Radiological and long-term clinical response to elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis with advanced lung disease.

INTRODUCTION: A triple combination of CFTR modulators ELE/TEZ/IVA (elexacaftor/tezacaftor/ivacaftor, Trikafta™) has been evaluated in clinical trials for people with cystic fibrosis (pwCF) and was approved to the European and US market. During registration and settling reimbursement in Europe, it could be requested on a compassionate use basis, for patients with advanced lung disease (ppFEV1 < 40). AIM: The aim of this study is to evaluate 2 years of experience with the clinical and radiological response of ELE/TEZ/IVA in pwCF in a compassionate use setting. METHODS: pwCF who started ELE/TEZ/IVA in a compassionate use setting were prospectively followed with assessment of spirometry, BMI, chest CT, CFQ-R and sweat chloride concentration (SCC) before start and after 3 months. Furthermore, spirometry, sputum cultures, and BMI were repeated after 1, 6, 12, 18, and 24 months. RESULTS: Eighteen patients were eligible for this evaluation, nine with F508del/F508del genotype (eight of whom were using dual CFTR modulators) and nine with F508del/minimal function mutation. After 3 months, mean change in SCC was -44.9 (p ≤ 0.001), together with significant improvement in CT (change in Brody score: -28.27 p ≤ 0.001) and CFQ-R results (change in respiratory domain: +18.8, p = 0.002). After 24 months, ppFEV1 change was +8.89 (p = 0.002), BMI had improved by +1.53 kg/m2 (p ≤ 0.001) and exacerbation rate declined from 5.94 in 24 months before start to 1.17 (p ≤ 0.001) in the 24 months after. CONCLUSION: pwCF with advanced lung disease experience relevant clinical benefit after 2 years of treatment with ELE/TEZ/IVA in a compassionate use setting. Structural lung damage, quality of life, exacerbation rate, and BMI improved significantly with treatment. Gain in ppFEV1 is lower compared to the phase III trials that included younger patients with moderately affected lung function.

VOCAL: An observational study of ivacaftor for people with cystic fibrosis and selected non-G551D-CFTR gating mutations.

BACKGROUND: VOCAL was an observational study of the effect of long-term ivacaftor on real-world clinical outcomes and healthcare resource utilization (HCRU) in people with cystic fibrosis (pwCF) in Italy, the Netherlands, and the UK. METHODS: pwCF aged ≥6 years with non-G551D-CFTR gating mutations were eligible. Prospective data were collected up to 48 months after enrollment; retrospective data were collected to ensure that 12 months of pre-ivacaftor data were available. Endpoints included absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) and measures of nutritional status. Pulmonary exacerbation (PEx) rates, HCRU, and respiratory microbiology during ivacaftor treatment were compared with data from the 12-month period before initiation. RESULTS: Seventy-three eligible pwCF were enrolled and received ivacaftor; 65 (89.0%) completed the study (48 [65.8%] completed ≥48 months of ivacaftor). During the first 6 months of ivacaftor, ppFEV1, body mass index (BMI), and BMI-for-age z-score showed least-squares mean absolute improvements of 10.8 percentage points, 0.79 kg/m2, and 0.54, respectively; improvements were maintained through 48 months. Rates of PEx, antibiotic use due to PEx, and hospitalization decreased by >50% during ivacaftor treatment compared with before ivacaftor. The number of respiratory cultures and sputum was lower post-ivacaftor, as was the percentage of pwCF with positive respiratory cultures for 3 of 9 pathogens evaluated (Pseudomonas aeruginosa, Aspergillus fumigatus, Stenotrophomonas maltophilia). Reported safety results were consistent with CF and ivacaftor's known safety profile. CONCLUSIONS: These results demonstrate the positive long-term effectiveness of ivacaftor on clinical outcomes and HCRU in pwCF with non-G551D-CFTR gating mutations in real-world settings.

Physiological predictors of cardiorespiratory fitness in children and adolescents with cystic fibrosis without ventilatory limitation.

OBJECTIVES: [1] To investigate the cardiorespiratory fitness (CRF) levels in children and adolescents with cystic fibrosis (CF) with no ventilatory limitation (ventilatory reserve ⩾ 15%) during exercise, and [2] to assess which physiological factors are related to CRF. METHODS: A cross-sectional study design was used in 8- to 18-year-old children and adolescents with CF. Cardiopulmonary exercise testing was used to determine peak oxygen uptake normalized to body weight as a measure of CRF. Patients were defined as having 'low CRF' when CRF was less than 82%predicted. Physiological predictors used in this study were body mass index z-score, P. Aeruginosa lung infection, impaired glucose tolerance (IGT) including CF-related diabetes, CF-related liver disease, sweat chloride concentration, and self-reported physical activity. Backward likelihood ratio (LR) logistic regression analysis was used. RESULTS: Sixty children and adolescents (51.7% boys) with a median age of 15.3 years (25th-75th percentile: 12.9-17.0 years) and a mean percentage predicted forced expiratory volume in 1 second of 88.5% (±16.9) participated. Mean percentage predicted CRF (ppVO2peak/kg) was 81.4% (±12.4, range: 51%-105%). Thirty-three patients (55.0%) were classified as having 'low CRF'. The final model that best predicted low CRF included IGT (p = 0.085; Exp(B) = 6.770) and P. Aeruginosa lung infection (p = 0.095; Exp(B) = 3.945). This model was able to explain between 26.7% and 35.6% of variance. CONCLUSIONS: CRF is reduced in over half of children and adolescents with CF with normal ventilatory reserve. Glucose intolerance and P. Aeruginosa lung infection seem to be associated to low CRF in children and adolescents with CF.

Lumacaftor/ivacaftor in people with cystic fibrosis with an A455E-CFTR mutation.

BACKGROUND: Previous in vitro organoid data showed A455E-CFTR, a rare CFTR mutation with 4.1% prevalence in the Netherlands, responds to lumacaftor/ivacaftor (LUM/IVA). We explored LUM/IVA's clinical efficacy in people with CF and ≥1 A455E-CFTR mutation. METHODS: Participants aged ≥12 years were randomized to 1 of 2 treatment sequences (LUM/IVA→placebo or placebo→LUM/IVA) with an 8-week washout period between. Primary endpoint was absolute change in ppFEV1 from study baseline through 8 weeks. Additional endpoints were change in sweat chloride concentration (SwCl) and CFQ-R respiratory domain score. Correlations between organoid-based measurements and clinical endpoints were investigated. RESULTS: Twenty participants were randomized at 2 sites in the Netherlands. Mean absolute change in ppFEV1 from study baseline through Week 8 showed a treatment difference of 0.1 percentage points (95% CI, -2.5 to 2.7; P = 0.928) between LUM/IVA (within-group mean change, 2.7) and placebo (within-group mean change, 2.6). The mean absolute change in SwCl concentration from study baseline through Week 8 showed a treatment difference of -7.8 mmol/L between LUM/IVA and placebo (P = 0.004), while the absolute change in CFQ-R respiratory domain score showed a treatment difference of 3.5 between LUM/IVA and placebo (P = 0.469). The in vitro organoid-based assay demonstrated a concentration-dependent swelling increase with LUM/IVA. Exploratory correlation analyses between organoid swelling and ppFEV1 and SwCl outcomes showed correlation coefficients of 0.49 and -0.11, respectively. CONCLUSIONS: In this exploratory study, LUM/IVA elicited an in vitro response in organoid swelling and in vivo response in SwCl in participants with CF and ≥1 A455E-CFTR mutation. The primary endpoint (ppFEV1) did not show a statistically significant difference between LUM/IVA and placebo; correlations between in vitro and in vivo responses were not established (NCT03061331).

Healthy play, better coping: The importance of play for the development of children in health and disease.

Play is of vital importance for the healthy development of children. From a developmental perspective, play offers ample physical, emotional, cognitive, and social benefits. It allows children and adolescents to develop motor skills, experiment with their (social) behavioural repertoire, simulate alternative scenarios, and address the various positive and negative consequences of their behaviour in a safe and engaging context. Children with a chronic or life-threatening disease may face obstacles that negatively impact play and play development, possibly impeding developmental milestones, beyond the actual illness itself. Currently, there is limited understanding of the impact of (1) aberrant or suppressed play and (2) play-related interventions on the development of chronic diseased children. We argue that stimulating play behaviour enhances the adaptability of a child to a (chronic) stressful condition and promotes cognitive, social, emotional and psychomotor functioning, thereby strengthening the basis for their future health. Systematic play research will help to develop interventions for young patients, to better cope with the negative consequences of their illness and stimulate healthy development.

Early growth characteristics and the risk of reduced lung function and asthma: A meta-analysis of 25,000 children.

BACKGROUND: Children born preterm or with a small size for gestational age are at increased risk for childhood asthma. OBJECTIVE: We sought to assess the hypothesis that these associations are explained by reduced airway patency. METHODS: We used individual participant data of 24,938 children from 24 birth cohorts to examine and meta-analyze the associations of gestational age, size for gestational age, and infant weight gain with childhood lung function and asthma (age range, 3.9-19.1 years). Second, we explored whether these lung function outcomes mediated the associations of early growth characteristics with childhood asthma. RESULTS: Children born with a younger gestational age had a lower FEV1, FEV1/forced vital capacity (FVC) ratio, and forced expiratory volume after exhaling 75% of vital capacity (FEF75), whereas those born with a smaller size for gestational age at birth had a lower FEV1 but higher FEV1/FVC ratio (P < .05). Greater infant weight gain was associated with higher FEV1 but lower FEV1/FVC ratio and FEF75 in childhood (P < .05). All associations were present across the full range and independent of other early-life growth characteristics. Preterm birth, low birth weight, and greater infant weight gain were associated with an increased risk of childhood asthma (pooled odds ratio, 1.34 [95% CI, 1.15-1.57], 1.32 [95% CI, 1.07-1.62], and 1.27 [95% CI, 1.21-1.34], respectively). Mediation analyses suggested that FEV1, FEV1/FVC ratio, and FEF75 might explain 7% (95% CI, 2% to 10%) to 45% (95% CI, 15% to 81%) of the associations between early growth characteristics and asthma. CONCLUSIONS: Younger gestational age, smaller size for gestational age, and greater infant weight gain were across the full ranges associated with childhood lung function. These associations explain the risk of childhood asthma to a substantial extent.

Preterm birth, infant weight gain, and childhood asthma risk: a meta-analysis of 147,000 European children.

BACKGROUND: Preterm birth, low birth weight, and infant catch-up growth seem associated with an increased risk of respiratory diseases in later life, but individual studies showed conflicting results. OBJECTIVES: We performed an individual participant data meta-analysis for 147,252 children of 31 birth cohort studies to determine the associations of birth and infant growth characteristics with the risks of preschool wheezing (1-4 years) and school-age asthma (5-10 years). METHODS: First, we performed an adjusted 1-stage random-effect meta-analysis to assess the combined associations of gestational age, birth weight, and infant weight gain with childhood asthma. Second, we performed an adjusted 2-stage random-effect meta-analysis to assess the associations of preterm birth (gestational age <37 weeks) and low birth weight (<2500 g) with childhood asthma outcomes. RESULTS: Younger gestational age at birth and higher infant weight gain were independently associated with higher risks of preschool wheezing and school-age asthma (P < .05). The inverse associations of birth weight with childhood asthma were explained by gestational age at birth. Compared with term-born children with normal infant weight gain, we observed the highest risks of school-age asthma in children born preterm with high infant weight gain (odds ratio [OR], 4.47; 95% CI, 2.58-7.76). Preterm birth was positively associated with an increased risk of preschool wheezing (pooled odds ratio [pOR], 1.34; 95% CI, 1.25-1.43) and school-age asthma (pOR, 1.40; 95% CI, 1.18-1.67) independent of birth weight. Weaker effect estimates were observed for the associations of low birth weight adjusted for gestational age at birth with preschool wheezing (pOR, 1.10; 95% CI, 1.00-1.21) and school-age asthma (pOR, 1.13; 95% CI, 1.01-1.27). CONCLUSION: Younger gestational age at birth and higher infant weight gain were associated with childhood asthma outcomes. The associations of lower birth weight with childhood asthma were largely explained by gestational age at birth.