Journal of Cystic Fibrosis最新文献

This review explores the changing landscape of drug safety in patients with cystic fibrosis (CF) prescribed Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator therapy. While serious adverse reactions are infrequent, they can necessitate treatment withdrawal and thereby negatively impact clinical outcomes. The CFTR correctors (vanzacaftor, elexacaftor, tezacaftor, lumacaftor) and potentiators (ivacaftor, deuterated ivacaftor) target the underlying CFTR defect to improve protein function. The CF patient population encounter a high prevalence of non-immediate adverse drug reactions and T-cell mediated hypersensitivity to β-lactam antibiotics are among the most well characterised. Piperacillin has been defined as a leading drug culprit within non-immediate drug allergy in patients with CF, with a growing body of evidence alluding to the central role of T-lymphocytes. The prevalence of reactions in CF is likely due to factors including exaggerated inflammation, overactive immune states and cumulative drug exposure. While the introduction of the CFTR modulators has led to improvements in patients inflammatory and immune states, some patients have been reported to develop drug-related allergies. Uniquely, patients presenting with drug hypersensitivity have been found to later tolerate CFTR modulators, often without the need for desensitisation protocols. This phenomenon has led us to hypothesise that increased levels of inflammation and dysregulation of regulatory T-cells in CF patients could propagate adverse reactions to CFTR modulators that resolve alongside underlying infection. The introduction of CFTR modulator therapies has been highly transformative for patients with CF, therefore, adverse reactions to these compounds that lead to cessation of treatment are serious and important to understand.

Background: Prenatal therapy with elexacaftor/tezacaftor/ivacaftor (ETI) has recently emerged as a potential strategy to modify the early natural history of cystic fibrosis (CF). While case reports have described prevention of meconium ileus and pancreatic insufficiency, data on male reproductive outcomes remain extremely limited.

Case presentation: We report a male infant with CF (homozygous F508del) whose heterozygous carrier mother initiated ETI at 27+4 weeks of gestation after prenatal diagnosis. Pregnancy was uneventful until preterm delivery at 35+2 weeks. The neonate presented with normal meconium passage, persistently normal fecal elastase, and no pulmonary abnormalities on magnetic resonance imaging. ETI was initiated directly in the infant at day 11 of life, with subsequent catch-up growth and discontinuation of pancreatic enzyme replacement therapy at 8 weeks. Remarkably, ultrasound at 8 weeks demonstrated bilateral vas deferens, a structure typically absent in nearly all male patients with CF at birth. Sweat chloride concentrations normalized under therapy, and no CF-typical manifestations were observed during the first 7 months of life.

Conclusion: This is the first report of a male infant with CF in whom prenatal ETI via a heterozygous carrier mother, started in the second trimester and continued postnatally, was associated with preserved exocrine pancreatic function, absence of pulmonary disease, and presence of vas deferens. These findings suggest that prenatal CFTR modulation - even when initiated late in gestation - may alter the trajectory of CF-related organ manifestations, including male reproductive development. Long-term follow-up is essential to determine whether these early benefits translate into sustained preservation of fertility and multiorgan function.

Background: Low bone mineral density (BMD) and increased fracture risk are common in individuals with cystic fibrosis (CF). The extent to which the CF transmembrane conductance regulator (CFTR) modulator elexacaftor-tezacaftor-ivacaftor (ETI) benefits BMD was a focus of the endocrine sub-study of PROMISE, a multicenter observational study of clinically prescribed ETI. We examined changes in whole-body (WB), lumbar spine (LS), total hip (TH), and femoral neck (FN) areal BMD (aBMD, g/cm²) in the 24-30 months (mos) following ETI initiation.

Methods: Participants had CF, ≥1 F508del mutation, and were aged ≥12 years (y). Dual-energy X-ray absorptiometry (DXA) scans of the WB, LS, TH, and FN were collected before and following 12-18 mos and 24-30 mos of ETI therapy. Changes in aBMD Z-scores (aBMDZ) were examined with longitudinal mixed effects models.

Results: Baseline aBMDZ was below-average at all skeletal sites in youth and adults (aBMDZ <0). Mixed model results for youth [n = 60 at baseline; average age 15y (range: 12-19.8); 48 % female] revealed decreases in WB (less head) (β-coefficient=-0.27; 95 %CI: -0.46, -0.09), LS (β=-0.26; 95 %CI: -0.42, -0.10), TH (β=-0.29; 95 %CI: -0.45, -0.13), and FN (β=-0.37; 95 %CI: -0.57, -0.17) aBMDZ between baseline and 12-18 mos. These changes persisted but did not worsen at 24-30 mos. Changes in adult [n = 73 at baseline; average age 28y (range: 20-58.8); 51 % female] aBMDZ were negative but modest compared to youth (no β-coefficient >-0.11).

Conclusions: Youth aBMDZ was lower at multiple skeletal sites 12-18 mos after ETI initiation, and these changes persisted at 24-30 mos. Adult aBMDZ generally remained unchanged.

Background: Smoke exposure affects one-third of children with CF (CwCF), but smoking cessation strategies for their caregivers have not been tested.

Methods: We developed and tested CEASE-CF, a randomized controlled smoking cessation intervention tailored to smoking caregivers of CwCF and delivered by a tobacco treatment specialist (TTS) integrated into the CF care team. The intervention arm received CF-specific smoke exposure education, intake assessment, and treatment (nicotine replacement therapy and 12 counseling sessions over 6 months). The control arm received education. Primary outcomes were feasibility and acceptability among caregivers and providers. Secondary outcomes were 6-month quit rates and child hair nicotine concentrations.

Results: 36 caregivers (24 intervention, 12 control) were recruited. Feasibility (64% accrual, 100% retention) and acceptability (86% caregivers satisfied and likely to recommend CEASE-CF, 67% finding it helpful) were high. Providers' (n = 19) mean scores were 4.7 (1-5 scale) for satisfaction, implementation, and recommendation to other clinics. At 6 months, 17% participants had quit smoking, and 78% had a 7-day point prevalence reduction of at least 17%, with an average reduction of 54%. Hair nicotine decreased from 2.7 (SE 0.17) ng/mg at baseline to 1.1 (SE 0.17) ng/mg at 6 months (p < 0.001). At baseline, all hair nicotine specimens were above the exposure threshold of 1.0 ng/mg, but only 41% at 6 months.

Conclusions: Tobacco treatment delivered by a TTS part of the CF care team reduces smoke exposure in CwCF. CEASE-CF is a feasible and acceptable model for smoking cessation that can be incorporated into CF clinical care.

The advent of CFTR modulators has revolutionised Cystic Fibrosis (CF) care, improving life expectancy, physiological parameters and reducing exacerbations. These are matched by changes in life expectations and ambitions of people living with CF (pwCF). This case study follows Sophie, a pwCF who completed a 54-day transatlantic row in early 2025, posing a unique challenge to our multidisciplinary team (MDT) that required bespoke support before, during and after her historic achievement.

Background: Allergic bronchopulmonary aspergillosis (ABPA) contributes to progressive lung damage in people with cystic fibrosis (pwCF), particularly when diagnosis is delayed. Early diagnosis remains challenging due to insidious onset and non-specific symptoms. We aimed to assess the utility of routinely collected biomarkers in predicting ABPA in children with CF.

Methods: A retrospective analysis of pwCF aged 0-18 years in Western Australia from 2000 to 2020. Longitudinal levels of total IgE, eosinophils (Eo), and Aspergillus-specific IgE (Asp-sp IgE) preceding ABPA diagnosis were compared with age- and sex-matched controls.

Results: Among 346 children with CF, 19 (5.4%) were diagnosed with ABPA. Distinct elevations in Asp-sp IgE, total IgE, and Eo were observed up to five years before clinical diagnosis. Total IgE almost doubled and Asp-sp IgE nearly tripled in the three years preceding diagnosis. Persistent normal values across all three markers were strongly associated with low risk of ABPA. Children with total IgE levels <500 IU/mL, Asp-sp IgE <0.35 IU/mL, and Eo <0.5 × 10⁹ cells/L, had a negligible risk (<1.0%) of ABPA over the next five years and very low risk (4.5%) over twelve years.

Discussion: Biomarker elevations in children who develop ABPA are not sudden but emerge early and persist over time. Conversely, children with low levels in at least two of total IgE, Eo, and Asp-sp IgE are at negligible risk of ABPA for at least five years and therefore may only require screening every five years. In contrast, children with elevated levels should be monitored more closely.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators (CFTRm) reduce the frequency of recurrent acute pancreatitis (RAP) among individuals with pancreas sufficient cystic fibrosis (PS-CF), but the impact on RAP among individuals with CFTR-related disorder (CFTR-RD) is unknown. CFTRm are thought to be similarly effective in CFTR-RD because the mechanism of AP is identical to PS-CF. However, there are limited reports of CFTRm for CFTR-RD in the literature. We present the case histories of three individuals with RAP due to CFTR-RD who commenced treatment with CFTRm. Including 8.5 person-years of follow up, there have been no additional AP episodes during treatment and all individuals have tolerated treatment very well. This report indicates that CFTRm are effective in reducing AP frequency in some individuals with RAP due to CFTR-RD. Therefore, clinical trials to assess the effects of CFTRm for CFTR-RD are warranted, particularly for RAP where pharmaceutical treatments are lacking.

Background: Tracheobronchomalacia (TBM) is characterised by abnormal collapsibility of the trachea and bronchi, often seen in children with cystic fibrosis (CF). This study aims to determine the impact of TBM on hospital admissions in young children with CF.

Methods: A retrospective study was conducted at a single paediatric tertiary CF centre, examining medical records of children with CF born between January 2009 and June 2019. TBM presence was identified through bronchoscopy records. Hospital admission data, including the number, length and reason for admissions, was collected and analysed.

Results: Of 101 children included, 59 had TBM. Children with TBM had significantly more hospital admissions and longer hospital stays compared to those without TBM. The risk of all hospital admissions increased by a factor of 2.00 in the first two years and 1.89 in the first four years of life. Risk of respiratory admissions were also higher, increasing by a factor of 3.06 and 2.17 respectively. The total number of days admitted to hospital for any reason increased by a factor of 2.3 in the first two years and 2.05 in the first four years, with respiratory bed days alone increasing by a factor of 3.14 in the first two years.

Conclusion: TBM in young children with CF is associated with increased hospital admissions and longer hospital stays, particularly for respiratory issues. These findings highlight the need for proactive management to address the increased healthcare burden in this population, and identifies areas for further research on effective interventions aimed at reducing hospitalisations.

Background: The depletion of short chain fatty acid (SCFA) producing bacterial species in cystic fibrosis (CF) is hypothesized to reduce overall SCFA production, contributing to the onset and persistence of gastrointestinal inflammation.

Methods: In a prospective longitudinal observational study, we compared children with CFto age-matched healthy controls (HC). Participants completed a validated food frequency questionnaire and provided fecal samples for SCFA analysis (targeted liquid chromatography-mass spectrometry (LC-MS)), fecal calprotectin, and microbial community composition (16S rRNA gene sequencing).

Results: 64 children with CF (cwCF) [median age (IQR) = 8.4 (4-11.9)] and 64 HC [median age (IQR) = 7.8 (3.4-13.4)] were recruited. Valerate and isobutyrate were significantly reduced and more variable over time in cwCF compared to HC. Age-associated increases in butyrate, valerate, isobutyrate and isovalerate observed in HC, were absent in CF. In CF, butyrate was positively correlated with alpha diversity (Richness = 0.3, p = 0.0005; Shannon diversity = 0.3, p = 0.0005) and inversely correlated with elevated calprotectin concentrations (-0.34, p = 0.01). CwCF had higher relative intake of fats, predominated by trans and saturated fats, alongside reduced relative intake of fibre, wholegrains and resistant starch.

Conclusions: Our findings indicate that reduced microbial diversity, depletion of key SCFA-producing taxa, and limited dietary fibre intake may promote alternative, less efficient pathways of butyrate synthesis in cwCF. When butyrate is reduced, heightened inflammation is more likely. Further investigation into the physiological roles of valerate and isobutyrate is needed to understand the implications of their depletion in CF.

Background: The 22-item sinonasal outcome test (SNOT-22) is widely used to evaluate quality of life (QOL) in cystic fibrosis chronic rhinosinusitis (CF-CRS) but lacks formal validation in people with CF (PwCF). This study explores the psychometric properties of the SNOT-22 following elexacaftor/tezacaftor/ivacaftor (ETI) administration.

Methods: Data from three prospective observational cohort studies investigating the impact of ETI on CF-CRS were pooled across four U.S. centers and used for validity assessments. SNOT-22 scores, Lund-Mackay (LM) computed tomography (CT) sinus scores, and Cystic Fibrosis Questionnaire-Revised (CFQ-R) scores were used to assess test-retest reliability, construct validity, and responsiveness to clinical change in SNOT-22 scores.

Results: Strong test-retest reliability was observed for the SNOT-22 during the first 6 months post-ETI (N = 53, all r ≥ 0.80, p < 0.001). SNOT-22 intraclass correlation coefficients were strong (0.883) at 3 and 6 months after ETI was initiated and moderate (0.693) across all time points. Mean individual scores in 20 SNOT-22 items decreased from baseline to post-ETI (90.1%, p < 0.05). Moderate convergent validity was observed between pre-treatment SNOT-22 scores and LM scores (r = -0.42, p = 0.002) and CFQ-R respiratory domain scores (r = -0.35, p = 0.025).

Conclusions: The SNOT-22 is a valid, reliable, and responsive instrument for evaluating CRS-specific QOL in adults with CF, and functions effectively as a unidimensional construct across most of its 22 items.