests SLC26A9 may act as an alternative anion transporter in CF and is a modifier gene associated with this lung phenotype.

Metabolomics analysis of bronchoalveolar lavage fluid predicts unique features of the lower airway in pediatric cystic fibrosis.

BACKGROUND: Progressive, obstructive lung disease resulting from chronic infection and inflammation is the leading cause of morbidity and mortality in persons with cystic fibrosis (PWCF). Metabolomics and next -generation sequencing (NGS) of airway secretions can allow for better understanding of cystic fibrosis (CF) pathophysiology. In this study, global metabolomic profiling on bronchoalveolar lavage fluid (BALF) obtained from pediatric PWCF and disease controls (DCs) was performed and compared to lower airway microbiota, inflammation, and lung function. METHODS: BALF was collected from children undergoing flexible bronchoscopies for clinical indications. Metabolomic profiling was performed using a platform developed by Metabolon Inc. Total bacterial load (TBL) was measured using quantitative polymerase chain reaction (qPCR), and bacterial communities were characterized using 16S ribosomal RNA (rRNA) sequencing. Random Forest Analysis (RFA), principal component analysis (PCA), and hierarchical clustering analysis (HCA) were performed. RESULTS: One hundred ninety-five BALF samples were analyzed, 142 (73 %) from PWCF. Most metabolites (425/665) and summed categories (7/9) were significantly increased in PWCF. PCA of the metabolomic data revealed CF BALF exhibited more dispersed clustering compared to DC BALF. Higher metabolite concentrations correlated with increased inflammation, increased abundance of Staphylococcus, and decreased lung function. CONCLUSIONS: The lower airway metabolome of PWCF was defined by a complex expansion of metabolomic activity. These findings could be attributed to heightened inflammation in PWCF and aspects of the CF airway polymicrobial ecology. CF-specific metabolomic features are associated with the unique underlying biology of the CF airway.

Short Cilia, Immunodeficiency, and Cystic Fibrosis in a Mother-Daughter Pair.

Patients with chronic rhinosinusitis (CRS) that is refractory to maximal medical and surgical therapy should be evaluated for other primary conditions. Cystic fibrosis (CF), primary immunodeficiency (PID), and primary ciliary dyskinesia (PCD) are potential risk factors for refractory CRS. These conditions present with variable disease severity and diagnosis may be delayed into adulthood. We report a case of a mother-daughter pair with CRS refractory to maximal medical management. The patients were further evaluated and found to have features consistent with CF, PID, and PCD. All 3 are rare disorders and thought to cause CRS in isolation. Patients with refractory CRS should be further evaluated to identify alternative diagnoses and ensure proper management. Refractory CRS may be multifactorial, with different risk factors simultaneously contributing to its persistence.

A Case Report of the First Filipino Infant Diagnosed with Cystic Fibrosis through the Philippine Newborn Screening Program.

Cystic Fibrosis (CF) is a rare condition among Asians and has not been reported in the Philippines as of this time. The inclusion of this disease in the Philippines' Expanded Newborn Screening Program (ENBS) has provided this Filipino family the opportunity of early detection and appropriate management of this condition that could ensure the survival of the proband and his other surviving siblings. Here we present a case of a 24-month-old male who had a positive Expanded Newborn Screening (ENBS) test for cystic fibrosis and eventually underwent further tests to confirm a homozygous deletion of exons 1 - 2 of the CFTR gene. He subsequently had recurrent pneumonia but is being managed by a team consisting of a pulmonologist, gastroenterologist, and a metabolic dietitian. The proband had an older sibling whose Newborn Screening (NBS) test was normal and who eventually expired from recurrent bouts of pneumonia. This sibling was never managed as a case of cystic fibrosis. Implications on the diagnosis and management of CF in the local setting is also discussed. The importance of an appropriate CF panel customized to the local population should be reiterated and carrier testing should be encouraged to help with proper family counseling for future pregnancies for the family involved.

Beyond antibiotics: Emerging antivirulence strategies to combat Pseudomonas aeruginosa in cystic fibrosis.

Pseudomonas aeruginosa is an opportunistic pathogen that poses a significant threat to individuals suffering from cystic fibrosis (CF). The pathogen is highly prevalent in CF individuals and is responsible for chronic infection, resulting in severe tissue damage and poor patient outcome. Prolonged antibiotic administration has led to the emergence of multidrug resistance in P. aeruginosa. In this direction, antivirulence strategies achieving targeted inhibition of bacterial virulence pathways, including quorum sensing, efflux pumps, lectins, and iron chelators, have been explored against CF isolates of P. aeruginosa. Hence, this review article presents a bird's eye view on the pulmonary infections involving P. aeruginosa in CF patients by laying emphasis on factors contributing to bacterial colonization, persistence, and disease progression along with the current line of therapeutics against P. aeruginosa in CF. We further collate scientific literature and discusses various antivirulence strategies that have been tested against P. aeruginosa isolates from CF patients.

ETD001: A novel inhaled ENaC blocker with an extended duration of action in vivo.

BACKGROUND: Inhibiting ENaC in the airways of people with cystic fibrosis (pwCF) is hypothesized to enhance mucociliary clearance (MCC) and provide clinical benefit. Historically, inhaled ENaC blockers have failed to show benefit in pwCF challenging this hypothesis. It is however unknown whether the clinical doses were sufficient to provide the required long duration of action in the lungs and questions whether a novel candidate could offer advantages where others have failed? METHODS: Dose-responses with the failed ENaC blockers (VX-371, BI 1265162, AZD5634, QBW276) together with ETD001 (a novel long acting inhaled ENaC blocker) were established in a sheep model of MCC and were used to predict clinically relevant doses that would provide a long-lasting enhancement of MCC in pwCF. In each case, dose predictions were compared with the selected clinical dose. RESULTS: Each of the failed candidates enhanced MCC in the sheep model. Translating these dose-response data to human equivalent doses, predicted that substantially larger doses of each candidate, than were evaluated in clinical studies, would likely have been required to achieve a prolonged enhancement of MCC in pwCF. In contrast, ETD001 displayed a long duration of action (≥16 h) at a dose level that was well tolerated in Phase 1 clinical studies. CONCLUSIONS: These data support that the ENaC blocker hypothesis is yet to be appropriately tested in pwCF. ETD001 has a profile that enables dosing at a level sufficient to provide a long duration of action in a Phase 2 clinical study in pwCF scheduled for 2024.

Symptom phenotyping in people with cystic fibrosis during acute pulmonary exacerbations using machine-learning K-means clustering analysis.

INTRODUCTION: People with cystic fibrosis (PwCF) experience frequent symptoms associated with chronic lung disease. A complication of CF is a pulmonary exacerbation (PEx), which is often preceded by an increase in symptoms and a decline in lung function. A symptom cluster is when two or more symptoms co-occur and are related; symptom clusters have contributed meaningful knowledge in other diseases. The purpose of this study is to discover symptom clustering patterns in PwCF during a PEx to illuminate symptom phenotypes and assess differences in recovery from PExs. METHODS: This study was a secondary, longitudinal analysis (N = 72). Participants at least 10 years of age and being treated with intravenous antibiotics for a CF PEx were enrolled in the United States. Symptoms were collected on treatment days 1-21 using the CF Respiratory Symptom Diary (CFRSD)-Chronic Respiratory Symptom Score (CRISS). K-means clustering was computed on day 1 symptom data to detect clustering patterns. Linear regression and multi-level growth models were performed. RESULTS: Symptoms significantly clustered based on severity: low symptom (LS)-phenotype (n = 42), high symptom (HS)-phenotype (n = 30). HS-phenotype had worse symptoms and CRISS scores (p< 0.01) than LS-phenotype. HS-phenotype was associated with spending 5 more nights in the hospital annually (p< 0.01) than LS-phenotype. HS-phenotype had worse symptoms over 21 days than LS-phenotype (p< 0.0001). CONCLUSION: Symptoms significantly cluster on day 1 of a CF-PEx. PwCF with HS-phenotype spend more nights in the hospital and are less likely to experience the same resolution in symptoms by the end of PEx treatment than LS-phenotype.

Development and preliminary validation of the personalized cystic fibrosis medication questionnaire (PCF-MQ).

BACKGROUND: A personalized approach to assessing medication knowledge may identify opportunities for education to support self-management of cystic fibrosis (CF). This project describes the development, scoring, and preliminary validity of the Personalized CF Medication Questionnaire (PCF-MQ), designed to assess knowledge of prescribed CF medication purpose, administration, and dose and frequency. METHODS: Participants completed the PCF-MQ, the Knowledge of Disease Management (KDM-CF), and the Cystic Fibrosis-Medication Beliefs Questionnaire (CF-MBQ). Prescribed regimens were abstracted from medical records. Eligibility criteria were age 12 years and older, diagnosed with CF, and prescribed a CF medication. Statistical analyses were conducted using R software. Spearman rho was used to test correlations between measures. RESULTS: Sixty people with CF (pwCF) were enrolled; three people reported a regimen that substantially deviated from the medical record and were excluded from the analyses. The mean (SD) age was 20.2 (7.3) years, 54 % were female, and 74 % had a FEV1pp ≥70 %. The mean (SD) PCF-MQ total score was 77.8 (12.3) and knowledge scores ranged from a low of 58.3 for levalbuterol to 100 for ivacaftor. The PCF-MQ total score correlated with the KDM total score and subscales (Spearman Rho= 0.32-0.59, p < 0.05) and was not correlated with the CF-MBQ subscales (p > 0.05)). CONCLUSIONS: The PCF-MQ was correlated with another measure of general CF knowledge, but not health beliefs; because of the small sample size, this should be considered preliminary evidence of its validity. Advantages over existing CF knowledge measures include its practicality for use to help assess pwCF's knowledge about their prescribed regimen.

Pharmacologic contraception methods for people with cystic fibrosis: A practical review for clinicians.

Over the last several decades, substantial treatment advances have improved the quality of life and median predicted survival in people with cystic fibrosis (PwCF). It is critical for CF clinicians to begin to discuss health considerations related to an aging and overall healthier CF population. Such considerations include family planning, reproductive health, and contraception. CF care teams are trusted sources of medical information and therefore often have initial discussions related to contraception for PwCF. The purpose of this article is to review the available pharmacologic contraceptive methods, with a specific focus on the benefits and risks that may be more relevant to PwCF.

Investigations, management and outcome of neonates presenting with distal intestinal obstruction: challenging the need for contrast enemas.

PURPOSE: To characterise the investigations, management and ultimate diagnosis of neonates with distal intestinal obstruction. METHODS: Retrospective review of term (> 37 weeks) neonates with admission diagnosis of distal intestinal obstruction over 10 years (2012-2022). Patient pathways were identified and associations between presentations, response to treatments and outcome investigated. RESULTS: A total of 124 neonates were identified and all included. Initial management was colonic irrigation in 108, contrast enema in 4, and laparotomy in 12. Of those responding to irrigations none underwent contrast enema. Ultimately, 22 neonates proceeded to laparotomy. Overall, 106 had a suction rectal biopsy and 41 had genetic testing for cystic fibrosis. Final diagnosis was Hirschsprung disease (HD) in 67, meconium ileus with cystic fibrosis (CF) in 9, meconium plug syndrome in 19 (including 3 with CF), intestinal atresia in 10 and no formal diagnosis in 17. Median length of neonatal unit stay was 11 days (7-19). CONCLUSIONS: Initial management of neonates with distal bowel obstruction should be colonic irrigation since this is therapeutic in the majority and significantly reduces the need for contrast enema. These infants should all have suction rectal biopsy to investigate for HD unless another diagnosis is evident. If a meconium plug is passed, testing for CF is recommended. Evaluation and therapy are multimodal and time consuming, placing burden on resources and families.