Long-term safety and efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis and at least one F508del allele: 144-week interim results from a 192-week open-label extension study.

BACKGROUND: In two pivotal phase 3 trials, up to 24 weeks of treatment with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was efficacious and safe in patients with cystic fibrosis (CF) ≥12 years of age who have at least one F508del allele. The aim of this study is to assess long-term safety and efficacy of ELX/TEZ/IVA in these patients. METHODS: In this phase 3, open-label, single-arm extension study, participants with F508del-minimal function (from a 24-week parent study; n=399) or F508del-F508del (from a 4-week parent study; n=107) genotypes receive ELX/TEZ/IVA at the same dose (ELX 200 mg once daily, TEZ 100 mg once daily and IVA 150 mg every 12 h). The primary end-point is safety and tolerability. A prespecified interim analysis was conducted when the last participant reached the Week 144 visit. RESULTS: At the Week 144 interim analysis, mean duration of exposure to ELX/TEZ/IVA in the extension study was 151.1 weeks. Exposure-adjusted rates of adverse events (AEs) (586.6 events per 100 participant-years) and serious AEs (22.4 events per 100 participant-years) were lower than in the ELX/TEZ/IVA treatment group in the 24-week parent study (1096.0 and 36.9 events per 100 participant-years, respectively); most participants had AEs classified as mild (16.4% of participants) or moderate (60.3% of participants) in severity. 14 participants (2.8%) had AEs that led to treatment discontinuation. Following initiation of ELX/TEZ/IVA, participants had increases in forced expiratory volume in 1 s (FEV1) percentage predicted, Cystic Fibrosis Questionnaire-Revised respiratory domain score and body mass index, and had decreases in sweat chloride concentration and pulmonary exacerbation rates that were maintained over the interim analysis period. The mean annualised rate of change in FEV1 % pred was +0.07 (95% CI -0.12-0.26) percentage points among the participants. CONCLUSIONS: ELX/TEZ/IVA was generally safe and well tolerated, with a safety profile consistent with the 24-week parent study. Participants had sustained improvements in lung function, respiratory symptoms, CF transmembrane conductance regulator function, pulmonary exacerbation rates and nutritional status. These results support the favourable safety profile and durable, disease-modifying clinical benefits of ELX/TEZ/IVA.

A systematic review on the use of bacteriophage in treating Staphylococcus aureus and Pseudomonas aeruginosa infections in cystic fibrosis.

BACKGROUND: Respiratory infections caused by Staphylococcus aureus and Pseudomonas aeruginosa are a major concern for cystic fibrosis (CF) patients due to increasing antibiotic resistance. Bacteriophages, which are viruses that selectively target and kill bacteria, are being studied as an alternative treatment for these infections. This systematic review evaluates the safety and effectiveness of bacteriophages for the treatment of CF-related infections caused by S. aureus and/or P. aeruginosa. We conducted a search for original, published articles in the English language up to March 2023. Studies that administered bacteriophages via intravenous, nebulised, inhaled, or intranasal routes were included, with no comparators required. In vitro and in vivo studies were eligible for inclusion, and only animal in vivo studies that utilised a CF transmembrane conductance regulator (CFTR) animal model were included. Bacteriophage treatment resulted in a decrease in bacterial load in both humans and animals infected with P. aeruginosa. Complete eradication of P. aeruginosa was only observed in one human subject. Additionally, there was a reduction in biofilm, improvement in resistance profile, and reduced pulmonary exacerbations in individual case reports. Evidence suggests that bacteriophage therapy may be a promising treatment option for CF-related infections caused by P. aeruginosa and S. aureus. However, larger and more robust trials are needed to establish its safety and efficacy and create necessary evidence for global legislative frameworks.

Approaches to the management of haemoptysis in young people with cystic fibrosis.

Haemoptysis occurs in up to 25 % of young people with Cystic fibrosis (CF) [1]. We undertook a literature review and described the management approach to haemoptysis in CF between 2010 and 2020 at an Australian tertiary paediatric centre, The Children's Hospital Westmead, Sydney, New South Wales, using a retrospective review of the medical records which identified 67 episodes. Sixty episodes met inclusion criteria, including 31 patients. Using the US CF Foundation guidelines, episodes were classified as scant (53.3 %), moderate (38.3 %) or massive (8.3 %). Fifty-two percent of patients were female, mean age at presentation was 15.4 years (SD+/- 2.4) and 58 % were homozygous for the Fdel508 genotype. Twelve episodes (9 patients) required bronchial artery embolization (BAE). BAE was used in all cases of massive haemoptysis 5/5 (100 %), 6/23 (22 %) episodes of moderate and 1/32 (3 %) episode of scant haemoptysis as an elective procedure for recurrent haemoptysis. Our literature review and institutional experience highlights the need for up-to-date management guidelines in the management of haemoptysis in Cystic Fibrosis. Based on our experience, we provide a proposed algorithm to help guide the management of haemoptysis in CF.

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.

Personalized tobramycin dosing in children with cystic fibrosis: a comparative clinical evaluation of log-linear and Bayesian methods.

BACKGROUND: Children with cystic fibrosis (CF) pulmonary exacerbations receive IV tobramycin therapy, with dosing guided by either log-linear regression (LLR) or Bayesian forecasting (BF). OBJECTIVES: To compare clinical and performance outcomes for LLR and BF. PATIENTS AND METHODS: A quasi-experimental intervention study was conducted at a tertiary children's hospital. Electronic medical records were extracted (from January 2015 to September 2021) to establish a database consisting of pre-intervention (LLR) and post-intervention (BF) patient admissions and relevant outcomes. All consecutive patients treated with IV tobramycin for CF pulmonary exacerbations guided by either LLR or BF were eligible. RESULTS: A total of 376 hospital admissions (LLR = 248, BF = 128) for CF pulmonary exacerbations were included. Patient demographics were similar between cohorts. There were no significant differences found in overall hospital length of stay, rates of re-admission within 1 month of discharge or change in forced expiratory volume in the first second (Δ FEV1) at the end of tobramycin treatment. Patients treated with LLR on average had twice the number of therapeutic drug monitoring (TDM) blood samples collected during a single hospital admission. The timeframe for blood sampling was more flexible with BF, with TDM samples collected up to 16 h post-tobramycin dose compared with 10 h for LLR. The tobramycin AUC0-24 target of ≥100 mg/L·h was more frequently attained using BF (72%; 92/128) compared with LLR (50%; 124/248) (P < 0.001). Incidence of acute kidney injury was rare in both groups. CONCLUSIONS: LLR and BF result in comparable clinical outcomes. However, BF can significantly reduce the number of blood collections required during each admission, improve dosing accuracy, and provide more reliable target concentration attainment in CF children.

Update in management of paediatric primary spontaneous pneumothorax.

Paediatric spontaneous pneumothorax (PSP) management continues to lack paediatric-specific guideline recommendations. There have been increasing reports of paediatric retrospective case studies supplemented by important well designed RCT (predominantly) adult studies. Taken together, these suggest that conservative management may have an increasing role to play in the management of PSP and that aspiration may have limited utility as a first line intervention. Our local experience, as part of a multicentre retrospective analysis and subsequent audit of management since, corroborates recent published data: it highlights an increasing trend towards conservative management in spontaneous pneumothorax with similar rates of recurrence, compared to intervention, and low use of aspiration with similarly low success rates. We have therefore updated our local practice guidelines and share these with readers. Specifically, we have removed aspiration in the management of primary spontaneous pneumothorax and reserved intervention for children who are clinically unstable or show evidence of increasing air leak irrespective of pneumothorax size. Whilst the success of this change in clinical practice will need to be reviewed in the next 5-10 years, the overall low incidence of the condition, demands a multicentre, and probably multinational, collaborative approach to allow the best chance of obtaining definitive evidence to guide clinical paediatric management.

Transition to adult care in cystic fibrosis: The challenges and the structure.

In developed countries, it is projected that there will be a 70% increase in the number of adults living with Cystic Fibrosis (CF) between 2010 and 2025. This shift in demographics highlights the importance of high-quality transition programmes with developmentally appropriate integrated health care services as the individual moves through adolescence to adulthood. Adolescents living with CF face additional and unique challenges that may have long-term impacts on their health, quality of life and life-expectancy. CF specific issues around socially challenging symptoms, body image, reproductive health and treatment burden differentiate people with CF from their peers and require clinicians to identify and address these issues during the transition process. This review provides an overview of the health, developmental and psychosocial challenges faced by individuals with CF, their guardians and health care teams considering the fundamental components and tools that are required to build a transition programme that can be tailored to suit individual CF clinics.

Pulmonary function testing during SARS-CoV-2: An ANZSRS/TSANZ position statement.

The Thoracic Society of Australia and New Zealand (TSANZ) and the Australian and New Zealand Society of Respiratory Science (ANZSRS) commissioned a joint position paper on pulmonary function testing during coronavirus disease 2019 (COVID-19) in July 2021. A working group was formed via an expression of interest to members of both organizations and commenced work in September 2021. A rapid review of the literature was undertaken, with a 'best evidence synthesis' approach taken to answer the research questions formed. This allowed the working group to accept findings of prior relevant reviews or societal document where appropriate. The advice provided is for providers of pulmonary function tests across all settings. The advice is intended to supplement local infection prevention and state, territory or national directives. The working group's key messages reflect a precautionary approach to protect the safety of both healthcare workers (HCWs) and patients in a rapidly changing environment. The decision on strategies employed may vary depending on local transmission and practice environment. The advice is likely to require review as evidence grows and the COVID-19 pandemic evolves. While this position statement was contextualized specifically to the COVID-19 pandemic, the working group strongly advocates that any changes to clinical/laboratory practice, made in the interest of optimizing the safety and well-being of HCWs and patients involved in pulmonary function testing, are carefully considered in light of their potential for ongoing use to reduce transmission of other droplet and/or aerosol borne diseases.

Paediatric pneumonia in high-income countries: Defining and recognising cases at increased risk of severe disease.

World Health Organisation definitions of pneumonia severity are routinely used in research. In high income health care settings with high rates of pneumococcal vaccination and low rates of mortality, malnutrition and HIV infection, these definitions are less applicable. National guidelines from leading thoracic and infectious disease societies describe 'severe pneumonia' according to criteria derived from expert consensus rather than a robust evidence base. Contemporary cohort studies have used clinical outcomes such as intensive care therapy or invasive procedures for complicated pneumonia, to define severe disease. Describing severe pneumonia in such clinically relevant terms facilitates the identification of risk factors associated with worsened disease and the subsequently increased morbidity, and need for tertiary level care. The early recognition of children at higher risk of severe pneumonia informs site of care decisions, antibiotic treatment decisions as well as guiding appropriate investigations. Younger age, malnutrition, comorbidities, tachypnoea, and hypoxia have been identified as important associations with 'severe pneumonia' by WHO definition. Most studies have been performed in low-middle income countries and whilst they provide some insight into those at risk of mortality or treatment failure, their generalisability to the high-income setting is limited. There is a need to determine more precise definitions and criteria for severe disease in well-resourced settings and to validate factors associated with intensive care admission or invasive procedures to enhance the early recognition of those at risk.

Surfactant protein disorders in childhood interstitial lung disease.

Surfactant, which was first identified in the 1920s, is pivotal to lower the surface tension in alveoli of the lungs and helps to lower the work of breathing and prevents atelectasis. Surfactant proteins, such as surfactant protein B and surfactant protein C, contribute to function and stability of surfactant film. Additionally, adenosine triphosphate binding cassette 3 and thyroid transcription factor-1 are also integral for the normal structure and functioning of pulmonary surfactant. Through the study and improved understanding of surfactant over the decades, there is increasing interest into the study of childhood interstitial lung diseases (chILD) in the context of surfactant protein disorders. Surfactant protein deficiency syndrome (SPDS) is a group of rare diseases within the chILD group that is caused by genetic mutations of SFTPB, SFTPC, ABCA3 and TTF1 genes.Conclusion: This review article seeks to provide an overview of surfactant protein disorders in the context of chILD. What is Known: • Surfactant protein disorders are an extremely rare group of disorders caused by genetic mutations of SFTPB, SPTPC, ABCA3 and TTF1 genes. • Given its rarity, research is only beginning to unmask the pathophysiology, inheritance, spectrum of disease and its manifestations. What is New: • Diagnostic and treatment options continue to be explored and evolve in these conditions. • It is, therefore, imperative that we as paediatricians are abreast with current development in this field.

Bronchopulmonary dysplasia: A review of the pulmonary sequelae in the post-surfactant era.

We describe the respiratory complications of bronchopulmonary dysplasia (BPD) in childhood and adolescence. The pathophysiology of bronchopulmonary dysplasia has evolved in the era of modern neonatal intensive care. In this review, we aim to summarise the contemporary evidence base and describe the common respiratory morbidities related to BPD including; home oxygen therapy, rehospitalisation, asthma and exercise limitation.

Quantitative assessment of nocturnal neural respiratory drive in children with and without obstructive sleep apnoea using surface EMG.

NEW FINDINGS: What is the central question of this study? Recent studies have suggested potential utility of non-normalized respiratory muscle EMG as an index of neural respiratory drive (NRD). Whether NRD measured using non-normalized surface EMG of the lateral chest wall overlying the diaphragm (sEMGcw) recorded during nocturnal clinical polysomnography can differentiate children with and without obstructive sleep apnoea (OSA) is not known. What is the main finding and its importance? Non-normalized sEMGcw was increased in children with OSA and an additional group of snoring children without OSA but subjectively increased respiratory effort compared with primary snorers. The sEMGcw has potential clinical utility in evaluation of children with sleep-disordered breathing as an objective, non-invasive, non-volitional marker of NRD. ABSTRACT: Our aim was to investigate whether neural respiratory drive measured by non-normalized surface EMG recorded from the chest wall overlying the diaphragm (sEMGcw) differentiates children with and without obstructive sleep apnoea (OSA). Polysomnography data of children aged 0-18 years were divided into the following three groups: (i) primary snorers (PS); (ii) snoring children without OSA but with increased work of breathing (incWOB; subjective physician report of increased respiratory effort during sleep); and (iii) children with OSA [obstructive apnoea-hypopnoea index (OAHI) >1 h-1 ]. Excerpts of sEMGcw obtained during tidal unobstructed breathing from light, deep and rapid eye movement sleep were exported for quantitative analysis. Overnight polysomnography data from 45 PS [median age 4.4 years (interquartile range 3.0-7.7 years), OAHI 0 h-1 (0.0-0.2 h-1 )], 19 children with incWOB [age 2.8 years (2.4-5.7 years), OAHI 0.1 h-1 (0.0-0.4 h-1 )] and 27 children with OSA [age 3.6 years (2.6-6.2 years), OAHI 3.7 h-1 (2.3-6.9 h-1 )] were analysed. The sEMGcw was higher in those with OSA [8.47 µV (5.98-13.07 µV); P < 0.0001] and incWOB [8.97 µV (5.94-13.43 µV); P < 0.001] compared with PS [4.633 µV (2.98-6.76 µV)]. There was no significant difference in the sEMGcw between children with incWOB and OSA (P = 0.78). Log sEMGcw remained greater in children with OSA and incWOB compared with PS after age, body mass index centiles, sleep stages and sleep positions were included in the mixed linear models (P < 0.0001). The correlation between sEMGcw and OAHI in children without OSA was small (rs  = 0.254, P = 0.04). The sEMGcw is increased in children with OSA and incWOB compared with PS.

Associations between circulating inflammatory markers, diabetes type and complications in youth.

BACKGROUND: Inflammation is implicated in the pathogenesis of diabetes and its complications in adults. Little is known about the relative contribution of inflammation in common types of diabetes in youth: type 1 diabetes (T1D), type 2 diabetes (T2D), and cystic fibrosis-related diabetes (CFRD). This study investigates inflammatory markers by diabetes type and complication status, and assesses indicators of inflammation and complications. METHODS: A cross-sectional study of 134 T1D, 32 T2D, 32 CFRD and 48 subjects without diabetes (including 11 with CF and normal glucose tolerance) was undertaken. Inflammation was assessed by sE-selectin by ELISA, hsCRP by turbidimetry, WCC and ESR. Nephropathy was defined by albuminuria, autonomic neuropathy by heart rate variability, and peripheral neuropathy by vibration and thermal threshold testing and retinopathy by seven-field stereoscopic fundus photography. Descriptive statistics, parametric and non-parametric ANOVA and regression analyses were performed, with significance at P < .05. RESULTS: Of 198 diabetic participants; 49% female, mean (SD) age, median diabetes duration and median HbA1c were 16 (2.5) and 6 (3-9) years, and 8.1 (6.9-9.3)%, respectively. All inflammatory markers were lower in T1D than in other diabetes groups (P < .05) but higher than in non-diabetic controls. T2D (n = 32) and CFRD (n = 32) subjects had comparable elevated levels of inflammation. Body mass index (BMI) was a strong independent explanatory variable of inflammation. In multivariate analysis, hsCRP and ESR were associated with complications in addition to HbA1c, BMI, and diastolic BP. CONCLUSIONS: Circulating inflammatory markers are elevated in adolescents with diabetes, being higher and comparable in T2D and CFRD than in T1D. Inflammation is independently associated with diabetes complications, consistent with inflammation driving vascular pathology in diabetes.

Disease caused by non-tuberculous mycobacteria in children with cystic fibrosis.

Non-tuberculous mycobacterial (NTM) (especially M. abscessus complex) infections pose a considerable challenge in the management of lung disease in patients with cystic fibrosis (CF). The apparent increase in prevalence is likely multifactorial. Emergent evidence of patient-to-patient transmission and isolation of highly resistant strains is a concern for all CF centers around the world. Treatment is often long and burdensome with multiple agents. Treatment side effects are frequent and can cause significant morbidity. Although consensus guidelines provide some direction, many units are faced with the challenges of: finding drug combinations for highly resistant strains; dealing with interruptions of treatment; discussing additional facilitating procedures in the form of gastrostomy and long-term vascular access devices; as well as supporting families emotionally and psychologically through the process.

Improving the quality of care for children with wheeze: The use of electronic asthma action plans and electronic pre-school wheeze action plans.

AIM: To measure the long-term improvement in the documented provision of an asthma action plan (AAP) to children with asthma and wheeze discharged from the Emergency Department following the introduction of the electronic AAP (eAAP) and to determine the need for an electronic pre-school wheeze action plan in our population. METHODS: A retrospective case note review, from July 2014 to June 2015, of all patients over 12 months old discharged from the Emergency Department or Emergency Medical Unit, with a discharge diagnosis of either asthma or wheeze. The primary outcome was the documentation of an AAP, either recorded electronically as an eAAP or a report of an AAP as part of the patient medical record. RESULTS: Two thousand three hundred and forty-two patients were included in the study, 926 with asthma and 1416 with wheeze. The median age was 3.3 years (interquartile range (IQR) 3.5, range 1-15.9 years). The median age of the children with asthma was 5.3 years (IQR 4.6) and of the children with wheeze was 2.5 years (IQR 2.0).Overall, 1683 (71.9%) children had a documented AAP, with a significant difference between those with a discharge diagnosis of asthma (85.9%) compared with wheeze (62.9%), P < 0.001. These results justified the design of the electronic pre-school wheeze action plan. CONCLUSIONS: The integration of an eAAP into the Emergency Department has resulted in a sustained improvement in the documented provision of an AAP to children with a discharge diagnosis of asthma. Children with a discharge diagnosis of wheeze are significantly less likely to receive an action plan.

Lung clearance index in cystic fibrosis subjects treated for pulmonary exacerbations.

Pulmonary exacerbations are important clinical events for cystic fibrosis (CF) patients. Studies assessing the ability of the lung clearance index (LCI) to detect treatment response for pulmonary exacerbations have yielded heterogeneous results. Here, we conduct a retrospective analysis of pooled LCI data to assess treatment with intravenous antibiotics for pulmonary exacerbations and to understand factors explaining the heterogeneous response.A systematic literature search was performed to identify prospective observational studies. Factors predicting the relative change in LCI and spirometry were evaluated while adjusting for within-study clustering.Six previously reported studies and one unpublished study, which included 176 pulmonary exacerbations in both paediatric and adult patients, were included. Overall, LCI significantly decreased by 0.40 units (95% CI -0.60- -0.19, p=0.004) or 2.5% following treatment. The relative change in LCI was significantly correlated with the relative change in forced expiratory volume in 1 s (FEV1), but results were discordant in 42.5% of subjects (80 out of 188). Higher (worse) baseline LCI was associated with a greater improvement in LCI (slope: -0.9%, 95% CI -1.0- -0.4%).LCI response to therapy for pulmonary exacerbations is heterogeneous in CF patients; the overall effect size is small and results are often discordant with FEV1.