J Cyst Fibros. 2024 Jun 27:S1569-1993(24)00781-1. doi: 10.1016/j.jcf.2024.06.012. Online ahead of print.

ABSTRACT

BACKGROUND: Data on the impact of liver transplantation (LT) in cystic fibrosis (CF) on lung function and exacerbations are limited. The objective of this study was to summarize the literature on lung function, nutritional status, survival, and complications following LT in people with CF.

METHODS: Three databases were searched until September 2023, to identify the impact of LT in CF. Lung transplant prior to LT and simultaneous liver-lung transplant were excluded. Pooled hazard ratios were calculated using random-effects models.

RESULTS: Thirty studies were included in this review, with 3 and 9 studies included in meta-analyses for nutritional status and lung function, respectively. Eighty-three percent of the studies used data that was more than a decade old. There was a significant increase in percent-predicted forced expiratory volume with mean change of 7.16 % (2.13, 12.19; p = 0.005) one year post-LT. Pulmonary exacerbations decreased in the short-term, however there was no significant change in body mass index (BMI). One-year survival post-LT ranged between 75 and 100 %, while five-year survival was lower at 64-89 %.

CONCLUSION: Existing data suggest that LT improves lung function in the short term and does not increase the likelihood of pulmonary exacerbations, despite ongoing immunosuppression in the setting of chronic lung infection.

PMID:38942722 | DOI:10.1016/j.jcf.2024.06.012

J Cyst Fibros. 2024 Jun 27:S1569-1993(24)00778-1. doi: 10.1016/j.jcf.2024.06.008. Online ahead of print.

ABSTRACT

AIMS: To study the prevalence of cystic fibrosis related liver disease (CFLD) as defined by ultrasound (US) and describe difference in clinical and radiological features in those with CFLD and those without CFLD (nCFLD); with and without portal hypertension (PHT and nPHT).

METHODS: Children with CF (CwCF) from our clinic who had regular screening liver US from 3 years of age were included. Liver parenchyma findings were classified into normal, homogeneous, heterogeneous and nodular. For our study, we defined PHT as US evidence of splenomegaly and/or ascites, abnormal portal flow, varices, ligamentum teres recanalization if present. Demographic, clinical, nutritional and lung function between the two groups-CFLD/nCFLD; and subgroups- PHT and nPHT were compared. Gamma glutamyl transferase (GGT)/ platelet ratio (GPR) as a marker of fibrosis was measured.

RESULTS: From 227 CwCF,40 (17 %) were excluded (below the age of 3 years or alternative cause of liver disease). Of the remaining 187, 107 (57 %) had a normal US, 80 (43 %) had CFLD; 25 (13.4 %) had PHT. There was no significant difference in demographics, BMI-z score, lung function, presence of gastrostomy or pancreatic insufficiency in CFLD vs nCFLD and PHT vs nPHT. CF related diabetes mellitus (CFRD) was significantly associated with CFLD vs nCFLD (P = 0.0086). GGT was higher and platelet count was lower in PHT vs nPHT (P = 0.0256 and P = 0.0001). Nodularity was strongly associated with an elevated GPR (P = 0.016). There was a strong association between nodularity on US and PHT (P = 0.0006).

CONCLUSION: Nodularity is a clear marker for advanced liver disease with higher scores for a non-invasive marker for fibrosis. There was no difference in nutrition and FEV1 between advanced liver disease and absent/ milder liver disease.

PMID:38942721 | DOI:10.1016/j.jcf.2024.06.008

J Cyst Fibros. 2024 Jun 27:S1569-1993(24)00780-X. doi: 10.1016/j.jcf.2024.06.011. Online ahead of print.

ABSTRACT

BACKGROUND: Most males with cystic fibrosis (MwCF) have congenital bilateral absence of the vas deferens and require assisted reproductive technology to conceive, yet many have limited knowledge about how CF affects sexual and reproductive health (SRH). This study evaluates the feasibility, acceptability, and potential effectiveness of telehealth fertility preservation (FP) counseling for MwCF.

METHODS: Pre-lung transplant MwCF ≥18 years, recruited from U.S. CF centers, social media, and via snowball sampling, received individualized telehealth counseling. Participants completed intervention feasibility/acceptability one week post-counseling and FP knowledge, care satisfaction, and self-efficacy assessments at baseline and two months post-counseling. We completed acceptability interviews one-week post-counseling and audio-recorded, transcribed, and thematically analyzed results. We descriptively analyzed survey results and conducted pre/post comparisons using paired t-tests.

RESULTS: Thirty MwCF (ages 22-49 years) completed counseling. Most were in a relationship (70 %) and White (86.7 %). Telehealth FP counseling was acceptable (M = 4.38/5 ± 0.60), appropriate (M = 4.37/5 ± 0.60), and feasible (M = 4.60/5 ± 0.45) to MwCF. FP knowledge (9.53 vs. 10.40/12; p = .010), care satisfaction (20.23 vs 26.67/32; p<.001), and self-efficacy (22.87 vs 25.20/30; p = .016) improved at two months post-counseling. Despite desiring provider-initiated SRH, wanting children (81 %), and perceiving the CF team as their primary care provider (97 %), 44 % report not receiving information about infertility by the CF team.

CONCLUSIONS: Integrating FP counseling into CF care is feasible and acceptable to MwCF and can improve FP knowledge, self-efficacy, and care satisfaction. MwCF desire early and regular provider-initiated SRH education.

PMID:38942720 | DOI:10.1016/j.jcf.2024.06.011

J Bacteriol. 2024 Jun 28:e0017624. doi: 10.1128/jb.00176-24. Online ahead of print.

ABSTRACT

The cystic fibrosis (CF) lung environment is conducive to the colonization of bacteria as polymicrobial biofilms, which are associated with poor clinical outcomes for persons with CF (pwCF). Streptococcus spp. are highly prevalent in the CF airway, but its role in the CF lung microbiome is poorly understood. Some studies have shown Streptococcus spp. to be associated with better clinical outcomes for pwCF, while others show that high abundance of Streptococcus spp. is correlated with exacerbations. Our lab previously reported a polymicrobial culture system consisting of four CF-relevant pathogens that can be used to study microbial behavior in a more clinically relevant setting. Here, we use this model system to identify genetic pathways that are important for Streptococcus sanguinis survival in the context of the polymicrobial community. We identified genes related to reactive oxygen species as differentially expressed in S. sanguinis monoculture versus growth of this microbe in the mixed community. Genetic studies identified Dpr as important for S. sanguinis survival in the community. We show that Dpr, a DNA-binding ferritin-like protein, and PerR, a peroxide-responsive transcriptional regulator of Dpr, are important for protecting S. sanguinis from phenazine-mediated toxicity in co-culture with Pseudomonas aeruginosa and when exposed to hydrogen peroxide, both of which mimic the CF lung environment. Characterizing such interactions in a clinically relevant model system contributes to our understanding of microbial behavior in the context of polymicrobial biofilm infections.

IMPORTANCE: Streptococcus spp. are recognized as a highly prevalent pathogen in cystic fibrosis (CF) airway infections. However, the role of this microbe in clinical outcomes for persons with CF is poorly understood. Here, we leverage a polymicrobial community system previously developed by our group to model CF airway infections as a tool to investigate a Pseudomonas-Streptococcus interaction involving reactive oxygen species (ROS). We show that protection against ROS is required for Streptococcus sanguinis survival in a clinically relevant polymicrobial system. Using this model system to study interspecies interactions contributes to our broader understanding of the complex role of Streptococcus spp. in the CF lung.

PMID:38940597 | DOI:10.1128/jb.00176-24

Pediatr Pulmonol. 2024 Jun 28. doi: 10.1002/ppul.27155. Online ahead of print.

ABSTRACT

BACKGROUND: Newborn screening (NBS) for cystic fibrosis (CF) is universal in the United States. Protocols vary but include an immunoreactive trypsinogen (IRT) level and CFTR variant panel. California CF NBS has a 3-step screening: IRT level, variant panel, and CFTR sequencing if only one variant identified on panel.

METHODS: This was a cohort study of infants with CF born in California (2007-2021) to examine racial and ethnic differences in having a false-negative NBS result for CF and at which step the false-negative occurred. We examined how different CFTR variant panels would improve detection of variants by race and ethnicity: original 39-variant panel, current 75-variant panel, and all 402 disease-causing CFTR variants in the CFTR2 database.

RESULTS: Of the 912 infants born in California with CF, 84 had a false-negative result: 38 due to low IRT level and 46 with a high IRT value (but incomplete variant detection). Asian (OR 6.3) and Black infants (OR 2.5) were more likely to have a false-negative screening result than non-Hispanic white infants. The majority of false-negative screening (but CF diagnosis) cases among American Indian/Native Alaskan and non-Hispanic White infants were due to low IRT levels. The majority of Asian and Hispanic infants with false-negative screening had no variants detected. Detection of two CFTR variants was improved with the 75-variant panel in Black, Hispanic, and non-Hispanic White infants and with the 402-variant panel in Black, Hispanic, non-Hispanic White, and other race infants.

CONCLUSIONS: Larger CFTR panels in NBS improved the detection of CF in all races and ethnicities.

PMID:38940324 | DOI:10.1002/ppul.27155

J Med Econ. 2024 Jun 28:1-16. doi: 10.1080/13696998.2024.2373000. Online ahead of print.

ABSTRACT

AimsWe aimed to describe the clinical, economic, and societal burdens of cystic fibrosis (CF) and impact of CF transmembrane conductance regulator modulator (CFTRm) treatment on people with CF, caregivers, and healthcare systems.Material and MethodsThis retrospective study used linked real-world data from Swedish national population-based registries and the Swedish CF Quality Registry to assess clinical, economic, and societal burden and CFTR impact in CF. Records from people with CF and a ten-fold control population without CF matched by sex, birth year, and location were compared during 2019. Outcomes for a subset aged >6 years initiating lumacaftor/ivacaftor (LUM/IVA) in 2018 were compared 12 months pre- and post-treatment initiation.ResultsPeople with CF (n = 743) had >10 times more inpatient and outpatient specialist visits annually vs controls (n = 7406). Those aged >18 had an additional 77·7 (95% CI: 70·3, 85·1) days of work absence, at a societal cost of €11,563 (95% CI: 10,463, 12,662), while caregivers of those aged <18 missed an additional 6.1 (5.0, 7.2) workdays. With LUM/IVA treatment, people with CF (n = 100) had significantly increased lung function (mean change in ppFEV1 [3·8 points; 95% CI: 1·1, 6·6]), on average 0·5 (95% CI: -0·8, -0·2) fewer pulmonary exacerbations and 45·2 (95% CI: 13·3, 77·2) fewer days of antibiotics. Days of work lost by caregivers of people with CF aged <18 decreased by 5·4 days (95% CI: 2·9, 7·9).ConclusionCF is associated with a high clinical economic and societal burden in Sweden. Improvements in clinical status observed in people with CF treated with LUM/IVA were reflected in reduced caregiver and societal burden.

PMID:38939921 | DOI:10.1080/13696998.2024.2373000

Thorax. 2024 Jun 27:thorax-2023-220558. doi: 10.1136/thorax-2023-220558. Online ahead of print.

ABSTRACT

BACKGROUND: Ivacaftor (IVA) has been shown to improve lung function and other clinical outcomes in people with cystic fibrosis (CF). A decade of real-world IVA availability has enabled the examination of long-term outcomes with this treatment. This retrospective, longitudinal cohort study investigated the impact of IVA on mortality rate and health outcomes among people with CF in the US.

METHODS: Data from the US CF Foundation Patient Registry from January 2010 to December 2019 were analysed. The IVA-treated cohort included people with a CF transmembrane conductance regulator (CFTR) gating mutation (excluding R117H); age-matched comparator cohort included people with a F508del and a minimal function CFTR mutation who had no prior CFTR modulator treatment. Baseline characteristics were balanced between cohorts using standardised mortality ratio weighting generated from propensity scores. Outcomes of interest were overall survival, lung transplant, percent predicted forced expiratory volume in 1 s (ppFEV1), body mass index (BMI), pulmonary exacerbations (PEx), outpatient visits and hospitalisations.

FINDINGS: Over a maximum follow-up of 7.9 years, the IVA-treated cohort (N=736) had lower rates of mortality (hazard ratio [HR] (95% CI): 0.22 (0.09 to 0.45)), lung transplant (HR: 0.11 (95% CI 0.02 to 0.28)), PEx (rate ratio: 0.49 (95% CI 0.42 to 0.55)) and all-cause hospitalisations (rate ratio: 0.50 (95% CI 0.43 to 0.56)) as well as better lung function (mean difference in ppFEV1: 8.46 (95% CI 7.34 to 9.75)) and higher BMI/BMI z-scores (mean difference 1.20 (95% CI 0.92 to 1.71) kg/m2 and 0.27 (95% CI 0.25 to 0.40), respectively) than the comparator cohort (N=733).

INTERPRETATION: Our analysis suggests that IVA provides sustained clinical benefits in people with CF over a follow-up period of approximately 8 years. These findings reinforce the existing real-world evidence that IVA can slow disease progression and decrease the healthcare burden of CF over the long term.

PMID:38937105 | DOI:10.1136/thorax-2023-220558

J Cyst Fibros. 2024 Jun 26:S1569-1993(24)00775-6. doi: 10.1016/j.jcf.2024.06.006. Online ahead of print.

ABSTRACT

BACKGROUND: With advancements in CF drug development, people with cystic fibrosis (PwCF) now take a median of seven medications daily, increasing treatment complexity, risk of drug therapy problems (DTPs), and interference with treatment goals. Given that some of these DTPs can be prevented with preemptive pharmacogenetic testing, the overall goal of this study was to test the clinical utility of a multi-gene pharmacogenetics (PGx) panel in potentially reducing DTPs in PwCF.

METHODS: A population based retrospective study of patients with CF was conducted at the University of Utah Health Care System. The patients were genotyped for CYP450 enzymes using a pharmacogenomic assay, and their drug utilization information was obtained retrospectively. This pharmacogenomic information was combined with clinical guidelines to predict the number of actionable PGx interventions in this patient cohort.

RESULTS: A total of 52 patients were included in this study. In the patient sample, a minimum of one order of actionable PGx medication was observed in 75 % of the cases. Results revealed that 4.2 treatment modifications per 10 patients can be enabled with the help of a PGx intervention in this patient population. Additionally, our findings suggest that polymorphisms in CYP2D6 and CYP2C19 are most likely to be the primary contributors to DTP's within PwCF.

CONCLUSION: This study provides evidence that the PGx panel has the potential to help alleviate the clinical burden of DTPs in PwCF and can assist in informing pharmacotherapy recommendations. Future research should validate these findings and evaluate which subgroups of PwCF would most benefit from pharmacogenetic testing.

PMID:38937211 | DOI:10.1016/j.jcf.2024.06.006

Farm Hosp. 2024 Jun 26:S1130-6343(24)00090-4. doi: 10.1016/j.farma.2024.05.010. Online ahead of print.

ABSTRACT

OBJECTIVE: Respiratory diseases present a challenge for the healthcare system due to their prevalence and clinical impact. The aim of this study was to explore the current situation of hospital pharmacy in the field of respiratory diseases.

METHOD: Observational, cross-sectional study, with a national scope, divided into 2 parts. In an initial phase, the activity and level of pharmaceutical care in respiratory diseases was evaluated through an online questionnaire using REDCap. The survey was addressed to department chiefs and consisted of 17 items, divided into 2 modules: general data and general activity. The second phase was open to hospital pharmacists, with the aim of exploring their opinion on care, training, and improvement needs. The number of items in this phase was 19, divided into 5 modules: general data, pharmaceutical care, competencies, training, and degree of satisfaction.

RESULTS: In the first phase, 23 hospitals were included. Most of them (n=20) had a pharmacist in charge of respiratory diseases. However, a large proportion of them dedicated less than 40% of their working day to this activity. The pharmacist's activity occurred at the level of external patients (n=21), hospitalised patients (n=16), and secondarily in management (n=8). Integration is greater in pathologies such as asthma, IPF, pulmonary hypertension, and bronchiectasis. Participation in committees was present in 15 hospitals, with variability in pathologies and degree of involvement. In the second phase, 164 pharmacists participated, who considered pharmaceutical care in cystic fibrosis, asthma, and lung transplant as a priority. 51% considered integration to be adequate and 91% considered it necessary to implement prioritisation criteria. Professional competencies ranged from 6.5 to 6.9 out of 10 points. Only 45% of participants had received specific training in the last 4 years, indicating greater priority for asthma, pulmonary hypertension, and IPF.

CONCLUSIONS: Most centers have pharmacists specialised in respiratory diseases. However, there is room for improvement in terms of subspecialisation, participation in multidisciplinary committees, implementation of prioritisation criteria, diversification in pathologies treated, as well as greater specific training in this area.

PMID:38937161 | DOI:10.1016/j.farma.2024.05.010

Ther Drug Monit. 2024 Jun 25. doi: 10.1097/FTD.0000000000001231. Online ahead of print.

ABSTRACT

BACKGROUND: The highly effective Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulator, elexacaftor-tezacaftor-ivacaftor, is now widely being used by people with cystic fibrosis. However, few independent studies have detailed the pharmacokinetics (PK) of CFTR modulators. Blood collection by venipuncture is the gold standard for PK measurements, but it is invasive. The aim of this study was to develop and clinically validate a quantification method for elexacaftor, tezacaftor, ivacaftor, and their main metabolites in dried blood spots (DBSs) using liquid chromatography with tandem mass spectrometry.

METHODS: Linearity, accuracy, precision, stability, hematocrit (Hct), spot-to-spot carryover, spot volume, and extraction efficiency were validated in DBS for all analytes. The clinical validation of elexacaftor-tezacaftor-ivacaftor in patients was performed by comparing 21 DBS samples with matched plasma samples.

RESULTS: The preset requirements for linearity, within-run and between-run accuracy, precision, Hct, spot volume, and extraction efficiency were met. Puncher carryover was observed and resolved by punching 3 blanks after each sample. The samples remained stable and showed no notable degradation across the tested temperatures and time intervals. Corrected DBS values with the Passing-Bablok regression equation showed good agreement in Bland-Altman plots, and acceptance values were within 20% of the mean for a minimum of 67% of the repeats, according to the EMA guidelines.

CONCLUSIONS: A quantification method for the analysis of elexacaftor, tezacaftor, ivacaftor, and their main metabolites was developed and clinically validated in DBS. This method could be valuable in both clinical care and research to address unanswered PK questions regarding CFTR modulators.

PMID:38935410 | DOI:10.1097/FTD.0000000000001231

Pediatr Pulmonol. 2024 Jun 27. doi: 10.1002/ppul.27143. Online ahead of print.

ABSTRACT

BACKGROUND: A primary palliative care model for cystic fibrosis (CF) recommends using the Integrated Palliative Care Outcome Scale (IPOS) for screening. Validation of the IPOS is needed.

METHODS: This secondary analysis utilized baseline data from a multisite trial of the palliative care model, Improving Life with CF. Adults with CF completed the IPOS, the Memorial Symptom Assessment Scale-CF (MSAS-CF), the CF Questionnaire-Revised (CFQ-R), the Patient Health Questionnaire (PHQ-8), the Generalized Anxiety Disorder (GAD-7), and the Perceived Stress Scale (PSS). IPOS structure was assessed using Cronbach α coefficients and a factor analysis. Construct validity was evaluated through bivariate relationships between IPOS scores and other questionnaire scores, and linear regressions assessing the extent to which the IPOS explains variance in quality-of-life domains.

RESULTS: The sample comprised 256 adults with complete IPOS data. α coefficients were .86 for the IPOS total score, .81 for the Physical Symptoms subscale, .79 for the Emotional Symptoms subscale, and .63 for the Communication/Practical Issues subscale. A two-component factor structure best aligned with the current subscales. IPOS scores were significantly associated with other measures; associations with MSAS-CF and CFQ-R subscales differentiated the IPOS Physical and Emotional subscales. The IPOS total score provided unique information about the variance in the CFQ-R Physical Functioning and Respiratory Symptoms domain scores.

CONCLUSIONS: In adults with CF, the IPOS has acceptable internal consistency and there is evidence of construct validity. These findings support adoption of the IPOS in the primary palliative care model for CF.

PMID:38934771 | DOI:10.1002/ppul.27143

mSystems. 2024 Jun 27:e0092923. doi: 10.1128/msystems.00929-23. Online ahead of print.

ABSTRACT

Airway microbiota are known to contribute to lung diseases, such as cystic fibrosis (CF), but their contributions to pathogenesis are still unclear. To improve our understanding of host-microbe interactions, we have developed an integrated analytical and bioinformatic mass spectrometry (MS)-based metaproteomics workflow to analyze clinical bronchoalveolar lavage (BAL) samples from people with airway disease. Proteins from BAL cellular pellets were processed and pooled together in groups categorized by disease status (CF vs. non-CF) and bacterial diversity, based on previously performed small subunit rRNA sequencing data. Proteins from each pooled sample group were digested and subjected to liquid chromatography tandem mass spectrometry (MS/MS). MS/MS spectra were matched to human and bacterial peptide sequences leveraging a bioinformatic workflow using a metagenomics-guided protein sequence database and rigorous evaluation. Label-free quantification revealed differentially abundant human peptides from proteins with known roles in CF, like neutrophil elastase and collagenase, and proteins with lesser-known roles in CF, including apolipoproteins. Differentially abundant bacterial peptides were identified from known CF pathogens (e.g., Pseudomonas), as well as other taxa with potentially novel roles in CF. We used this host-microbe peptide panel for targeted parallel-reaction monitoring validation, demonstrating for the first time an MS-based assay effective for quantifying host-microbe protein dynamics within BAL cells from individual CF patients. Our integrated bioinformatic and analytical workflow combining discovery, verification, and validation should prove useful for diverse studies to characterize microbial contributors in airway diseases. Furthermore, we describe a promising preliminary panel of differentially abundant microbe and host peptide sequences for further study as potential markers of host-microbe relationships in CF disease pathogenesis.IMPORTANCEIdentifying microbial pathogenic contributors and dysregulated human responses in airway disease, such as CF, is critical to understanding disease progression and developing more effective treatments. To this end, characterizing the proteins expressed from bacterial microbes and human host cells during disease progression can provide valuable new insights. We describe here a new method to confidently detect and monitor abundance changes of both microbe and host proteins from challenging BAL samples commonly collected from CF patients. Our method uses both state-of-the art mass spectrometry-based instrumentation to detect proteins present in these samples and customized bioinformatic software tools to analyze the data and characterize detected proteins and their association with CF. We demonstrate the use of this method to characterize microbe and host proteins from individual BAL samples, paving the way for a new approach to understand molecular contributors to CF and other diseases of the airway.

PMID:38934598 | DOI:10.1128/msystems.00929-23

Heliyon. 2024 Jun 4;10(11):e32424. doi: 10.1016/j.heliyon.2024.e32424. eCollection 2024 Jun 15.

ABSTRACT

Current in vitro biofilm modelling of the opportunistic pathogen, Pseudomonas aeruginosa (PA) in people with cystic fibrosis (PwCF) is limited in its ability to mimic the complexities of the cystic fibrosis (CF) lung environment. Recent adaptations of the Microbial Identification after Passive CLARITY Technique (MiPACT) in CF research have allowed for the direct imaging of PA biofilm spatial organization and structure in expectorated sputum. Here, we performed a comparative analysis of in vitro and within patient (ex vivo) measures of PA biofilms using sputa from new onset infected children with CF. MiPACT-fluorescent in situ hybridization (FISH) and fluorescent anti-Psl monoclonal antibody (mAb) staining was performed to directly visualize PA and Psl (exopolysaccharide in PA biofilm matrix) in 11 CF sputum specimens. Corresponding PA isolates, recovered from the same sputum samples, were grown as biofilms in a glass slide chamber model, then visualized by fluorescent live-cell and anti-Psl mAb staining. We observed that PA biovolume, aggregation and Psl antibody binding (normalized per PA biovolume) in CF sputum did not correlate with the in vitro model, although a trend towards significance in the biovolume relationship was observed with the addition of sputum supernatant to the in vitro model.

PMID:38933957 | PMC:PMC11200346 | DOI:10.1016/j.heliyon.2024.e32424

Front Pharmacol. 2024 Jun 12;15:1392986. doi: 10.3389/fphar.2024.1392986. eCollection 2024.

ABSTRACT

Background: Cystic fibrosis transmembrane conductance regulator modulators are the only available treatment for cystic fibrosis. Although elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is well-tolerated, rash has been reported as very frequent. In severe rashes, ELX/TEZ/IVA withdrawal is necessary, leading to clinical deterioration. The objective of the study is to increment the experience of ELX/TEZ/IVA desensitization. Methods: Adult patients who developed a delayed hypersensitivity rash to ELX/TEZ/IVA between December 2021 and February 2023 and required withdrawal due to ineffective rescue medication were included. Skins test for ELX/TEZ/IVA and IVA were conducted to establish hypersensitivity mechanism. Balijepally ELX/TEZ/IVA desensitization protocol was selected. In cases where desensitization had to be discontinued due to rash, an extended desensitization was proposed. Clinical and health-related quality of life parameters were collected before ELX/TEZ/IVA and after desensitization. Results: 162 patients (81 women, 31.2 [23.8-42.5] years) started ELX/TEZ/IVA, developing rash 12 of them (7.4%, six women). Six patients (five women) required stopping ELX/TEZ/IVA and were selected for desensitization. Skin tests indicated delayed type-IV hypersensitivity in one patient. Two patients presented adequate tolerance to desensitization; while, four patients developed rash. Three of these patients, successfully concluded extended desensitization (one patient declined participation). No significant clinical deterioration or quality of life worsening was observed during desensitization; in fact, there was an improvement in practically all mesured parameters. All five patients who resumed ELX/TEZ/IVA are currently receiving therapy with good tolerance. Conclusion: Desensitization to ELX/TEZ/IVA could be a successful and safe strategy for reintroducing this essential treatment in cases of a delayed hypersensitivity rash.

PMID:38933680 | PMC:PMC11203995 | DOI:10.3389/fphar.2024.1392986

Polymers (Basel). 2024 Jun 12;16(12):1663. doi: 10.3390/polym16121663.

ABSTRACT

MUC2 mucin, the primary gel-forming component of intestinal mucus, is well researched and a model of polymerisation and post-secretory organisation has been published previously. Recently, several significant developments have been made which either introduce new ideas or challenge previous theories. New ideas include an overhaul of the MUC2 C-terminal globular structure which is proposed to harbour several previously unobserved domains, and include a site for an extra intermolecular disulphide bridge dimer between the cysteine 4379 of adjacent MUC2 C-termini. MUC2 polymers are also now thought to be secreted attached to the epithelial surface of goblet cells in the small intestine and removed following secretion via a metalloprotease meprin β-mediated cleavage of the von Willebrand D2 domain of the N-terminus. It remains unclear whether MUC2 forms intermolecular dimers, trimers, or both, at the N-termini during polymerisation, with several articles supporting either trimer or dimer formation. The presence of a firm inner mucus layer in the small intestine is similarly unclear. Considering this recent research, this review proposes an update to the previous model of MUC2 polymerisation and secretion, considers conflicting theories and data, and highlights the importance of this research to the understanding of MUC2 mucus layers in health and disease.

PMID:38932019 | DOI:10.3390/polym16121663

Nutrients. 2024 Jun 8;16(12):1811. doi: 10.3390/nu16121811.

ABSTRACT

Background: Modulator therapies improve weight and body mass index (BMI) in cystic fibrosis (CF) patients. We aimed to compare the nutritional risk index (NRI) in adult CF patients receiving modulator (MT) or only non-modulator (conventional) therapies (non-MT). Methods: A single-center prospective cohort study was conducted between June and December 2023. The NRI based on weight gain and albumin was calculated at beginning and end of a 12-week period in both groups. This design was pragmatic, since it was based on individual patient access to MT for 12 weeks. Results: In total, 107 patients were included [mean (SD) age: 23.85 (4.98) years, 54.7% male, 46.7% MT]. In the MT group, mean (SD) weight (kg) and albumin (g/dL) increased significantly [changes: +3.09 (2.74) and +0.17 (0.37); p < 0.001]. In the non-MT group, weight and albumin decreased significantly [changes: -0.99 (1.73) and -0.12 (0.30); p < 0.001]. Compared to the MT group, baseline mean (SD) NRI in the non-MT group was significantly higher [100.65 (11.80) vs. 104.10 (10.10); p = 0.044]. At the end of the 12 weeks, mean (SD) NRI in the MT group was higher than in the non-MT group [104.18 (10.40) vs. 102.58 (12.39); p = 0.145]. In the MT group, the NRI category improved in 22 (44%), and worsened in 3 (6%) patients (p < 0.001). In the non-MT group, the NRI category improved in 2 (3.5%), and worsened in 10 (17.5%) patients (p < 0.001). Conclusions: This is the first study reporting on a positive effect of MT on NRIs, based on weight gain and albumin. Personalized nutrition and routine follow-up of adults with CF based on NRI is recommended prior to MT initiation.

PMID:38931166 | DOI:10.3390/nu16121811

J Clin Med. 2024 Jun 7;13(12):3372. doi: 10.3390/jcm13123372.

ABSTRACT

Background: Disorders of mucociliary clearance, such as cystic fibrosis (CF), primary ciliary dyskinesia (PCD) and bronchiectasis of unknown origin, are characterised by periods with increased respiratory symptoms, referred to as pulmonary exacerbations. These exacerbations are hard to predict and associated with lung function decline and the loss of quality of life. To optimise treatment and preserve lung function, there is a need for non-invasive and reliable methods of detection. Breath analysis might be such a method. Methods: We systematically reviewed the existing literature on breath analysis to detect pulmonary exacerbations in mucociliary clearance disorders. Extracted data included the study design, technique of measurement, definition of an exacerbation, identified compounds and diagnostic accuracy. Results: Out of 244 identified articles, 18 were included in the review. All studies included patients with CF and two also with PCD. Age and the definition of exacerbation differed between the studies. There were five that measured volatile organic compounds (VOCs) in exhaled breath using gas chromatography with mass spectrometry, two using an electronic nose and eleven measured organic compounds in exhaled breath condensate. Most studies showed a significant correlation between pulmonary exacerbations and one or multiple compounds, mainly hydrocarbons and cytokines, but the validation of these results in other studies was lacking. Conclusions: The detection of pulmonary exacerbations by the analysis of compounds in exhaled breath seems possible but is not near clinical application due to major differences in results, study design and the definition of an exacerbation. There is a need for larger studies, with a longitudinal design, international accepted definition of an exacerbation and validation of the results in independent cohorts.

PMID:38929901 | DOI:10.3390/jcm13123372

J Pers Med. 2024 Jun 14;14(6):636. doi: 10.3390/jpm14060636.

ABSTRACT

The ATP-binding cassette (ABC) transporters are a vast group of 48 membrane proteins, some of which are of notable physiological and clinical importance. Some ABC transporters are involved in functions such as the transport of chloride ions, bilirubin, reproductive hormones, cholesterol, and iron. Consequently, genetic or physiological disruption in these functions is manifested in various disease processes like cystic fibrosis, Tangier disease, and sideroblastic anemia. Among other etiologies, primary sideroblastic anemia results from a genetic mutation in the ATP-binding cassette-7 (ABCB7), a member of the ABC transporter family. There are not many articles specifically tackling the disease processes caused by ABC transporters in detail. Some testing methodologies previously reported in the available literature for investigating sideroblastic anemia need updating. Here, we expound on the relevance of ABCB7 as a clinically important ABC transporter and a rare participant in the disease process of Sideroblastic anemia. The other genetic and secondary etiologies of sideroblastic anemia, which do not involve mutations in the ABCB7 protein, are also described. We review the pathophysiology, clinical course, symptoms, diagnosis, and treatment of sideroblastic anemia with a focus on modern technologies for laboratory testing.

PMID:38929857 | DOI:10.3390/jpm14060636

Int J Mol Sci. 2024 Jun 18;25(12):6692. doi: 10.3390/ijms25126692.

ABSTRACT

Cystic fibrosis (CF), also known as mucoviscidosis, is the most common autosomal recessive genetic disease in the Caucasian population, with an estimated frequency of 1:2000-3000 live births. CF results from the mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene localized in the long arm of chromosome 7. The product of CFTR gene expression is CFTR protein, an adenosine triphosphate (ATP)-binding cassette (ABC) transporter that regulates the transport of chloride ions (Cl-) across the apical cell membrane. Primary manifestations of CF include chronic lung and pancreas function impairment secondary to the production of thick, sticky mucus resulting from dehydrated secretions. It is well known that CF can cause both anterior and posterior ocular abnormalities. Conjunctival and corneal xerosis and dry eye disease symptoms are the most characteristic manifestations in the anterior segment. In contrast, the most typical anatomical and functional changes relating to the posterior segment of the eye include defects in the retinal nerve fiber layer (RNFL), vascular abnormalities, and visual disturbances, such as reduced contrast sensitivity and abnormal dark adaptation. However, the complete background of ophthalmic manifestations in the course of CF has yet to be discovered. This review summarizes the current knowledge regarding ocular changes in cystic fibrosis.

PMID:38928397 | DOI:10.3390/ijms25126692

Int J Mol Sci. 2024 Jun 8;25(12):6367. doi: 10.3390/ijms25126367.

ABSTRACT

The Cystic Fibrosis Conductance Transmembrane Regulator gene encodes for the CFTR ion channel, which is responsible for the transport of chloride and bicarbonate across the plasma membrane. Mutations in the gene result in impaired ion transport, subsequently leading to perturbed secretion in all exocrine glands and, therefore, the multi-organ disease cystic fibrosis (CF). In recent years, several studies have reported on CFTR expression in immune cells as demonstrated by immunofluorescence, flow cytometry, and immunoblotting. However, these data are mainly restricted to single-cell populations and show significant variation depending on the methodology used. Here, we investigated CFTR transcription and protein expression using standardized protocols in a comprehensive panel of immune cells. Methods: We applied a high-resolution Western blot protocol using a combination of highly specific monoclonal CFTR antibodies that have been optimized for the detection of CFTR in epithelial cells and healthy primary immune cell subpopulations sorted by flow cytometry and used immortalized cell lines as controls. The specificity of CFTR protein detection was controlled by peptide competition and enzymatic Peptide-N-Glycosidase-F (PNGase) digest. CFTR transcripts were analyzed using quantitative real-time PCR and normalized to the level of epithelial T84 cells as a reference. Results: CFTR mRNA expression could be shown for primary CD4+ T cells, NK cells, as well as differentiated THP-1 and Jurkat T cells. In contrast, we failed to detect CFTR transcripts for CD14+ monocytes and undifferentiated THP-1 cells, as well as for B cells and CD8+ T cells. Prominent immunoreactive bands were detectable by immunoblotting with the combination of four CFTR antibodies targeting different epitopes of the CFTR protein. However, in biosamples of non-epithelial origin, these CFTR-like protein bands could be unmasked as false positives through peptide competition or PNGase digest, meaning that the observed mRNA transcripts were not necessarily translated into CFTR proteins, which could be detected via immunoblotting. Our results confirm that mRNA expression in immune cells is many times lower than in that cells of epithelial origin. The immunoreactive signals in immune cells turned out to be false positives, and may be provoked by the presence of a high-affinity protein with a similar epitope. Non-specific binding (e.g., Fab-interaction with glycosyl branches) might also contribute to false positive signals. Our findings highlight the necessity of accurate controls, such as CFTR-negative cells, as well as peptide competition and glycolytic digest in order to identify genuine CFTR protein by immunoblotting. Our data suggest, furthermore, that CFTR protein expression data from techniques such as histology, for which the absence of a molecular weight or other independent control prevents the unmasking of false positive immunoreactive signals, must be interpreted carefully as well.

PMID:38928073 | DOI:10.3390/ijms25126367