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. Keywords: children; cystic fibrosis; elexacaftor; ivacaftor; tezacaftor

Bacterial Causes of Empyema in Children, Australia, 2007–2009

Most infections were caused by non–7-valent pneumococcal conjugate vaccine serotypes

Paediatric acute respiratory distress syndrome: consider the role of lymphatics

We present a case of a 7-day-old male infant with severe respiratory disease requiring venoarterial extracorporeal membrane oxygenation therapy with evidence of lymphangiectasia on lung biopsy. Differentiating primary versus secondary lymphangiectasis in this patient remains a riddle despite extensive investigations including an infective screen, lung biopsy and whole-genome sequencing. In addition to the standard therapies used in paediatric acute respiratory distress syndrome, such as lung-protective ventilation, permissive hypoxaemia and hypercarbia, nursing in the prone position, early use of muscle relaxants, rescue intravenous corticosteroids and broad-spectrum antibiotics, the patient was also given octreotide despite the absence of a chylothorax based on the theoretical benefit of altering the lymphatic flow. His case raises an interesting discussion around the role of lymphatics in the pathophysiology of paediatric and adult respiratory distress syndrome and prompts the exploration of novel agents which may affect lymphatic vessels used as an adjunctive therapy

Exercise testing in children with lung diseases

Exercise is an important aspect of health and development in children. By placing the pulmonary system under stress, exercise testing may reveal subtle dynamic abnormalities that are not apparent on conventional static pulmonary function tests. Furthermore, exercise testing assesses the functional impact of respiratory disease on children. Exercise testing has been used in children with a variety of respiratory diseases such as exercise induced bronchoconstriction, asthma, cystic fibrosis and bronchopulmonary dysplasia to assess the severity of disease as well as response to various interventions. Furthermore, there is good evidence that exercise testing is a useful tool to help determine prognosis in patients with cystic fibrosis. In addition to the clinical utility, exercise testing is also becoming an increasingly important outcome measure in research studies

Surgery in nontuberculous mycobacteria pulmonary disease

Medical treatment of pulmonary nontuberculous mycobacteria (NTM) disease has highly variable outcomes. Despite the use of multiple antibiotics, sputum clearance is often difficult to achieve, especially in cases with macrolide resistant NTM infection. Immunocompromised patients and those with structural lung disease are at increased risk, although occurrence in immunocompetent patients without structural lung disease is well recognised. Most pulmonary NTM disease involves Mycobacterium avium complex (MAC), but with enhanced identification multiple species have now been recognised as opportunistic pathogens. The observed increase in NTM disease, especially infection with multidrug-resistant Mycobacterium abscessus complex, is probably multifactorial. Surgery has been used as adjuvant treatment in patients with 1) focal disease that can be removed or 2) bothersome symptoms despite medical treatment that can be ameliorated. Early post-surgical mortality is low, but long-term morbidity and mortality are highly dependent on the degree of lung involvement and the residual lung function, the potency of medical treatment and the type of surgical intervention. In conjunction with antibiotic therapy, reported post-surgical sputum clearance was excellent, although publication bias should be considered. Bronchopleural fistulae were problematic, especially in pneumonectomy cases. Study results support the use of minimal resection surgery, in a carefully selected subgroup of patients with focal disease or persistent symptoms. Educational aims To critically review the literature describing the use of surgery in the treatment of pulmonary disease caused by nontuberculous mycobacteria (NTM). To assess the outcomes and complications observed with different surgical approaches used in the treatment of pulmonary NTM disease

Increased day-to-day variability of forced oscillatory resistance in poorly controlled or persistent pediatric asthma

BACKGROUND: Pediatric asthma lacks sensitive objective measures for asthma monitoring. The forced oscillation technique (FOT) offers strong feasibility across the pediatric age range, but relationships between FOT parameter day-to-day variability and pediatric asthma severity and control are unknown.METHODS: Day-to-day variability in FOT respiratory system resistance (Rrs) and respiratory system reactance (Xrs) compared with peak expiratory flow (PEF) were defined in 22 children with asthma (mean ± SD age, 10.4 ± 1.1 years) during a 5-day asthma camp. FOT was performed at 6 Hz in triplicate on each test occasion. Relationships between day-to-day FOT variability (expressed as within-subject SD [SDW ] and asthma control and severity (defined according to GINA [Global Initiative for Asthma] recommendations) were explored. For comparison, normal baseline FOT values and variability, measured on two occasions, were defined in a separate cohort of 38 healthy children (age, 9.5 ± 1.0 years).RESULTS: Day-to-day Rrs variability was greater in persistent (n = 16) vs intermittent (n = 6) asthma (mean SDW, 0.69 cm H O/L/s vs 0.39 cm H O/L/s; P ≤ .01). Day-to-day Rrs variability was increased in uncontrolled (n = 13) vs partly controlled asthma (n 5 9) (mean SDW, 0.75 cm H O/L/s vs 0.42 cm H O/L/s; P ≤ .05). PEF variability did not differentiate the groups. Day-to-day variability of Rrs and Xrs but not baseline values were increased in children with asthma vs control children (Rrs mean SDW, 0.61 cm H O/L/s vs 0.33 cm H O/L/s [ P ≤ .05]; Xrs mean SDW, 0.24 cm H O/L/s vs 0.15 cm H O/L/s [ P ≤ .05]).CONCLUSIONS: Increased day-to-day FOT variability exists in school-aged children with asthma. Day-to-day Rrs variability was associated with asthma severity and asthma control. FOT may be a useful objective monitoring tool in pediatric asthma and warrants further study .TRIAL REGISTRY: Australian and New Zealand Clinical Trials Registry; No.: ACTRN12614000885695; URL: Www.anzctr.org.au

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

Single-arm, open-labelled, safety and tolerability of intrabronchial and nebulised bacteriophage treatment in children with cystic fibrosis and Pseudomonas aeruginosa

Introduction Cystic fibrosis (CF) is a multisystem condition that is complicated by recurrent pulmonary infections requiring aggressive antibiotic treatment. This predisposes the patient to complications such as sensorineural hearing loss, renal impairment, hypersensitivity and the development of antibiotic resistance. Pseudomonas aeruginosa is one of the more common organisms which cause recurrent infections and result in greater morbidity and mortality in people living with CF. Bacteriophages have been identified as a potential alternative or adjunct to antibiotics. We hypothesise that bacteriophage therapy is a safe and well-tolerated treatment in children with CF infected with P. aeruginosa infection in their airways.Methods This single-arm, open-labelled, non-randomised trial will run for a maximum period of 36 months with up to 10 participants. Adolescents (≥12 years and &lt;18 years of age) who continue to shed P.aeruginosa (within 3 months of enrolment) despite undergoing eradication therapy previously, will be considered for this trial. Non-genetically modified bacteriophages that have demonstrated obligate lytic activity against each of the study participants’ P. aeruginosa strains will be selected and prepared according to a combination of established protocols (isolation, purification, sterility testing and packaging) to achieve close to good manufacturing practice recommendations. The selected bacteriophage will be administered endo-bronchially first under direct vision, followed by two times a day nebulisation for 7 days in addition to standard CF treatment (intravenous antibiotics, physiotherapy to be completed as inpatient for 10–14 days). Safety and tolerability will be defined as the absence of (1) fever above 38.5°C occurring within 1 hour of the administration of the nebulised bacteriophage, (2) a 10% decline in spirometry (forced expiratory volume in 1 s %) measured preadministration and postadministration of the first dose of nebulised bacteriophage. Clinical reviews including repeat sputum cultures and spirometry will be performed at 3, 6, 9 and 12 months following bacteriophage treatment.Ethics and dissemination Our clinical trial is conducted in accordance with (1) good clinical practice, (2) Australian legislation, (3) National Health and Medical Research Council guidelines for the ethical conduct of research.Trial registration number Australia and New Zealand Clinical Trial Registry (ACTRN12622000767707)