Unsupervised home spirometry is not equivalent to supervised clinic spirometry in children and young people with cystic fibrosis: Results from the CLIMB-CF study.

BACKGROUND: Handheld spirometry allows monitoring of lung function at home, of particular importance during the COVID-19 pandemic. Pediatric studies are unclear on whether values are interchangeable with traditional, clinic-based spirometry. We aimed to assess differences between contemporaneous, home (unsupervised) and clinic (supervised) spirometry and the variability of the former. The accuracy of the commercially available spirometer used in the study was also tested. METHODS: Data from participants in the Clinical Monitoring and Biomarkers to stratify severity and predict outcomes in children with cystic fibrosisc (CLIMB-CF) Study aged ≥ 6 years who had paired (±1 day) clinic and home forced expiratory volume in 1 s (FEV1 ) readings were analyzed. Variability during clinical stability over 6-months was assessed. Four devices from Vitalograph were tested using 1 and 3 L calibration syringes. RESULTS: Sixty-seven participants (median [interquartile range] age 10.7 [7.6-13.9] years) provided home and clinic FEV1 data pairs. The mean (SD) FEV1 % bias was 6.5% [±8.2%]) with wide limits of agreement (-9.6% to +22.7%); 76.2% of participants recorded lower results at home. Coefficient of variation of home FEV1 % during stable periods was 9.9%. Data from the testing of the handheld device used in CLIMB-CF showed a potential underread. CONCLUSION: In children and adolescents, home spirometry using hand-held equipment cannot be used interchangeably with clinic spirometry. Home spirometry is moderately variable during clinical stability. New handheld devices underread, particularly at lower volumes of potential clinical significance for smaller patients; this suggests that supervision does not account fully for the discrepancy. Opportunities should be taken to obtain dual device measurements in clinic, so that trend data from home can be utilized more accurately.

Genotype-related respiratory progression in Duchenne muscular dystrophy-A multicenter international study.

INTRODUCTION/AIMS: Mutations amenable to skipping of specific exons have been associated with different motor progression in Duchenne muscular dystrophy (DMD). Less is known about their association with long-term respiratory function. In this study we investigated the features of respiratory progression in four DMD genotypes relevant in ongoing exon-skipping therapeutic strategies. METHODS: This was a retrospective longitudinal study including DMD children followed by the UK NorthStar Network and international AFM Network centers (May 2003 to October 2020). We included boys amenable to skip exons 44, 45, 51, or 53, who were older than 5 years of age and ambulant at first recorded visit. Subjects who were corticosteroid-naive or enrolled in interventional clinical trials were excluded. The progression of respiratory function (absolute forced vital capacity [FVC] and calculated as percent predicted [FVC%]) was compared across the four subgroups (skip44, skip45, skip51, skip53). RESULTS: We included 142 boys in the study. Mean (standard deviation) age at first visit was 8.6 (2.5) years. Median follow-up was 3 (range, 0.3-8.3) years. In skip45 and skip51, FVC% declined linearly from the first recorded visit. From the age of 9 years, FVC% declined linearly in all genotypes. Skip44 had the slowest (2.7%/year) and skip51 the fastest (5.9%/year) annual FVC% decline. The absolute FVC increased progressively in skip44, skip45, and skip51. In skip53, FVC started declining from 14 years of age. DISCUSSION: The progression of respiratory dysfunction follows different patterns for specific genotype categories. This information is valuable for prognosis and for the evaluation of exon-skipping therapies.

Intrathoracic prosthesis in children in preventing post pneumonectomy syndrome: Its role in congenital single lung and post pneumonectomy situations.

BACKGROUND: Postpneumopnectomy syndrome (PPS) is an extreme rotation and malposition of mediastinum causing dynamic and symptomatic central airway compression, arisingafter pneumonectomy or more uncommonly, in congenital single lung physiology. Affected patients present with severe respiratory compromise. Intrathoracic prosthesis placement is an evolving technique in children that mitigate the effects of thoracic dead space. RESEARCH QUESTION: Assessment of clinical recovery and functional benefit in children undergoing placement of intrathoracic prosthesis following pneumonectomy or in congenital single lung situations. STUDY DESIGN AND METHODS: Retrospective chart review of patients at Great Ormond Street Hospital from 2010 to 2020 was performed of all patients who underwent intrathoracic tissue expander placement. We summarize the outcomes of twenty four children, including those with both congenital and postpneumonectomy PPS etiology. RESULTS: 24 Children who underwent placement of intrathoracic prosthesis for PPS in the study period with median age of 3.5 months and weight of 5 kg. Single lung etiology was congenital in 15 children (6 agenesis, 9 hypoplasia), and postpneumonectomy in 9 children. In seven patients, there was associated long segment tracheal stenosis. Pre operative ECMO was required in 2 patients, and pre operative ventilation was required in 12 patients all of whom had congenital single lung. Intrathoracic prosthesis placement was concurrent with intracardiac repair in 5 patients. There were no operative deaths, but one early postoperative death related to septicaemia. Median follow up was 75 months with 10 patients on continued respiratory support and 3 on nocturnal support with good quality of life. Two children needed reoperations for replacement of prosthesis. CONCLUSION: The use of tissue expanders is within the armamentarium of most plastic surgeons' practice. We also therefore advocate for a collaborative team approach involving Plastic and Cardiothoracic Surgery for surgical treatment of these patients. This multidisciplinary strategy has improved management of this rare and debilitating condition of PPS, thereby offering significant improvements in general progress of these sick children having single lung physiology. Evidence is still lacking on functional outcomes in these children and further work is necessary to prove that this is indeed achievable.

The role of the nasopharyngeal prong in craniofacial disorders in particular the Pierre Robin sequence.

There are a wide range of surgical and maxillofacial options to alleviate upper airway obstruction in children with craniofacial disorders. The nasopharyngeal prong (NPP) is a simple idea where the airway obstruction arising from the posteriorly placed tongue secondary to a small mandible can be overcome quickly and without resorting to more invasive surgical procedures. The role of the NPP is of particular interest in Robin sequence (RS). RS describes a congenital anomaly with retrognathia (often with associated U-shaped cleft palate) where in some children the tongue and small jaw can significantly impact on airway patency with upper airway obstruction. The NPP is a modified endotracheal tube, of ideal diameter and cut to a desired length that can bypass the airway obstruction and regain patency to the upper airway. RS has a natural history of mandibular growth and resolution of the symptoms with time and thus the NPP presents a medium term solution precluding the need in selected children of more permanent and potentially unnecessary surgical procedures. The role of the NPP in other craniofacial disorders (either as a temporary solution or longer term option) requires further research.

Managing infants with craniofacial malformations - Where to go next?

Treatment of infants with craniofacial malformations, e.g. Robin sequence, is characterized by considerable heterogeneity and a lack of randomized trials to identify an optimal approach. We propose to establish an international register using a common minimal dataset that will better allow for a comparison between key determinants and outcomes in these patients. In infants, this should include an assessment of mandibular micrognathia, glossoptosis, upper airway obstruction, weight gain and mode of feeding. Later on, neurocognition, speech development, hearing and quality of life should also be included. Together, these data will help better to advice parents on which treatment to choose for their baby with a craniofacial malformation.

KIAA0753-related skeletal ciliopathy: a ninth case, extending the phenotype and reporting a novel variant.

KIAA0753-related skeletal ciliopathy is a recently described recessive disorder causing skeletal dysplasia and overlapping features of certain ciliopathies; Joubert, Jeune and Oro-facial-digital syndromes. We describe a ninth case that expands the phenotype; a 10-year-old girl with rhizomelic short stature (-5.6 SD), macrocephaly, developmental delay, CNS anomalies (thin corpus callosum, bilateral ventriculomegaly), cone-rod dystrophy, nystagmus, mild conductive hearing loss and recurrent chest infections secondary to confirmed ciliary dyskinesia. Testing for FGFR3 achondroplasia-related hotspots and mucopolysaccharidosis were negative. Whole-exome sequencing, aged eight, via skeletal dysplasia panel analysis and subsequent whole-genome sequencing (via the 100,000 genomes project) found no cause. WGS data reanalysis using exomiser uncovered compound heterozygous pathogenic KIAA0753 variants (frameshift and splice site). Further clinical and radiological surveys were consistent with the expected phenotype. We discuss the emerging phenotype of this uncommon disorder. This report details the sixth published case of skeletal dysplasia in all cases of KIAA0753-related disease and the first case to describe a novel c.1830-2A>G splice variant. Our case is the eldest woman reported to date (aged ten years) and the only known case to report associated hearing loss, leg-length discrepancy, pectus carinatum, respiratory ciliary dyskinesia and late-onset (9 years old) neuro-degenerative regression.

Unsupervised phenotypic clustering for determining clinical status in children with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is a multisystem disease in which the assessment of disease severity based on lung function alone may not be appropriate. The aim of the study was to develop a comprehensive machine-learning algorithm to assess clinical status independent of lung function in children. METHODS: A comprehensive prospectively collected clinical database (Toronto, Canada) was used to apply unsupervised cluster analysis. The defined clusters were then compared by current and future lung function, risk of future hospitalisation, and risk of future pulmonary exacerbation treated with oral antibiotics. A k-nearest-neighbours (KNN) algorithm was used to prospectively assign clusters. The methods were validated in a paediatric clinical CF dataset from Great Ormond Street Hospital (GOSH). RESULTS: The optimal cluster model identified four (A-D) phenotypic clusters based on 12 200 encounters from 530 individuals. Two clusters (A and B) consistent with mild disease were identified with high forced expiratory volume in 1 s (FEV1), and low risk of both hospitalisation and pulmonary exacerbation treated with oral antibiotics. Two clusters (C and D) consistent with severe disease were also identified with low FEV1. Cluster D had the shortest time to both hospitalisation and pulmonary exacerbation treated with oral antibiotics. The outcomes were consistent in 3124 encounters from 171 children at GOSH. The KNN cluster allocation error rate was low, at 2.5% (Toronto) and 3.5% (GOSH). CONCLUSION: Machine learning derived phenotypic clusters can predict disease severity independent of lung function and could be used in conjunction with functional measures to predict future disease trajectories in CF patients.

Growth, Body Composition, and Lung Function in Prepubertal Children with Cystic Fibrosis Diagnosed by Newborn Screening.

BACKGROUND: Children with cystic fibrosis (CF) are at risk of altered body composition (BC). Newborn screening (NBS) may lead to improved BC outcomes. We investigated BC and its relationship with lung function in prepubertal children diagnosed with CF by NBS. Secondary aims explored predictors of fat-free mass (FFM) and lung function. METHODS: Thirty-seven screened (non-meconium ileus) children with CF (20 boys) born 2007-2012 had a dual-energy x-ray absorptiometry scan at 5-8 years to determine whole-body (WB) and appendicular BC. Anthropometry was performed and routine spirometry recorded. Results were converted to z-scores, height-adjusted (fat mass index [FMI] and FFM index [FFMI]) and compared with population mean values. Predictors of forced expiratory volume in 1 second (FEV1 ) were assessed using linear regression. RESULTS: Height, body mass index (BMI), and FEV1 were within normal limits, however, weight and BC were significantly low compared with reference data (weight, P = .03; WB FMI, P = .001; WB FFMI, P = .009). Gender differences were detected, with lower appendicular BC in boys and lower weight, BMI, and BC in girls. The association between FEV1 and WB FFMI (r = 0.38; P = .02) was stronger than with BMI (r = 0.29; P = .08). WB FFMI was the only significant predictor of FEV1 in a multivariable model (95% CI, 0.11-0.99; P = .016). CONCLUSION: In this NBS CF population, gender differences in growth and BC were apparent despite preserved lung function. These results support BC assessment in prepubertal children, particularly girls, with an opportunity to direct interventions to optimize FFM.

Cardiorespiratory Progression Over 5 Years and Role of Corticosteroids in Duchenne Muscular Dystrophy: A Single-Site Retrospective Longitudinal Study.

BACKGROUND: Corticosteroids (CSs) have prolonged survival and respiratory function in boys with Duchenne muscular dystrophy (DMD) when compared with CSs-naïve boys. RESEARCH QUESTION: The differential impact of frequently used CSs and their regimens on long-term (> 5 years) cardiorespiratory progression in children with DMD is unknown. STUDY DESIGN AND METHODS: This was a retrospective longitudinal study including children with DMD followed at Dubowitz Neuromuscular Centre, Great Ormond Street Hospital London, England, from May 2000 to June 2017. Patients enrolled in any interventional clinical trials were excluded. We collected patients' anthropometrics and respiratory (FVC, FVC % predicted and absolute FVC, and noninvasive ventilation requirement [NIV]) and cardiac (left ventricular shortening function [LVFS%]) function. CSs-naïve patients had never received CSs. Patients who were treated with CSs took either deflazacort or prednisolone, daily or intermittently (10 days on/10 days off) for > 1 month. Average longitudinal models were fitted for yearly respiratory (FVC % predicted) and cardiac (LVFS%) progression. A time-to-event analysis to FVC % predicted < 50%, NIV start, and cardiomyopathy (LVFS% < 28%) was performed in CS-treated (daily and intermittent) vs CS-naïve patients. RESULTS: There were 270 patients, with a mean age at baseline of 6.2 ± 2.3 years. The median follow-up time was 5.6 ± 3.5 years. At baseline, 263 patients were ambulant. Sixty-six patients were treated with CSs daily, 182 patients underwent CSs intermittent > 60% treatment, and 22 were CS-naïve patients. Yearly FVC % predicted declined similarly from 9 years (5.9% and 6.9% per year, respectively; P = .27) in the CSs-daily and CSs-intermittent groups. The CSs-daily group declined from a higher FVC % predicted than the CSs-intermittent group (P < .05), and both reached FVC % predicted < 50% and NIV requirement at a similar age, > 2 years later than the CS-naïve group. LVFS% declined by 0.53% per year in the CSs-treated group irrespective of the CSs regimen, significantly slower (P < .01) than the CSs-naïve group progressing by 1.17% per year. The age at cardiomyopathy was 16.6 years in the CSs-treated group (P < .05) irrespective of regimen and 13.9 years in the CSs-naïve group. INTERPRETATION: CSs irrespective of the regimen significantly improved respiratory function and delayed NIV requirement and cardiomyopathy.

The role of the pediatrician in caring for children with tracheobronchomalacia.

INTRODUCTION: Children with tracheobronchomalacia (TBM) experience excessive dynamic collapse of the central airway(s). TBM remains an under-diagnosed condition, and there is on ongoing need to raise awareness amongst pediatricians. AREAS COVERED: The literature from PubMed, MEDLINE, EMBASE and Cochrane Controlled Trials Register electronic databases was searched from 1 January 1980 to 14 January 2020. Eligible studies relating to the diagnosis, investigation and management of tracheobronchomalacia in children were included. In this review, we highlight the clinical symptoms of TBM such as the typical barking cough, wheezing, recurrent lower respiratory tract infections or acute life-threatening events. These symptoms worsen when the child is making increased respiratory efforts, such as during crying, coughing and during intercurrent infective illness. This article focuses on the role of the pediatrician in recognizing the condition, the investigative process, and the medical management based on the clinical severity. The principle of management should be holistic, tackling the medical issues of TBM and associated comorbidities, as providing support to families. EXPERT OPINION: There remains a need to devise objective and reproducible bronchoscopic and radiological definitions of severity of TBM. Further studies looking at long-term outcomes of medical therapies used in TBM are required.

Minimal change in structural, functional and inflammatory markers of lung disease in newborn screened infants with cystic fibrosis at one year.

BACKGROUND: With the widespread introduction of newborn screening for cystic fibrosis (CF), there has been considerable emphasis on the need to develop objective markers of lung health that can be used during infancy. We hypothesised that in a newborn screened (NBS) UK cohort, evidence of airway inflammation and infection at one year would be associated with adverse structural and functional outcomes at the same age. METHODS: Infants underwent lung function testing, chest CT scan and bronchoscopy with bronchoalveolar lavage (BAL) at 1 year of age when clinically well. Microbiology cultures were also available from routine cough swabs. RESULTS: 65 infants had lung function, CT and BAL. Mean (SD) lung clearance index and forced expiratory volume in 0.5 s z-scores were 0.9(1.2) and -0.6(1.1) respectively; median Brody II CF-CT air trapping score on chest CT =0 (interquartile range 0-1, maximum possible score 27). Infants isolating any significant pathogen by 1 yr of age had higher LCI z-score (mean difference 0.9; 95%CI:0.4-1.4; p = 0.001) and a trend towards higher air trapping scores on CT (p = 0.06). BAL neutrophil elastase was detectable in 23% (10/43) infants in whom BAL supernatant was available. This did not relate to air trapping score on CT. CONCLUSIONS: In this UK NBS cohort at one year of age, lung and airway damage is much milder and associations between inflammation, abnormal physiology and structural changes were at best weak, contrary to our hypothesis and previously published reports. Continued follow-up will clarify longer term implications of these very mild structural, functional and inflammatory changes.

ERS statement on tracheomalacia and bronchomalacia in children.

Tracheomalacia and tracheobronchomalacia may be primary abnormalities of the large airways or associated with a wide variety of congenital and acquired conditions. The evidence on diagnosis, classification and management is scant. There is no universally accepted classification of severity. Clinical presentation includes early-onset stridor or fixed wheeze, recurrent infections, brassy cough and even near-death attacks, depending on the site and severity of the lesion. Diagnosis is usually made by flexible bronchoscopy in a free-breathing child but may also be shown by other dynamic imaging techniques such as low-contrast volume bronchography, computed tomography or magnetic resonance imaging. Lung function testing can provide supportive evidence but is not diagnostic. Management may be medical or surgical, depending on the nature and severity of the lesions, but the evidence base for any therapy is limited. While medical options that include bronchodilators, anti-muscarinic agents, mucolytics and antibiotics (as well as treatment of comorbidities and associated conditions) are used, there is currently little evidence for benefit. Chest physiotherapy is commonly prescribed, but the evidence base is poor. When symptoms are severe, surgical options include aortopexy or posterior tracheopexy, tracheal resection of short affected segments, internal stents and external airway splinting. If respiratory support is needed, continuous positive airway pressure is the most commonly used modality either via a face mask or tracheostomy. Parents of children with tracheobronchomalacia report diagnostic delays and anxieties about how to manage their child's condition, and want more information. There is a need for more research to establish an evidence base for malacia. This European Respiratory Society statement provides a review of the current literature to inform future study.

Tracheobronchial stenting for airway malacia.

Tracheobronchomalacia is a rare but clinically troublesome condition in paediatrics. The softening of the major airways - which can include some or all of the tracheobronchial tree can lead to symptoms ranging from the minor (harsh barking cough, recurrent chest infections) to severe respiratory difficulties including prolonged ventilator support and 'near death attacks'. The causes are broadly divided into intrinsic softening of the airway wall which is considered a primary defect (e.g. syndromes; post tracheo-oesophageal fistula repair; extreme prematurity) or secondary malacia due to external compression from vascular structures or cardiac components. These secondary changes can persist even when the external compression is relieved, for example, following the repair of a pulmonary artery sling or double aortic arch. For children with severe clinical symptoms attributed to malacia, consideration is given to possible surgical remedies such as an aortopexy for short limited areas of malacia, or long term positive pressure support with CPAP either by non invasive or tracheostomy interface. More recently the role of stenting in children is receiving attention, especially with the development of newer techniques such as bioabsorbable stents which buy time for a natural history of improvement in the malacia to occur. This paper reviews the stents available and discusses the pros and cons of stenting in paediatric airway malacia.

Cystic fibrosis newborn screening: outcome of infants with normal sweat tests.

Newborn babies positively screened for cystic fibrosis (CF) (high serum immunoreactive trypsin (IRT) with DNA analysis) are referred for a diagnostic sweat test, which may be normal (sweat chloride <30 mmol/L). Unless two gene mutations are identified during Newborn screening (NBS), the babies are discharged from follow-up. We wished to check that none had subsequently developed symptoms suggestive of CF. We retrospectively reviewed patient notes and contacted general practitioners of all babies with a negative sweat test, conducted in one of the four paediatric specialist CF centres in London, over the first 6 years of screening in South East England.Of 511 babies referred, 95 (19%) had a normal sweat test. Five (5%) had CF diagnosed genetically, two of them on extended genome sequencing after clinical suspicion. Eleven (12%) were designated as CF screen positive inconclusive diagnosis (CFSPID); one of the five CF children was originally designated as CFSPID. Seventy-nine (83%) were assumed to be false-positive cases and discharged; follow-up data were available for 51/79 (65%); 32/51 (63%) had no health issues, 19/51 (37%) had other significant non-CF pathology.These results are reassuring in that within the limitations of those lost to follow-up, CF symptoms have not emerged in the discharged children. The high non-CF morbidity in these children may relate to known causes of high IRT at birth. Clinicians need to be aware that a child can have CF despite a normal sweat test following NBS, and if symptoms suggest the diagnosis, further testing, including extended genome sequencing, is required.

Pulmonary function deficits in newborn screened infants with cystic fibrosis managed with standard UK care are mild and transient.

With the advent of novel designer molecules for cystic fibrosis (CF) treatment, there is huge need for early-life clinical trial outcomes, such as infant lung function (ILF). We investigated the degree and tracking of ILF abnormality during the first 2 years of life in CF newborn screened infants.Forced expiratory volume in 0.5 s (FEV0.5), lung clearance index (LCI) and plethysmographic functional residual capacity were measured at ∼3 months, 1 year and 2 years in 62 infants with CF and 34 controls.By 2 years there was no significant difference in FEV0.5 z-score between CF and controls, whereas mean LCI z-score was 0.81 (95% CI 0.45-1.17) higher in CF. However, there was no significant association between LCI z-score at 2 years with either 3-month or 1-year results. Despite minimal average group changes in any ILF outcome during the second year of life, marked within-subject changes occurred. No child had abnormal LCI or FEV0.5 on all test occasions, precluding the ability to identify "high-risk" infants in early life.In conclusion, changes in lung function are mild and transient during the first 2 years of life in newborn screened infants with CF when managed according to a standardised UK treatment protocol. Their potential role in tracking disease to later childhood will be ascertained by ongoing follow-up.

Filamin A (FLNA) mutation-A newcomer to the childhood interstitial lung disease (ChILD) classification.

AIM: Interstitial lung disease (ILD) in infants represents a rare and heterogenous group of disorders, distinct from those occurring in adults. In recent years a new entity within this category is being recognized, namely filamin A (FLNA) mutation related lung disease. Our aims are to describe the clinical and radiological course of patients with this disease entity to aid clinicians in the prognostic counseling and management of similar patients they may encounter. METHOD: A retrospective case note review was conducted of all patients treated at our institution (a specialist tertiary referral childrens' center) for genetically confirmed FLNA mutation related lung disease. The clinical presentation, evolution, management and radiological features were recorded and a medical literature review of Medline indexed articles was conducted. RESULTS: We present a case series of four patients with interstitial lung disease and genetically confirmed abnormalities within the FLNA gene. Their imaging findings all reveal a pattern of predominantly upper lobe overinflation, coarse pulmonary lobular septal thickening and diffuse patchy atelectasis. The clinical outcomes of our patients have been variable ranging from infant death, lobar resection and need for supplemental oxygen and bronchodilators. CONCLUSION: The progressive nature of the pulmonary aspect of this disorder and need for early aggressive supportive treatment make identification crucial to patient management and prognostic counseling.