Pediatric long-term noninvasive respiratory support in children with central nervous system disorders.

RATIONALE: The use of long-term noninvasive respiratory support is increasing in children along with an extension of indications, in particular in children with central nervous system (CNS) disorders. OBJECTIVE: The aim of this study was to describe the characteristics of children with CNS disorders treated with long-term noninvasive respiratory support in France. METHODS: Data were collected from 27 French pediatric university centers through an anonymous questionnaire filled for every child treated with noninvasive ventilatory support ≥3 months on 1st June 2019. MAIN RESULTS: The data of 182 patients (55% boys, median age: 10.2 [5.4;14.8] years old [range: 0.3-25]) were collected: 35 (19%) patients had nontumoral spinal cord injury, 22 (12%) CNS tumors, 63 (35%) multiple disabilities, 26 (14%) central alveolar hypoventilation and 36 (20%) other CNS disorders. Seventy five percent of the patients were treated with noninvasive ventilation (NIV) and 25% with continuous positive airway pressure (CPAP). The main investigations performed before CPAP/NIV initiation were nocturnal gas exchange recordings, alone or coupled with poly(somno)graphy (in 29% and 34% of the patients, respectively). CPAP/NIV was started in an acute setting in 10% of the patients. Median adherence was 8 [6;10] hours/night, with 12% of patients using treatment <4 h/day. Nasal mask was the most common interface (70%). Airway clearance techniques were used by 31% of patients. CONCLUSION: CPAP/NIV may be a therapeutic option in children with CNS disorders. Future studies should assess treatment efficacy and patient reported outcome measures.

Non-Contrast-Enhanced Functional Lung MRI to Evaluate Treatment Response of Allergic Bronchopulmonary Aspergillosis in Patients With Cystic Fibrosis: A Pilot Study.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF) patients is associated with severe lung damage and requires specific therapeutic management. Repeated imaging is recommended to both diagnose and follow-up response to treatment of ABPA in CF. However, high risk of cumulative radiation exposure requires evaluation of free-radiation techniques in the follow-up of CF patients with ABPA. PURPOSE: To evaluate whether Fourier decomposition (FD) functional lung MRI can detect response to treatment of ABPA in CF patients. STUDY TYPE: Retrospective longitudinal. POPULATION: Twelve patients (7M, median-age:14 years) with CF and ABPA with pre- and post-treatment MRI. FIELD STRENGTH/SEQUENCE: 2D-balanced-steady-state free-precession (bSSFP) sequence with FD at 1.5T. ASSESSMENT: Ventilation-weighted (V) and perfusion-weighted (Q) maps were obtained after FD processing of 2D-coronal bSSFP time-resolved images acquired before and 3-9 months after treatment. Defects extent was assessed on the functional maps using a qualitative semi-quantitative score (0 = absence/negligible, 1 = <50%, 2 = >50%). Mean and coefficient of variation (CV) of the ventilation signal-intensity (VSI) and the perfusion signal-intensity (QSI) were calculated. Measurements were performed independently by three readers and averaged. Inter-reader reproducibility of the measurements was assessed. Pulmonary function tests (PFTs) were performed within 1 week of both MRI studies as markers of the airflow-limitation severity. STATISTICAL TESTS: Comparisons of medians were performed using the paired Wilcoxon-test. Reproducibility was assessed using intraclass correlation coefficient (ICC). Correlations between MRI and PFT parameters were assessed using the Spearman-test (rho correlation-coefficient). A P-value <0.05 was considered as significant. RESULTS: Defects extent on both V and Q maps showed a significant reduction after ABPA treatment (4.25 vs. 1.92 for V-defect-score and 5 vs. 2.75 for Q-defect-score). VSI_mean was significantly increased after treatment (280 vs. 167). Qualitative analyses reproducibility showed an ICC > 0.90, while the ICCs of the quantitative measurements was almost perfect (>0.99). Changes in VSI_cv and QSI_cv before and after treatment correlated inversely with changes of FEV1%p (rho = -0.68 for both). DATA CONCLUSION: Non-contrast-enhanced FD lung MRI has potential to reproducibly assess response to treatment of ABPA in CF patients and correlates with PFT obstructive parameters. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 3.

ALPINE2: Efficacy and safety of 14-day vs 28-day inhaled aztreonam for Pa eradication in children with cystic fibrosis.

BACKGROUND: Antibiotic eradication therapies recommended for newly isolated Pseudomonas aeruginosa (Pa) in people with cystic fibrosis (pwCF) can be burdensome. ALPINE2 compared the efficacy and safety of a shortened 14-day course of aztreonam for inhalation solution (AZLI) with 28-day AZLI in paediatric pwCF. METHODS: ALPINE2 (a double-blind, phase 3b study) included children aged 3 months to <18 years with CF and new-onset Pa infection. Participants were randomized to receive 75 mg AZLI three times daily for either 28 or 14 days followed by 14 days' matched placebo. The primary endpoint was rate of primary Pa eradication (no Pa detected during the 4 weeks post AZLI treatment). Non-inferiority was achieved if the lower 95% CI bound of the treatment difference between the two arms was above -20%. Secondary endpoints included assessments of Pa recurrence during 108 weeks of follow-up after primary eradication. Safety endpoints included treatment-emergent adverse events (TEAEs). RESULTS: In total, 149 participants were randomized (14-day AZLI, n = 74; 28-day AZLI, n = 75) and 142 (95.3%) completed treatment. Median age: 6.0 years (range: 0.3-17.0). Baseline characteristics were similar between treatment arms. Primary Pa eradication rates: 14-day AZLI, 55.9%; 28-day AZLI, 63.4%; treatment difference (CI), -8.0% (-24.6, 8.6%). Pa recurrence rates at follow-up end: 14-day AZLI, 54.1% (n = 20/37); 28-day AZLI, 41.9% (n = 18/43). TEAEs were similar between treatment arms. No new safety signals were observed. CONCLUSIONS: Non-inferiority of 14-day AZLI versus 28-day AZLI was not demonstrated. Both courses were well tolerated, further supporting AZLI short-term safety in paediatric and adolescent pwCF. CLINICALTRIALS: GOV: NCT03219164.

Home-spirometry exacerbation profiles in children with cystic fibrosis.

BACKGROUND: Pulmonary exacerbations (PEx) are strong predictors of respiratory disease progression in children with cystic fibrosis (CwCF) and may be associated with persistent decreased lung function after acute management. Telemonitoring devices can be used for early detection and monitoring of PEx, but its utility is debated. RESEARCH QUESTION: Which symptoms and telemonitoring spirometry characterics are related to outcome dynamics following initial PEx management? METHODS: This retrospective study included CwCF followed at Bordeaux University Hospital, France. All severe PEx episodes treated with intravenous (IV) antibiotics (ATB) between 1 January 2017 and 31 December 2021 in CwCF using home telemonitoring were analyzed. Symptoms and home spirometry data were collected 45 days before and up to 60 days after each IV ATB course. We defined three response profiles based on terciles of baseline forced expiratory volume in 1 s (FEV1 ) recovery. RESULTS: A total of 346 IV ATB courses for PEx were administered to 65 CwCF during the study period. The drop in FEV1 became significant 8 days before IV ATB initiation. Forty-one percent of IV ATB courses failed to restore baseline FEV1 . The magnitude of FEV1 drop and a greater delay in the initiation of treatment correlated with a low response level. On the 14th day of the IV treatment, a FEV1 recovery less than 94% of baseline was associated with a nonresponder profile. INTERPRETATION: Home spirometry may facilitate the early recognition of PEx to implement earlier interventions. This study also provides an outcome lung function threshold which identifies low responders to IV ATB.

The gut-lung axis in the CFTR modulator era.

The advent of CFTR modulators represents a turning point in the history of cystic fibrosis (CF) management, changing profoundly the disease's clinical course by improving mucosal hydration. Assessing changes in airway and digestive tract microbiomes is of great interest to better understand the mechanisms and to predict disease evolution. Bacterial and fungal dysbiosis have been well documented in patients with CF; yet the impact of CFTR modulators on microbial communities has only been partially deciphered to date. In this review, we aim to summarize the current state of knowledge regarding the impact of CFTR modulators on both pulmonary and digestive microbiomes. Our analysis also covers the inter-organ connections between lung and gut communities, in order to highlight the gut-lung axis involvement in CF pathophysiology and its evolution in the era of novel modulators therapies.

Longitudinal Evaluation of Bronchial Changes in Cystic Fibrosis Patients Undergoing Elexacaftor/Tezacaftor/Ivacaftor Therapy Using Lung MRI With Ultrashort Echo-Times.

BACKGROUND: Lung magnetic resonance imaging (MRI) with ultrashort echo-times (UTE-MRI) allows high-resolution and radiation-free imaging of the lung structure in cystic fibrosis (CF). In addition, the combination of elexacaftor/tezacaftor/ivacaftor (ETI) has improved CF clinical outcomes such as need for hospitalization. However, the effect on structural disease still needs longitudinal evaluation at high resolution. PURPOSE: To analyze the effects of ETI on lung structural alterations using UTE-MRI, with a focus on bronchiectasis reversibility. STUDY TYPE: Retrospective. POPULATION: Fifty CF patients (mean age 24.3 ± 9.2; 23 males). FIELD STRENGTH/SEQUENCE: 1.5 T, UTE-MRI. ASSESSMENT: All subjects completed both UTE-MRI and pulmonary function tests (PFTs) during two annual visits (M0 and M12), and 30 of them completed a CT scan. They initiated ETI treatment after M0 within a maximum of 3 months from the annual examinations. Three observers scored a clinical MRI Bhalla score on UTE-MRI. Bronchiectasis reversibility was defined as a reduction in both outer and inner bronchial dimensions. Correlations were searched between the Bhalla score and PFT such as the forced expiratory volume in 1 second percentage predicted (FEV1%p). STATISTICAL TESTS: Comparison was assessed using the paired t-test, correlation using the Spearman correlation test with a significance level of 0.05. Concordance and reproducibility were assessed using intraclass correlation coefficient (ICC). RESULTS: There was a significant improvement in MRI Bhalla score after ETI treatment. UTE-MRI demonstrated bronchiectasis reversibility in a subgroup of 18 out of 50 CF patients (36%). These patients with bronchiectasis reversibility were significantly younger, with lower severity of wall thickening but no difference in mucus plugging extent (P = 0.39) was found. The reproducibility of UTE-MRI evaluations was excellent (ICC ≥ 0.95), was concordant with CT scan (N = 30; ICC ≥ 0.90) and significantly correlated to FEV1% at PFT at M0 (N = 50; r = 0.71) and M12 (N = 50; r = 0.72). DATA CONCLUSION: UTE-MRI is a reproducible tool for the longitudinal follow-up of CF patients, allowing to quantify the response to ETI and demonstrating the reversibility of some structural alterations such as bronchiectasis in a substantial fraction of this study population. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 2.

Generating High-Resolution Synthetic CT from Lung MRI with Ultrashort Echo Times: Initial Evaluation in Cystic Fibrosis.

Background Lung MRI with ultrashort echo times (UTEs) enables high-resolution and radiation-free morphologic imaging; however, its image quality is still lower than that of CT. Purpose To assess the image quality and clinical applicability of synthetic CT images generated from UTE MRI by a generative adversarial network (GAN). Materials and Methods This retrospective study included patients with cystic fibrosis (CF) who underwent both UTE MRI and CT on the same day at one of six institutions between January 2018 and December 2022. The two-dimensional GAN algorithm was trained using paired MRI and CT sections and tested, along with an external data set. Image quality was assessed quantitatively by measuring apparent contrast-to-noise ratio, apparent signal-to-noise ratio, and overall noise and qualitatively by using visual scores for features including artifacts. Two readers evaluated CF-related structural abnormalities and used them to determine clinical Bhalla scores. Results The training, test, and external data sets comprised 82 patients with CF (mean age, 21 years ± 11 [SD]; 42 male), 28 patients (mean age, 18 years ± 11; 16 male), and 46 patients (mean age, 20 years ± 11; 24 male), respectively. In the test data set, the contrast-to-noise ratio of synthetic CT images (median, 303 [IQR, 221-382]) was higher than that of UTE MRI scans (median, 9.3 [IQR, 6.6-35]; P < .001). The median signal-to-noise ratio was similar between synthetic and real CT (88 [IQR, 84-92] vs 88 [IQR, 86-91]; P = .96). Synthetic CT had a lower noise level than real CT (median score, 26 [IQR, 22-30] vs 42 [IQR, 32-50]; P < .001) and the lowest level of artifacts (median score, 0 [IQR, 0-0]; P < .001). The concordance between Bhalla scores for synthetic and real CT images was almost perfect (intraclass correlation coefficient, ≥0.92). Conclusion Synthetic CT images showed almost perfect concordance with real CT images for the depiction of CF-related pulmonary alterations and had better image quality than UTE MRI. Clinical trial registration no. NCT03357562 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Schiebler and Glide-Hurst in this issue.

Dietary intake assessment in children with cystic fibrosis using 3-day food diaries: a single-centre study.

Background: Malnutrition is both a feature and major cause of morbidity in cystic fibrosis (CF). Therefore, nutritional management is an essential element of patient care. In 2016, an international guideline for nutritional management in patients with CF was published. In light of these recommendations, the aim of this study was to investigate the dietary intake of children with CF at the University Hospital of Bordeaux. Methods: We conducted a retrospective study at the Paediatric CF Centre of the University Hospital of Bordeaux. Patients aged 2-18 years with CF who completed a 3-day food diary at home between January 2015 and December 2020 were included. Results: A total of 130 patients, with a median age of 11.8 [interquartile range (IQR): 8.3; 13.4] years, were included. The median Z-score for BMI was -0.35 (IQR: -0.9; 0.2) and 20% of the patients had a Z-score for BMI < -1. Recommended total energy intakes were achieved in 53% of the patients, particularly those with nutritional support. Recommended protein intake was met in 28% of the cases, while fat and carbohydrate intakes were met in 54%. Vitamin and micronutrient levels were normal in 80% of the patients, with the exception of vitamin K, which was within the therapeutic range in only 42% of the cases. Conclusion: Recommended nutritional targets are difficult to achieve in patients with CF, and providing nutritional support during follow-up remains a challenge.

Nutritional impact of CFTR modulators in children with cystic fibrosis.

Background: Nutritional status is a major prognostic factor for breathing and the survival of patients with cystic fibrosis (CF). Since 2012, the development of CFTR modulators has considerably transformed the outcome of this disease. Indeed, both lung function and body mass index are improved by CFTR modulators, such as Lumacaftor/Ivacaftor. However, few data exist regarding the outcome of nutritional intakes under Lumacaftor/Ivacaftor. Methods: We conducted a prospective single-center study in children with CF treated with Lumacaftor/Ivacaftor to evaluate their nutritional intake before and after treatment. Results: Thirty-four children were included in this study, with a median age of 12.4 years [11.9; 14.7]. There was no significant improvement in weight, height or BMI. Patients' total energy intake was not significantly changed with Lumacaftor/Ivacaftor, while carbohydrate intakes decreased significantly. We found that blood levels of vitamin E and Selenium were significantly increased under Lumacaftor/Ivacaftor, without a significant increase in supplementation. In patients with a BMI Z-score < 0 at treatment initiation, there was a significant improvement in weight and BMI Z-score, while TEI and carbohydrate intakes were significantly lower. Conclusion: We showed that treatment with Lumacaftor/Ivacaftor improved the nutritional status of patients without necessarily being associated with an increase in nutritional intake. Although these data need to be confirmed in larger cohorts, they support the hypothesis that weight gain under modulators is multifactorial, and may be related to a decrease in energy expenditure or an improvement in absorption.

Effects of Lumacaftor-Ivacaftor on Airway Microbiota-Mycobiota and Inflammation in Patients with Cystic Fibrosis Appear To Be Linked to Pseudomonas aeruginosa Chronic Colonization.

Lumacaftor-ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination approved for patients with cystic fibrosis (CF) who are homozygous for the F508del allele. This treatment showed significant clinical improvement; however, few studies have addressed the evolution of the airway microbiota-mycobiota and inflammation in patients receiving lumacaftor-ivacaftor treatment. Seventy-five patients with CF aged 12 years or older were enrolled at the initiation of lumacaftor-ivacaftor therapy. Among them, 41 had spontaneously produced sputa collected before and 6 months after treatment initiation. Airway microbiota and mycobiota analyses were performed via high-throughput sequencing. Airway inflammation was assessed by measuring the calprotectin levels in sputum; the microbial biomass was evaluated via quantitative PCR (qPCR). At baseline (n = 75), bacterial alpha-diversity was correlated with pulmonary function. After 6 months of lumacaftor-ivacaftor treatment, a significant improvement in the body mass index and a decreased number of intravenous antibiotic courses were noted. No significant changes in bacterial and fungal alpha- and beta-diversities, pathogen abundances, or calprotectin levels were observed. However, for patients not chronically colonized with Pseudomonas aeruginosa at treatment initiation, calprotectin levels were lower, and a significant increase in bacterial alpha-diversity was observed at 6 months. This study shows that the evolution of the airway microbiota-mycobiota in CF patients depends on the patient's characteristics at lumacaftor-ivacaftor treatment initiation, notably chronic colonization with P. aeruginosa. IMPORTANCE The management of cystic fibrosis has been transformed recently by the advent of CFTR modulators, including lumacaftor-ivacaftor. However, the effects of such therapies on the airway ecosystem, particularly on the microbiota-mycobiota and local inflammation, which are involved in the evolution of pulmonary damage, are unclear. This multicenter study of the evolution of the microbiota under protein therapy supports the notion that CFTR modulators should be started as soon as possible, ideally before the patient is chronically colonized with P. aeruginosa. (This study has been registered at ClinicalTrials.gov under identifier NCT03565692).

Adherence, reliability, and variability of home spirometry telemonitoring in cystic fibrosis.

Introduction: Forced spirometry is the gold standard to assess lung function, but its accessibility may be limited. By contrast, home spirometry telemonitoring allows a multi-weekly lung function follow-up but its real-life adherence, reliability, and variability according to age have been poorly studied in patients with CF (PwCF). We aimed to compare real-life adherence, reliability and variability of home spirometry between children, teenagers and adults with CF. Methods: This real-life observational study included PwCF followed for six months in whom lung function (i.e, forced expiratory volume maximum in 1 s (FEV1), forced vital capacity (FVC), forced mid-expiratory flow (FEF) and FEV1/FVC ratio) was monitored by both conventional and home spirometry between July 2015 and December 2021. The adherence, reliability and variability of home spirometry was assessed in all PwCF and compared between children (<12years old), teenagers (12-18 years old) and adults. Results: 174 PwCF were included (74 children, 43 teenagers and 57 adults). Home spirometry was used at least one time per week by 64.1 ± 4.9% PwCF, more frequently in children and teenagers than in adults (79.4 ± 2.9%, 69.2 ± 5.5% and 40.4 ± 11.5% respectively). The reliability to conventional lung function testing was good for all assessed parameters (e.g., FEV1: r = 0.91, p < 0.01) and the variability over the 6 months of observation was low (FEV1 coefficient of variation = 11.5%). For each parameter, reliability was better, and the variability was lower in adults than in teenagers than in children. Conclusion: Home spirometry telemonitoring appears to be a reliable tool for multi-weekly lung function follow-up of PwCF.

Cost savings analysis of prescription assistance programs at a student-run free clinic.

The Free Clinic at Lubbock Impact (TFC) is a student-run, volunteer free clinic affiliated with Texas Tech University Health Sciences Center in Lubbock, Texas, that provides free weekly health services to the local uninsured patient population. The clinic also helps patients enroll in prescription assistance programs (PAPs) from pharmaceutical companies, which supply eligible patients with certain medications at little or no cost. This study presents a cost savings analysis of TFC patients enrolled in PAPs from February 2019 through February 2020. Cost savings were calculated by matching medication doses and units with the cost per unit for each brand-name medication listed on GoodRx.com at Walgreens pharmacies located in TFC's zip code, 79410. Sixty-one patients received 23 different medications with a total cost savings value of $222,563. Medications were sorted into diabetic, respiratory, and miscellaneous disease categories, for which cost savings totaled $114,110, $60,219, and $48,234, respectively. This study highlights the value of utilizing PAPs at a free clinic to address the barrier of medication cost for uninsured patients in Lubbock, Texas, and surrounding areas.

Prevalence of Substance use disorder among young adults hospitalized in the US hospital: A decade of change.

INTRODUCTION: Mental health disorders (MHD) and substance use disorders (SUD) lead to outstanding socioeconomic costs and increased hospital visits. However, very few studies have quantified this trend over time and across specific conditions. ​​Our study aims to investigate and compare the prevalence of MHDs and SUDs in hospitalizations between 2007 and 2017. METHODS: We used hospital records for 2007 and 2017 from the National Inpatient Sample (NIS) datasets to identify young adults (18-44 years) hospitalized with MHD and SUD. The prevalence of MHD in hospitalized patients in 2017 vs. 2007 was measured and compared. We generated a multivariable logistic regression analysis controlled for confounders, including age, sex, race, and payer status. We evaluated these outcomes using Odds Ratio (OR) and 95% Confidence Interval (CI). RESULTS: A total 10,353,890 patients were included in 2007, and 8,569,789 patients were included in 2017. The prevalence of drug abuse among hospitalized patients was 8.4% in 2017 vs. 6.2% in 2007. Prevalence increased in both genders (15.7% vs. 13.0% among male, 5.7% vs. 3.9% among females) in 2017 vs. 2007. All psychiatric disorders showed a higher prevalence in 2017 compared to 2007. When stratified by race, the prevalence of substance use disorder increased among all races except Black race between 2017 vs. 2007. On multivariable analysis, widespread drug abuse was significantly associated with hospital admissions in 2017 vs. 2007 (OR: 1.27, 95% CI: 1.20-1.34, p<0.001). These associations held across many substance abuse cases and mental health disorders except cocaine abuse (OR: 0.84, 95%CI: 0.76-0.93, p<0.001). CONCLUSION: There was a significant rise in substance use disorder and psychiatric disorder a decade later, from 2007, in hospitalized patients in the age group 18-44 years. The most increase was observed in amphetamine use disorder and anxiety disorder. Suicide and intentional self-inflicted injury increased in all races, with a maximum increase observed in Native Americans. Further studies evaluating the factors responsible for this upward trend would be beneficial.

Artificial intelligence in computed tomography for quantifying lung changes in the era of CFTR modulators.

BACKGROUND: Chest computed tomography (CT) remains the imaging standard for demonstrating cystic fibrosis (CF) airway structural disease in vivo. However, visual scoring systems as an outcome measure are time consuming, require training and lack high reproducibility. Our objective was to validate a fully automated artificial intelligence (AI)-driven scoring system of CF lung disease severity. METHODS: Data were retrospectively collected in three CF reference centres, between 2008 and 2020, in 184 patients aged 4-54 years. An algorithm using three 2D convolutional neural networks was trained with 78 patients' CT scans (23 530 CT slices) for the semantic labelling of bronchiectasis, peribronchial thickening, bronchial mucus, bronchiolar mucus and collapse/consolidation. 36 patients' CT scans (11 435 CT slices) were used for testing versus ground-truth labels. The method's clinical validity was assessed in an independent group of 70 patients with or without lumacaftor/ivacaftor treatment (n=10 and n=60, respectively) with repeat examinations. Similarity and reproducibility were assessed using the Dice coefficient, correlations using the Spearman test, and paired comparisons using the Wilcoxon rank test. RESULTS: The overall pixelwise similarity of AI-driven versus ground-truth labels was good (Dice 0.71). All AI-driven volumetric quantifications had moderate to very good correlations to a visual imaging scoring (p<0.001) and fair to good correlations to forced expiratory volume in 1 s % predicted at pulmonary function tests (p<0.001). Significant decreases in peribronchial thickening (p=0.005), bronchial mucus (p=0.005) and bronchiolar mucus (p=0.007) volumes were measured in patients with lumacaftor/ivacaftor. Conversely, bronchiectasis (p=0.002) and peribronchial thickening (p=0.008) volumes increased in patients without lumacaftor/ivacaftor. The reproducibility was almost perfect (Dice >0.99). CONCLUSION: AI allows fully automated volumetric quantification of CF-related modifications over an entire lung. The novel scoring system could provide a robust disease outcome in the era of effective CF transmembrane conductance regulator modulator therapy.

Real-world assessment of LCI following lumacaftor-ivacaftor initiation in adolescents and adults with cystic fibrosis.

Lung clearance index (LCI) is a biomarker of ventilation inhomogeneity. Data are scarce on its usefulness in daily practice for monitoring the effects of treatments in older children and adults with CF. In this French observational study of lumacaftor-ivacaftor, 63 of 845 patients (7.5%) had available LCI performed at baseline and at six (M6; n=34) or 12 months (M12; n=46) after lumacaftor-ivacaftor initiation. At inclusion, median [IQR] age was 16 years [13-17], ppFEV1 was 72.8 [59.6-80.7], and LCI was 12.3 [10.3-15.0]. At both M6 and M12, no statistically significant LCI increases of 0.13 units or 1.34% (95% CI: -4.85-7.53) and 0.6 units or 6.66% (95% CI: -0.03-13.5) were observed. Discordant results between LCI and ppFEV1 were observed in one-third of the patients. In daily practice, LCI monitoring in adolescents and young adults with moderate lung disease gives results that are more heterogenous than those reported in children with milder disease.

Cystic fibrosis and noninvasive liver fibrosis assessment methods in children.

BACKGROUND: Noninvasive assessments of liver fibrosis are currently used to evaluate cystic fibrosis (CF)-related liver disease. However, there is scarce data regarding their repeatability and reproducibility, especially in children with CF. The present study aimed to evaluate the repeatability and reproducibility of transient elastography (TE) (FibroScan®) and point shear-wave elastography using virtual touch quantification (pSWE VTQ) in children with CF. METHODS: TE and pSWE VTQ were performed in 56 children with CF by two different operators. Analysis of repeatability and reproducibility was available in 33 patients for TE and 46 patients for pSWE VTQ. Intra- and interobserver agreement were assessed using the intraclass correlation coefficient (ICC) and their 95% confidence interval (CI), and Bland and Altman graphs. RESULTS: For TE, ICC was 0.91 (0.83-0.95) for intraobserver agreement and 0.92 (95% CI: 0.86-0.96) for interobserver agreement. For pSWE VTQ, ICC was 0.83 (0.72-0.90) for intraobserver agreement and 0.67 (0.48-0.80) for interobserver agreement. CONCLUSIONS: Both technics can be proposed in the follow-up of patients, according to their availability in CF centers. IMPACT: This study shows that TE and pSWE VTQ are reliable methods to evaluate liver fibrosis in children with CF. This study shows for the first time that TE and pSWE VTQ are both repeatable and reproducible in children with CF. These data indicate that both TE and pSWE VTQ can be proposed for the follow-up of patients with CF, according to their availability in each CF center.

Inflammation biomarkers in sputum for clinical trials in cystic fibrosis: current understanding and gaps in knowledge.

RATIONALE: Sputum biomarkers hold promise as a direct measure of inflammation within the cystic fibrosis (CF) lung, but variability in study design and sampling methodology have limited their use. A full evaluation of the reliability, validity and clinical relevance of individual biomarkers is required to optimise their use within CF clinical research. OBJECTIVES: A biomarker Special Interest Working Group was established within the European Cystic Fibrosis Society-Clinical Trials Network Standardisation Committee, to perform a review of the evidence regarding sputum biomarkers in CF. METHODS: From the 139 included articles, we identified 71 sputum biomarkers to undergo evaluation of their clinimetric properties, responsiveness, discriminant, concurrent and convergent validity. RESULTS: Current evidence confirms the potential of sputum biomarkers as outcome measures in clinical trials. Inconsistency in responsiveness, concurrent and convergent validity require further research into these markers and processing standardisation before translation into wider use. Of the 71 biomarkers identified, Neutrophil Elastase (NE), IL-8, TNF-α and IL-1ß, demonstrated validity and responsiveness to be currently considered for use in clinical trials. Other biomarkers show future promise, including IL-6, calprotectin, HMGB-1 and YKL-40. CONCLUSION: A concerted international effort across the cystic fibrosis community is needed to promote high quality biomarker trial design, establish large population-based biomarker studies, and work together to create standards for collection, storage and analysis of sputum biomarkers.

Long-Term Outcomes in Real Life of Lumacaftor-Ivacaftor Treatment in Adolescents With Cystic Fibrosis.

Background: The combination of the CFTR corrector lumacaftor (LUM) and potentiator ivacaftor (IVA) has been labeled in France since 2015 for F508del homozygote cystic fibrosis (CF) patients over 12 years. In this real-life study, we aimed (i) to compare the changes in lung function, clinical (e.g., body mass index and pulmonary exacerbations) and radiological parameters, and in sweat chloride concentration before and after initiation of LUM/IVA treatment; (ii) to identify factors associated with response to treatment; and (iii) to assess the tolerance to treatment. Materials and Methods: In this tri-center, non-interventional, and observational cohort study, children (12-18 years old) were assessed prospectively during the 2 years of therapy, and retrospectively during the 2 years preceding treatment. Data collected and analyzed for the study were exclusively extracted from the medical electronic system records of the patients. Results: Forty adolescents aged 12.0-17.4 years at LUM/IVA initiation were included. The lung function decreased significantly during and prior to treatment and increased after LUM/IVA initiation, becoming significant after 2 years of treatment. LUM/IVA significantly improved the BMI Z-score and sweat chloride concentration. By contrast, there was no significant change in exacerbation rates, antibiotic use, or CT scan scores. Age at LUM/IVA initiation was lower in good responders and associated with greater ppFEV1 change during the 2 years of treatment. LUM/IVA was well-tolerated. Conclusion: In F508del homozygote adolescents, real-life long-term LUM/IVA improved the ppFEV1 trajectory, particularly in the youngest patients, nutritional status, and sweat chloride concentration but not exacerbation rates or radiological scores. LUM/IVA was generally well-tolerated and safe.

Using chest CT scan and unsupervised machine learning for predicting and evaluating response to lumacaftor-ivacaftor in people with cystic fibrosis.

OBJECTIVES: Lumacaftor-ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator known to improve clinical status in people with cystic fibrosis (CF). This study aimed to assess lung structural changes after one year of lumacaftor-ivacaftor treatment, and to use unsupervised machine learning to identify morphological phenotypes of lung disease that are associated with response to lumacaftor-ivacaftor. METHODS: Adolescents and adults with CF from the French multicenter real-world prospective observational study evaluating the first year of treatment with lumacaftor-ivacaftor were included if they had pretherapeutic and follow-up chest computed tomography (CT)-scans available. CT scans were visually scored using a modified Bhalla score. A k-mean clustering method was performed based on 120 radiomics features extracted from unenhanced pretherapeutic chest CT scans. RESULTS: A total of 283 patients were included. The Bhalla score significantly decreased after 1 year of lumacaftor-ivacaftor (-1.40±1.53 points compared with pretherapeutic CT; p<0.001). This finding was related to a significant decrease in mucus plugging (-0.35±0.62 points; p<0.001), bronchial wall thickening (-0.24±0.52 points; p<0.001) and parenchymal consolidations (-0.23±0.51 points; p<0.001). Cluster analysis identified 3 morphological clusters. Patients from cluster C were more likely to experience an increase in percent predicted forced expiratory volume in 1 sec (ppFEV1) ≥5 under lumacaftor-ivacaftor than those in the other clusters (54% of responders versus 32% and 33%; p=0.01). CONCLUSION: One year treatment with lumacaftor-ivacaftor was associated with a significant visual improvement of bronchial disease on chest CT. Radiomics features on pretherapeutic CT scan may help in predicting lung function response under lumacaftor-ivacaftor.