Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation: A Phase 3b, Randomized, Placebo-controlled Study.

Rationale: The triple-combination regimen elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children aged 6 through 11 years with cystic fibrosis and at least one F508del-CFTR allele in a phase 3, open-label, single-arm study. Objectives: To further evaluate the efficacy and safety of ELX/TEZ/IVA in children 6 through 11 years of age with cystic fibrosis heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) in a randomized, double-blind, placebo-controlled phase 3b trial. Methods: Children were randomized to receive either ELX/TEZ/IVA (n = 60) or placebo (n = 61) during a 24-week treatment period. The dose of ELX/TEZ/IVA administered was based on weight at screening, with children <30 kg receiving ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours, and children ⩾30 kg receiving ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours (adult dose). Measurements and Main Results: The primary endpoint was absolute change in lung clearance index2.5 from baseline through Week 24. Children given ELX/TEZ/IVA had a mean decrease in lung clearance index2.5 of 2.29 units (95% confidence interval [CI], 1.97-2.60) compared with 0.02 units (95% CI, -0.29 to 0.34) in children given placebo (between-group treatment difference, -2.26 units; 95% CI, -2.71 to -1.81; P < 0.0001). ELX/TEZ/IVA treatment also led to improvements in the secondary endpoint of sweat chloride concentration (between-group treatment difference, -51.2 mmol/L; 95% CI, -55.3 to -47.1) and in the other endpoints of percent predicted FEV1 (between-group treatment difference, 11.0 percentage points; 95% CI, 6.9-15.1) and Cystic Fibrosis Questionnaire-Revised Respiratory domain score (between-group treatment difference, 5.5 points; 95% CI, 1.0-10.0) compared with placebo from baseline through Week 24. The most common adverse events in children receiving ELX/TEZ/IVA were headache and cough (30.0% and 23.3%, respectively); most adverse events were mild or moderate in severity. Conclusions: In this first randomized, controlled study of a cystic fibrosis transmembrane conductance regulator modulator conducted in children 6 through 11 years of age with F/MF genotypes, ELX/TEZ/IVA treatment led to significant improvements in lung function, as well as robust improvements in respiratory symptoms and cystic fibrosis transmembrane conductance regulator function. ELX/TEZ/IVA was generally safe and well tolerated in this pediatric population with no new safety findings.

Pulmonary function tests for evaluating the severity of Duchenne muscular dystrophy disease.

AIM: In Duchenne muscular dystrophy (DMD), lung disease contributes significantly to morbidity and mortality. This study aimed to assess the usefulness of various pulmonary function tests in evaluating DMD severity. METHODS: This retrospective study analysed lung function tests of patients with DMD-treated in the multidisciplinary respiratory neuromuscular clinic at Schneiders' Children Medical Center of Israel. Data were analysed according to age, ambulatory status and glucocorticoid treatment. RESULTS: Among 90 patients with DMD, 40/63 (63.5%) ambulatory patients and 22/27 (81.5%) nonambulatory patients successfully performed spirometry. Significant annual declines were demonstrated among nonambulatory patients, in percentile predicted forced vital capacity (3.8%) and in total lung capacity (5.5%) per year. The decline correlated with age and loss of ambulation but not with steroid treatment. Peak cough flow values were randomly distributed and did not correlate with age, ambulation or treatment. In nonambulatory patients, transcutaneous carbon dioxide measurement correlated significantly with age (r = 0.55, p = 0.02). CONCLUSION: Forced vital capacity, total lung capacity and transcutaneous carbon dioxide correlated with the clinical severity of disease in children with DMD. These measures may be useful in follow-up and clinical trials. A comparable correlation was not found for peak cough flow.

Videofluoroscopy compared with clinical feeding evaluation in children with suspected aspiration.

AIM: Videofluoroscopy swallow studies (VFSS) are gold standard to diagnose aspiration in children but require resources and radiation compared with clinical feeding evaluation (CFE). We evaluated their added value for diagnosis, feeding management and clinical status. METHODS: A retrospective single-centre cross-sectional study of children aged 0-18 years, with respiratory morbidity, referred for VFSS at a tertiary pediatric hospital. RESULTS: A total of 113 children, median age (range) 2.2 years (0.1-17.9), underwent VFSS. Diagnosis included chronic pulmonary aspiration (CPA), 87 (77%); neurological, 73 (64%); gastrointestinal, 73 (64%) and congenital heart disease, 42 (37%), not mutually exclusive. Forty-six (41%) aspirated, 9 (8%) only overtly and 37 (33%) including silent aspirations. Those with CPA or cerebral palsy were more likely to have VFSS aspiration, OR 3.2 and 9.8 respectively. Feeding recommendations after VFSS differed significantly from those based on prior CFE, p < 0.001: The rate of exclusively orally fed children rose from 65% to 79%, p = 0.006; exclusively enterally fed children from 10% to 14%; p = 0.005. During the year after VFSS, there were significantly less antibiotic courses, total and respiratory admissions. CONCLUSION: In this population with high prevalence of clinically suspected CPA, VFSS altered feeding management compared with CFE and may have contributed to subsequent clinical improvement.

VX-659-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles.

BACKGROUND: The next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-659, in triple combination with tezacaftor and ivacaftor (VX-659-tezacaftor-ivacaftor), was developed to restore the function of Phe508del CFTR protein in patients with cystic fibrosis. METHODS: We evaluated the effects of VX-659-tezacaftor-ivacaftor on the processing, trafficking, and function of Phe508del CFTR protein using human bronchial epithelial cells. A range of oral VX-659-tezacaftor-ivacaftor doses in triple combination were then evaluated in randomized, controlled, double-blind, multicenter trials involving patients with cystic fibrosis who were heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del-MF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del genotype). The primary end points were safety and the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1). RESULTS: VX-659-tezacaftor-ivacaftor significantly improved the processing and trafficking of Phe508del CFTR protein as well as chloride transport in vitro. In patients, VX-659-tezacaftor-ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. VX-659-tezacaftor-ivacaftor resulted in significant mean increases in the percentage of predicted FEV1 through day 29 (P<0.001) of up to 13.3 points in patients with Phe508del-MF genotypes; in patients with the Phe508del-Phe508del genotype already receiving tezacaftor-ivacaftor, adding VX-659 resulted in a further 9.7-point increase in the percentage of predicted FEV1. The sweat chloride concentrations and scores on the respiratory domain of the Cystic Fibrosis Questionnaire-Revised improved in both patient populations. CONCLUSIONS: Robust in vitro activity of VX-659-tezacaftor-ivacaftor targeting Phe508del CFTR protein translated into improvements for patients with Phe508del-MF or Phe508del-Phe508del genotypes. VX-659 triple-combination regimens have the potential to treat the underlying cause of disease in approximately 90% of patients with cystic fibrosis. (Funded by Vertex Pharmaceuticals; VX16-659-101 and VX16-659-001 ClinicalTrials.gov numbers, NCT03224351 and NCT03029455 .).

Efficacy of Problem-Solving Intervention to Improve Adherence in Adolescents and Adults with Cystic Fibrosis.

BACKGROUND: Adherence to treatment by adolescents and adults with cystic fibrosis (CF) is often poor. OBJECTIVES: To assess the impact of a focused clinical intervention on adherence in individual patients, including help in problem-solving key barriers to adherence. To implement a patient-centered problem-solving intervention using CF My Way tools. To identify and overcome a selected barrier to adherence. METHODS: Medication possession ratios (MPRs), number of airway clearance sessions, forced expiratory volume (FEV1), body mass index (BMI), and health-related quality of life (HRQoL) were measured before and after the intervention. RESULTS: Sixteen patients with CF, aged 23.4 ± 6.7 years, participated. MPR increased for colistimethate sodium and tobramycin inhalations from a median of 21 (range 0-100) to 56 (range 0-100), P = 0.04 and 20 (range 0-100) to 33.3 (range 25-100), P = 0.03, respectively. BMI standard deviation score rose from -0.37 to -0.21, P = 0.05. No significant improvements were found in FEV1, airway clearance, or HRQoL scores. CONCLUSIONS: The CF My Way problem-solving intervention increased adherence to medical treatments by removing barriers directly related to the needs and goals of young adults with CF.

[DIAGNOSIS AND TREATMENT OF BRONCHIECTASIS: POSITION PAPER OF THE ISRAELI PULMONOLOGY SOCIETY AND THE ISRAELI PEDIATRIC PULMONOLOGY SOCIETY].

INTRODUCTION: Bronchiectasis is anatomically defined by irreversible distortion of the bronchi. Clinically, its manifestations are cough with sputum production and a predisposition to pulmonary infections. Unlike asthma and COPD, where ample clinical data are present regarding the course and effective treatment, knowledge of bronchiectasis has yet to evolve. Lately, bronchiectasis is gaining renewed attention among the medical community, with growing basic and clinical research-based data. In Israel, no registered treatments exist for bronchiectasis, which makes it difficult to treat these patients. This paper is a summary of the position of the Israeli Pulmonology Association and the Israeli Pediatric Pulmonology Association for diagnosis and treatment of bronchiectasis.

Lung transplantation in cystic fibrosis patients in Israel: The importance of ethnicity and nutritional status.

OBJECTIVES: To assess the characteristics that correlate with better outcomes after lung transplantation for patients with cystic fibrosis (CF). METHODS: We retrospectively reviewed the charts of all patients with CF who underwent lung transplantation between 1996 and 2014 at Rabin Medical Center, Israel. RESULTS: Fifty patients with CF underwent 55 lung transplantations. Eighteen patients (36%) died during the study period. Actuarial survival was 83%, 68%, 62%, and 39% at 1, 3, 5, and 10 years, respectively. Better survival correlated with: BMI at 6 months and 1 year after transplantation (P = .002 and P = .003, respectively), ischemic time of less than 300 minutes (P = .023), absence of liver disease (P = .012), and Jewish compared to Arab ethnicity (P = .007). Freedom from bronchiolitis obliterans syndrome (BOS) was 87%, 75%, and 72% at 1, 3, and 5 years, respectively. BOS was more common and appeared earlier in the Arab than in the Jewish population (P = .012, P = .007). Additionally, prolonged time free of BOS correlated with male gender (P = .039), older age (P < .001), absence of liver disease (P = .012), and higher BMI 1 year after transplantation (P < .001). CONCLUSIONS: Clinically important determinants for survival include BMI pre- and 1-year post-transplantation and improved freedom from BOS. Arab ethnicity correlated with higher incidence and earlier onset of BOS compared to Jewish ethnicity in Israel.

Real-life comparison of three general paediatric wards showed similar outcomes for children with bronchiolitis despite different treatment regimens.

AIM: This study evaluated the effectiveness of three different treatments for bronchiolitis in a tertiary paediatric facility. METHODS: Patients with bronchiolitis who were younger than two years of age and were randomly allocated to three general wards at Schneider Children's Medical Center, Israel, after admission were included. Different treatment protocols in the wards were retrospectively compared. RESULTS: The study comprised 286 children. The clinical and laboratory parameters on admission were similar between the wards. In Ward C where nebulised hypertonic saline was infrequently administered (6.7%), the mean number of days with oxygen saturation under 92% and the meanlength of hospital stay (1.8 and 3.8 days) were significantly lower than Ward A (2.8 and 5.3 days) and Ward B, (2.9 and 4.7 days) where nebulised hypertonic saline was given more frequently (38.7%-74.7%). Multivariate analysis indicated that low saturation on admission, leukocytosis and use of nebulised hypertonic saline or adrenalin were independent predictors of a longer period of desaturation and hospital stay. CONCLUSION: Different treatment protocols for bronchiolitis were used in three paediatric wards in this real-life study. No treatment regimen proved superior. Inhalations of hypertonic saline or adrenaline were associated with a longer hospital stay.

Pseudomonas aeruginosa identified as a key pathogen in hospitalised children with aspiration pneumonia and a high aspiration risk.

AIM: Data on the causative pathogens and optimal empirical therapy of aspiration pneumonia in children are limited. This study sought to describe the bacteriology of aspiration pneumonia in hospitalised children with a high aspiration risk. METHODS: Respiratory tract specimens were prospectively collected using the induced sputum technique from children with a high aspiration risk who were hospitalised for aspiration pneumonia in a tertiary paediatric medical centre from 2009 to 2014. Clinical, microbiological and treatment data were recorded and analysed for each admission. RESULTS: The cohort comprised 50 children with 235 hospital admissions. Of the 183 respiratory tract cultures performed, 110 were positive for bacteria, with 169 isolates, mostly Gram-negative. The most common Gram-negative pathogen was Pseudomonas aeruginosa. If patients had Pseudomonas aeruginosa isolation, the risk of them having the pathogen again was 81%. The multivariate analysis showed that the use of antibiotic prophylaxis and number of hospitalisations were significantly associated with Pseudomonas aeruginosa isolation. CONCLUSION: Gram-negative bacilli, especially Pseudomonas aeruginosa, were the major causative agents of paediatric aspiration pneumonia in our study. Empiric antipseudomonas treatment should be considered, particularly in patients who are receiving antibiotic prophylaxis, have experienced recurrent hospitalisations or with previous respiratory cultures that showed Pseudomonas aeruginosa isolation.

Acquired tracheoesophageal fistula following rubber toy ingestion.

We depict an uncommon presentation of rubber toy ingestion which remained impacted in the esophagus for months, gradually eroding the mucosa, and ultimately causing a traumatic acquired tracheoesophageal fistula.

Wearing face masks while climbing stairs influences respiratory physiology.

During the COVID-19 pandemic wearing face masks was mandatory. Nowadays, face masks are still encouraged indoors, especially in hospitals. People climbing stairs with masks describe unpredictable dyspnea. In this study, healthy adults climbed 5 floors with and without a mask. Various cardio-respiratory parameters were measured, including O2-saturation (O2-Sat) and end-tidal CO2(EtCO2), at baseline and on the top floor. Subjective indexes, such as Borg's scale, were evaluated. Thirty-two volunteers (16 males), median age 39 years (IQR 32.5-43), median BMI = 23.6 (IQR 21.5-25.1), with good fitness levels, participated. Comparing baseline to end-activity, median (IQR): O2-Sat change was -1.0% (-2-0) without mask, versus -3.0% (-4-0) with mask,p= 0.003; EtCO2+ 7.0 (+3.3-+9) without mask, versus +8.0 (+6-+12) with mask,p= 0.0001. Hypercarbia was seen in 5 (15.6%) participants without mask, median = 48 mmHg (IQR 47.5-51), and in 11 (34%) participants with mask, median = 50 mmHg (IQR 47-54),p< 0.001. Desaturation (O2-Sat < 95%) was seen in 5 (15.6%) participants without mask, median = 94% (IQR 93%-94%), and in 10 (31%) participants with mask, median = 91.5% (IQR 90%-93%),p= 0.06. Regression analysis demonstrated that only male sex was significantly associated with abnormal EtCO2(OR = 26.4, 95% CI = 1.9-366.4,p= 0.005). Ascent duration increased from median (IQR) of 94 s (86-100) without mask to 98 s (89-107) with mask,p< 0.001. Borg's scale of perceived exertion (range 0-10) increased from median (IQR) of 3.0 (2.5-3.87) without mask to 4.0 (3.0-4.37) with mask,p< 0.001. To conclude, during routine daily activities, such as stair-climbing, face masks cause dyspnea, and have measurable influences on ventilation, including true desaturation and hypercapnia, especially in males.

Eradication of Nontuberculous Mycobacteria in People with Cystic Fibrosis Treated with Elexacaftor/Tezacaftor/Ivacaftor: A Multicenter Cohort Study.

BACKGROUND: The prevalence of nontuberculous mycobacteria (NTM) infections is rising in people with cystic fibrosis (pwCF). NTM infection, especially infection with Mycobacterium abscessus complex (MABC), is commonly associated with severe lung deterioration. The current treatment modalities, including multiple intravenous antibiotics, frequently fail to achieve airway eradication. Although treatment with elexacaftor/tezacaftor/ivacaftor (ETI) has been shown to modulate the lung microbiome, data regarding its role in eradicating NTM in pwCF is lacking. Our aim was to evaluate the impact of ETI on the rate of NTM eradication in pwCF. METHODS: This retrospective multicenter cohort study included pwCF from five CF centers in Israel. PwCF aged older than 6 who had at least one positive NTM airway culture in the past two years and were treated with ETI for at least one year were included. The annual NTM and bacterial isolations, pulmonary function tests, and body mass index were analyzed before and after ETI treatment. RESULTS: Fifteen pwCF were included (median age 20.9 years, 73.3% females, 80% pancreatic insufficient). In nine patients (66%) NTM isolations were eradicated following treatment with ETI. Seven of them had MABC. The median time between the first NTM isolation and treatment with ETI was 2.71 years (0.27-10.35 years). Eradication of NTM was associated with improved pulmonary function tests (p<0.05). CONCLUSIONS: For the first time, we report successful eradication of NTM, including MABC, following treatment with ETI in pwCF. Additional studies are needed to assess whether treatment with ETI can result in the long-term eradication of NTM.

Cardiopulmonary exercise testing in adolescence following extremely premature birth.

BACKGROUND: Although extremely premature birth disrupts lung development, adolescent survivors of extreme prematurity show good clinical and physiologic outcomes. Cardiopulmonary limitations may not be clinically evident at rest. Data regarding exercise limitation in adolescents following preterm birth in the postsurfactant era are limited. RESEARCH QUESTION: What are the long-term effects of bronchopulmonary dysplasia (BPD) and extreme prematurity (<29 weeks) on ventilatory response during exercise in adolescents in the postsurfactant era? STUDY DESIGN AND METHODS: We followed a longitudinally recruited cohort of children aged 13-19 years who were born at a gestational age of <29 weeks (study group - SG). We compared the cardiopulmonary exercise testing (CPET) results of those with and without BPD, to their own CPET results from elementary school age (mean 9.09 ± 1.05 years). RESULTS: Thirty-seven children aged 15.73 ± 1.31 years, mean gestational age 26 weeks ( ± 1.19), completed the study. CPET parameters in adolescence were within the normal range for age, including mean V̇O2 peak of 91% predicted. The BPD and non-BPD subgroups had similar results. In the longitudinal analysis of the SG, improvement was observed in adolescence, compared with elementary school age, in breathing reserve (36.37 ± 18.99 vs. 26.58 ± 17.92, p = 0.044), tidal volume as a fraction of vital capacity achieved at maximal load (0.51 ± 0.13 vs. 0.37 ± 0.08, p < 0.001), and respiratory exchange ratio at maximal load (1.18 ± 0.13 vs. 1.11 ± 0.10, p = 0.021). INTERPRETATION: In the current cohort, adolescents born extremely premature have essentially normal ventilatory response during exercise, unrelated to BPD diagnosis. CPET results in this population improve over time.

Maternal and fetal outcomes in multiparous women with Cystic Fibrosis.

BACKGROUND: Quality of life and survival in Cystic Fibrosis (CF) have improved dramatically, making family planning a feasible option. Maternal and perinatal outcomes in women with CF (wwCF) are similar to those seen in the general population. However, the effect of undergoing multiple pregnancies is unknown. METHODS: A multinational-multicenter retrospective cohort study. Data was obtained from 18 centers worldwide, anonymously, on wwCF 18-45 years old, including disease severity and outcome, as well as obstetric and newborn complications. Data were analyzed, within each individual patient to compare the outcomes of an initial pregnancy (1st or 2nd) with a multigravid pregnancy (≥3) as well as secondary analysis of grouped data to identify risk factors for disease progression or adverse neonatal outcomes. Three time periods were assessed - before, during, and after pregnancy. RESULTS: The study population included 141 wwCF of whom 41 (29%) had ≥3 pregnancies, "multiparous". Data were collected on 246 pregnancies, between 1973 and 2020, 69 (28%) were multiparous. A greater decline in ppFEV1 was seen in multiparous women, primarily in pancreatic insufficient (PI) wwCF and those with two severe (class I-III) mutations. Multigravid pregnancies were shorter, especially in wwCF over 30 years old, who had high rates of prematurity and newborn complications. There was no effect on pulmonary exacerbations or disease-related complications. CONCLUSIONS: Multiple pregnancies in wwCF are associated with accelerated respiratory deterioration and higher rates of preterm births. Therefore, strict follow-up by a multidisciplinary CF and obstetric team is needed in women who desire to carry multiple pregnancies.

Influenza vaccination in children with pulmonary disease during the COVID-19 pandemic.

INTRODUCTION: Influenza is associated with considerable respiratory morbidity and mortality. Healthcare authorities recommend immunization of all children as vaccinations protect vulnerable populations, minimize influenza triggered asthma attacks, and reduced the burden of respiratory illnesses during the SARS-CoV-2 pandemic. Medical professionals should counsel parents of children with chronic lung disease to receive annual influenza vaccinations as part of supportive care. We aimed to describe adherence to influenza vaccination in respiratory patients and identify potential reasons for non-vaccination. METHODS: This study included questionnaires reviewing personal experience and beliefs regarding influenza vaccination, provided by parents of patients who visited the Pediatric Pulmonary Institute at Schneider Children's Medical Center with their children, during March-August 2021. RESULTS: Of 198 parents who completed our questionnaire, 114 (57.3 %) vaccinated their children against influenza during that year. Average age was 6.9 ± 4.5 years. Demographic data were similar between the vaccinated and unvaccinated groups. Influenza vaccination rates differed significantly between parents who received an explanation from their primary physician and those who did not (65.4 % vs. 43.7 %, respectfully, p = 0.003), and parents who received explanations from a pulmonary specialist and those who did not (77.3 % vs. 48.8 %, respectively, p = 0.004). The combined recommendation of a primary physician and pulmonologist translated to a significantly higher vaccination rate among those who received such recommendations, as compared to those who did not (p < 0.001). Parents who believed in vaccine efficacy and safety were more likely to vaccinate their children (p < 0.001). Factors significantly affecting the decision of the parents to have their child vaccinated were their knowledge, beliefs, and conceptions about the vaccine. CONCLUSIONS: Pediatric respiratory patients' influenza vaccination rate was 57 %. Major factors encouraging vaccination were correct parental knowledge and receiving recommendations from their primary physician\pulmonologist. This emphasizes the need for providing patients with information, by first explaining the vaccine's importance to physicians.

Dynamic Hyperinflation While Exercising-A Potential Predictor of Pulmonary Deterioration in Cystic Fibrosis.

BACKGROUND: Lung function deterioration in cystic fibrosis (CF) is typically measured by a decline in the forced expiratory volume in one second (FEV1%), which is thought to be a late marker of lung disease. Dynamic hyperinflation (DH) is seen in obstructive lung diseases while exercising. Our aim was to assess whether DH could predict pulmonary deterioration in CF; a secondary measure was the peak VO2. METHODS: A retrospective study was conducted of people with CF who performed cardiopulmonary exercise tests (CPETs) during 2012-2018. The tests were classified as those demonstrating DH non-DH. Demographic, genetic, and clinical data until 12.2022 were extracted from patient charts. RESULTS: A total of 33 patients aged 10-61 years performed 41 valid CPETs with valid DH measurements; sixteen (39%) demonstrated DH. At the time of the CPETs, there was no difference in the FEV1% measurements between the DH and non-DH groups (median 83.5% vs. 87.6%, respectively; p = 0.174). The FEV1% trend over 4 years showed a decline in the DH group compared to the non-DH group (p = 0.009). A correlation was found between DH and the lung clearance index (LCI), as well as the FEV1% (r = 0.36 and p = 0.019 and r = -0.55 and p = 0.004, respectively). Intravenous (IV) antibiotic courses during the 4 years after the CPETs were significantly more frequent in the DH group (p = 0.046). The peak VO2 also correlated with the FEV1% and LCI (r = 0.36 and p = 0.02 and r = -0.46 and p = 0.014, respectively) as well as with the IV antibiotic courses (r = -0.46 and p = 0.014). CONCLUSIONS: In our cohort, the DH and peak VO2 were both associated with lung function deterioration and more frequent pulmonary exacerbations. DH may serve as a marker to predict pulmonary deterioration in people with CF.

High flow nasal cannula therapy in the pediatric home setting.

BACKGROUND: High-flow nasal cannula (HFNC) therapy may be better tolerated than traditional noninvasive ventilation (NIV) and is rapidly gaining acceptance in pediatric acute care. In Israel, HFNC is approved for domestic use. We aim to describe its indications, efficacy, parental satisfaction, and safety. METHODS: Retrospective study of children treated with home HFNC therapy in three pediatric centers. Data included demographic parameters, indication of use, weight and days of hospitalization before and after initiation. Safety, tolerability, and parental satisfaction were assessed via standardized telephone questionnaire. RESULTS: Median (interquartile range [IQR]) age of initiating home HFNC in 75 children was 8.3 (2.2, 29.6) months. Indications were obstructive sleep apnea (33; 44%), airway malacia (19; 25%), chronic lung disease (15; 20%), neuromuscular disease (4; 5%), and postextubation support (4; 5%). Weight standard deviation score rose from -2.3 pre-HFNC to -1.7 at 6.7 months post-HFNC initiation, p < 0.001. Hospital admission days during the 2 months pre- versus post-HFNC initiation were 22 (5.5, 60) and 5 (0, 14.7) respectively, p < 0.008. Median (IQR) parental satisfaction score was 5/5 (4, 5). Fifty of 60 (83%) respondents would recommend home HFNC to other families in a similar situation. There were no serious adverse events. CONCLUSION: In our population, domestic HFNC appeared safe and well tolerated for a variety of indications. Its introduction was associated with improved weight gain, fewer hospitalization days and high parental satisfaction. Further work is required to characterize groups of children most likely to benefit from HFNC, as opposed to traditional modes of NIV.

Treatment effects of Elexacaftor/Tezacaftor/Ivacaftor in people with CF carrying non-F508del mutations.

BACKGROUND: In vitro studies have demonstrated rescue of CFTR function with Elexacaftor/Tezacaftor/Ivacaftor (ETI) in several mutations other than F508del. However, clinical efficacy was not tested in vivo in people with CF (pwCF) carrying mutations other than F508del. We report effects of treatment with ETI in pwCF with non-F508del mutations. METHODS: We retrospectively analyzed pwCF with non-F508del mutations who received treatment with ETI. We evaluated sweat chloride, nutritional status, spirometry, antibiotic treatment, and pulmonary exacerbations (PEx), at baseline and 3-6 months after commencing treatment with ETI. RESULTS: We included 16 pwCF, including eight without previous use of CFTR modulators. Median time on treatment was 5.3 (range, 1.8-7.7) months. Compared to baseline, in the "naïve" group sweat chloride concentration was reduced from 113.0 (98-129) to 64.0 (32-97) mEq/L (n=7; median (IQR), p=0.018), and rate of pulmonary exacerbations declined from a median of 1.5 (IQR 1, 2.75) in the previous year to 0 (0,0) (p= 0.019) with a significant decline in annualized days with antibiotics (oral + parenteral) per year: 36 (17.5; 42) in the year before to 0 (0,0) (median (IQR), p= 0.027). Mean FEV1% changed from 66.3±25 to 72.4±29 % (mean ± SD, p=0.058). In the group of patients previously treated with Ivacaftor or Tezacaftor/Ivacaftor, we didn't observe significant improvements in any of the parameters. CONCLUSIONS: We demonstrate the clinical efficacy of ETI in pwCF carrying CFTR processing non-F508del mutations which are predicted to respond by in vitro studies. Our results support routine clinical use of ETI in this patient group.

Evaluation of sputum cultures in children with spinal Muscular atrophy.

BACKGROUND: Spinal Muscular Atrophy (SMA) is a severe neuromuscular disorder. Despite increased survival due to novel therapies, morbidity from respiratory complications still persists. We aim to describe these patients' sputum cultures as an expression of chronic infectious airway disease. METHODS: Retrospective review of medical records of all children with SMA followed at the multidisciplinary respiratory neuromuscular clinic at Schneider Childrens' Medical Center of Israel over a 16-year period. Sputum cultures were obtained during routine visits or pulmonary exacerbations. RESULTS: Sixty-one SMA patients, aged 1 month to 21 years, were included in this cohort. Of these, sputum cultures were collected from 41 patients. Overall, 288 sputum cultures were obtained, and 98 (34%) were negative for bacterial growth. For the first culture taken from each patient, 12 out of 41 (29%) were sterile. The most common bacteria were pseudomonas aeruginosa (PSA) (38%) and staphylococcus aureus (19.6%). PSA was found in SMA type I patients more frequently than in type II patients (15/26 = 58% vs 4/13 = 31%, p < 0.001). PSA infection was positively associated with noninvasive ventilation, recurrent atelectasis, recurrent pneumonias, swallowing difficulties, but no significant association was found with cough assist machine usage. The incidence of positive cultures did not differ between those treated with Onasemnogene abeparvovec or Nusinersen compared to those without treatment, but the age of first PSA isolation was slightly older with Nusinersen treatment (p = 0.01). CONCLUSIONS: Airway bacterial colonization is common in SMA type I patients and is not decreased by Onasemnogene abeparvovec or Nusinersen treatment.