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BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection.METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis.RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives.CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has accelerated the move towards home spirometry monitoring, including in children. The aim of this study is to determine whether the remote supervision of spirometry by a physiologist improves the technical quality and failure rate of the maneuvers. METHOD: Children with cystic fibrosis who had been provided with NuvoAir home spirometers were randomly allocated to either supervised or unsupervised home spirometry following a detailed training session. Home spirometry was performed every 2 weeks for 12 weeks. Tests were assigned a quality factor (QF) using our laboratory grading system as per American Thoracic Society/European Respiratory Society standards, with tests marked from A to D, or Fail. In our laboratory, we aim for QF A in all spirometry tests, but report results of QF B or C with a cautionary note. QF A was, therefore, the primary outcome, and QF A-C, the secondary outcome. RESULTS: Sixty-one patients were enrolled; 166 measurements were obtained in the supervised group, and 153 in the unsupervised group. Significantly more measurements achieved QF A in the supervised compared to unsupervised group (89% vs. 74%; p =

BackgroundElexacaftor plus tezacaftor plus ivacaftor is a triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be generally safe and efficacious in people with cystic fibrosis aged 12 years or older with at least one F508del-CFTR allele. We aimed to assess the magnitude and durability of the clinical effects of this triple combination regimen in people with cystic fibrosis homozygous for the F508del-CFTR mutation.MethodsWe conducted a multicentre, randomised, double-blind, active-controlled, phase 3b trial of elexacaftor plus tezacaftor plus ivacaftor at 35 medical centres in Australia, Belgium, Germany, and the UK. Eligible participants were those with cystic fibrosis homozygous for the F508del-CFTR mutation, aged 12 years or older with stable disease, and with a percent predicted FEV1 of 40–90% inclusive. After a 4-week run-in period, in which participants received tezacaftor 100 mg orally once daily and ivacaftor 150 mg orally every 12 h, participants were randomly assigned (1:1) to receive 24 weeks of either elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (elexacaftor plus tezacaftor plus ivacaftor group) or tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (tezacaftor plus ivacaftor group). Randomisation was stratified by percent predicted FEV1, age at screening visit, and whether the participant was receiving CFTR modulators at the time of the screening visit. Patients, investigators, and sponsor's study execution team were masked to treatment assignment. The primary endpoint was the absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline (ie, at the end of the tezacaftor plus ivacaftor run-in period) up to and including week 24. The key secondary endpoint was the absolute change from baseline in percent predicted FEV1 up to and including week 24; other secondary endpoints were the absolute change from baseline in sweat chloride concentrations up to and including week 24, and safety and tolerability. All endpoints were assessed in all randomised patients who had received at least one dose of their assigned regimen. This study is registered with ClinicalTrials.gov, NCT04105972.FindingsBetween Oct 3, 2019, and July 24, 2020, 176 participants were enrolled. Following the 4-week tezacaftor plus ivacaftor run-in period, 175 participants were randomly assigned (87 to the elexacaftor plus tezacaftor plus ivacaftor group and 88 to the tezacaftor plus ivacaftor group) and dosed in the treatment period. From baseline up to and including week 24, the mean CFQ-R respiratory domain score increased by 17·1 points (95% CI 14·1 to 20·1) in the elexacaftor plus tezacaftor plus ivacaftor group and by 1·2 points (−1·7 to 4·2) in the tezacaftor plus ivacaftor group (least squares mean treatment difference 15·9 points [95% CI 11·7 to 20·1], pInterpretationThe elexacaftor plus tezacaftor plus ivacaftor regimen was safe and well tolerated, and led to significant and clinically meaningful improvements in respiratory-related quality of life and lung function, as well as improved CFTR function, changes that were durable over 24 weeks and superior to those seen with tezacaftor plus ivacaftor in this patient population.

Paediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rarely results in a critical respiratory presentation. It is not yet known which children are at particular risk of adverse outcomes. We describe a paediatric case of critical SARS-CoV-2 infection requiring Extra Corporeal Membrane Oxygenation (ECMO), who made a full recovery after receiving a dual antiviral therapy of remdesivir and nitazoxanide.

Introduction: The COVID-19 pandemic has accelerated the move towards home spirometry monitoring, including in children. Our aim was to determine whether the remote supervision of spirometry by a physiologist improves the technical quality and failure rate of the manoeuvres. Method: Children with cystic fibrosis who had been provided with NuvoAir home spirometers were randomly allocated to either supervised or unsupervised home spirometry following a detailed training session. Home spirometry was performed every 2 weeks for 12 weeks. Tests were assigned a quality factor (QF) using our laboratory grading system as per ATS/ERS standards, with tests marked from A to D, or Fail. In our laboratory we aim for QF A in all spirometry tests, but report results of QF B or C with a cautionary note. QF A was therefore the primary outcome, and QF A-C the secondary outcome. Results: 61 patients were enrolled; 166 measurements were obtained in the supervised group, and 153 in the unsupervised group. Significantly more measurements achieved QF A in the supervised compared to unsupervised group (89% vs 74%; p=

Bronchiolitis obliterans (BO) is a chronic and irreversible obstructive lung disease leading to the obstruction and/or obliteration of the small airways. Three main BO entities are distinguished: post-infectious BO (PIBO); BO post lung transplantation; and BO after bone marrow transplantation (BMT) or hematopoietic stem cell transplantation (HSCT). All three entities are separate, however, there are similarities in histopathological characteristics and possibly in aspects of the development pathway. Areas covered: We review current evidence of bronchiolitis obliterans diagnosis and management in children. The diagnosis of BO is usually based on a combination of history, clinical and radiological findings, although lung biopsy and histopathology remain the gold standard approaches to confirm BO. Expert opinion: At present, we do not have a clear understanding of the mechanisms of the development of BO and lack strong evidence for treatment. Although most BO in children is post-infectious, most of the current evidence for treatment originates from studies analyzing BO in adult lung transplant and HSCT patients. BO management requires multidisciplinary approach and care in specialized centers.

Background: Sensitised patients undergoing Human Leukocyte Antigen-incompatible transplantation are at increased risk of hyperacute rejection and may be predisposed to antibody-mediated rejection, chronic lung allograft dysfunction and higher mortality. Case: We present a case of primary lung transplantation in the setting of late identification of donor specific antibodies treated with intraoperative target plasma exchange. The patient was treated with fresh human plasma to a final volume of 1.5 times the patient’s systemic circulation. From a pre-transplant mean fluorescence intensity of 5002, donor-specific antibodies were undetectable following plasma exchange on single antigen bead assay. Conclusions: This method represents a potential desensitisation technique for use in the intraoperative period.

Interstitial lung diseases (ILDs) that present in childhood (chILD) are seen far less frequently than ILDs presenting in adults which themselves constitute rare disorders [1]. Histopathological [2, 3] and imaging [4] characterisation of chILD disease subtypes therefore lags behind adult ILDs. The field has also been constrained by comparisons with disease morphology in adults, despite the developmental differences in terms of growth and healing in the paediatric lung, which may alter disease patterns and distributions. The American Thoracic Society [5] and European [1] chILD management guidelines both specify a pivotal role for computed tomography (CT) imaging in the work-up of chILD patients to: 1) determine whether a chILD is present or not; and 2) where possible, to make a specific diagnosis of the underlying cause. For the second aim to be achieved, diagnostic reviews need to be reproducible between experts. Our study uniquely examined agreement between observers of varying experience in the CT evaluation of chILD to inform whether the current status of CT imaging and knowledge can be diagnostic of specific chILDs. We hypothesised that observer agreement for chILD groups and diagnoses would be limited. The study was not designed to relate CT agreement to final diagnosis. As a secondary analysis, we examined how CT interpretation differed between observers in children under and over 2 years of age., Making chILD diagnoses on CT is poorly reproducible, even amongst sub-specialists. CT might best improve diagnostic confidence in a multidisciplinary team setting when augmented with clinical, functional and haematological results. http://bit.ly/327jRCw

Supplemental Digital Content is available in the text., Background: Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH, we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods: We analyzed 13 037 participants enrolled in the NBR study (NIHR BioResource—Rare Diseases), of which 1148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension, we used the Bayesian rare variant association method BeviMed. Results: Heterozygous, high impact, likely loss-of-function variants in the kinase insert domain receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (posterior probability=0.989) and older age at diagnosis (posterior probability=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the 5 patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions: The Bayesian inference approach allowed us to independently validate KDR, which encodes for the VEGFR2 (vascular endothelial growth factor receptor 2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.

Infants with a history of neonatal chronic respiratory problems may demonstrate hypoxaemia when at in-flight oxygen levels, despite normal sea-level oxygen requirements. The British Thoracic Society recommend these infants have hypoxic challenge testing (HCT) before air travel, SpO2 Aim To establish how many infants fell into each of the threshold categories during HCT; SpO2 90%, 85–90% and which of these patients were recommended to fly ± supplemental oxygen (suppO2). Methods Our HCT protocol for infants is 20 minutes in 15% FiO2 within a body plethysmograph. SpO2 is monitored throughout and suppO2 administered via nasal cannula if SpO2 85% but Results Data collected from 65 infants, median age 27.6 weeks (range 5 to 51.6), 37 were male. None were receiving suppO2 in room air prior to testing; all had baseline SpO2 ≥96%. In 40 infants, SpO2 did not dip to In the 85–90% category, all 9 infants were advised by their clinician to use suppO2 for air travel.The flight times in this subgroup ranged from 90 to 450 minutes. Conclusion Infants with baseline SpO2 ≥96% may still exhibit SpO2 desaturation during HCT. We found all paediatricians recommended in-flight oxygen for infants with HCT SpO2

Background Mycobacterium abscessus infection has been associated with variable outcomes following lung transplantation. M abscessus comprises three subspecies (M abscessus subsp abscessus, M abscessus subsp massiliense, and M abscessus subsp bolletii). We investigated whether lung transplantation outcome in cystic fibrosis (CF) patients in a single center was related to the M abscessus subspecies and genetic cluster. Methods CF patients with chronic M abscessus infection transplanted at Great Ormond Street Hospital between 2004 and 2017 were retrospectively examined. All M abscessus isolates were identified to subspecies level by polymerase chain reaction and sequencing. Genetic cluster was determined by variable number tandem repeat profiling and whole-genome sequencing (WGS), and sequence type inferred from WGS. Results Thirteen patients with chronic M abscessus infection underwent heart/lung or lung transplantation. Subspecies identification showed n = 1 with M abscessus bolletii, n = 5 with M abscessus massiliense, and n = 7 with M abscessus abscessus infection. Eight (62%) patients (one with M abscessus massiliense and seven with M abscessus abscessus) died post-lung transplant. The patient with M abscessus bolletii and three patients with M abscessus massiliense did well post-transplant. One patient with M abscessus massiliense is receiving ongoing treatment. Conclusions Dramatically worse outcomes are observed in patients infected with M abscessus subspecies abscessus, the majority of whom were infected with ST-1 and ST-26 strains. Patients infected with other M abcsessus strains can have acceptable outcomes.

We performed a prospective, observational, cohort study of children newly diagnosed with children’s interstitial lung disease (ChILD), with structured follow-up at 4, 8, 12 weeks and 6 and 12 months. 127 children, median age 0.9 (IQR 0.3–7.9) years had dyspnoea (68%, 69/102), tachypnoea (75%, 77/103) and low oxygen saturation (SpO2) median 92% (IQR 88–96). Death (n=20, 16%) was the most common in those 2

Background Different interfaces (mouthpiece/nose clip vs. facemask) are used during multiple breath washout (MBW) tests in young children. Methods We investigated the effect of interface choice and breathing modalities on MBW outcomes in healthy adults and preschool children. Results In adults (n = 26) facemask breathing significantly increased LCI, compared to mouthpiece use (mean difference (95% CI) 0.4 (0.2; 0.6)), with results generalizable across sites and different equipment. Exclusively nasal breathing within the facemask increased LCI, as compared to oral breathing. In preschoolers (2–6 years, n = 46), no significant inter-test difference was observed across interfaces for LCI or FRC. Feasibility and breathing stability were significantly greater with facemask (incorporating dead space volume minimization), vs. mouthpiece. This was more pronounced in subjects Conclusion Both nasal vs. oral breathing and mouthpiece vs. facemask affect LCI measurements in adults. This effect was minimal in preschool children, where switching between interfaces is most likely to occur.

BACKGROUND Scond is a multiple breath washout (MBW) index that measures convection-dependent ventilation inhomogeneity (CDI) arising within conductive airways, but the calculation method is unreliable in subjects with advanced cystic fibrosis (CF) lung disease. A new CDI index, Scond *, has been proposed for use in adults with CF and moderate to severe ventilation inhomogeneity. We aimed to evaluate the most appropriate CDI index in children and adolescents with CF and various degrees of inhomogeneity, and from that the most appropriate diffusion-convection-interaction index (Sacin or Sacin *). METHODS Scond , Sacin and the alternative indices, Scond *, and Sacin * were retrospectively calculated in subjects with CF aged 3 to 18 years and age-matched controls, who underwent sulfur hexafluoride MBW between 2003 and 2015. The upper limit of normal was based on 95th percentile of the control population. RESULTS One hundred and twenty-seven subjects with CF (44% male; mean age ± SD: 7.5 years ± 4.9) and 94 controls (53% male; 7.9 years ± 5.1) were included in the final analysis. All measures of ventilation inhomogeneity were significantly higher in children with CF. As predicted, Scond reached a maximum value at lung clearance index (LCI) values of approximately 9. In subjects with LCI ≥ 9 Scond * showed good correlation with LCI, whilst Scond had no relationship with LCI (Spearman rank correlation Scond */LCI, 0.49; P

BackgroundPrimary ciliary dyskinesia (PCD), a genetically heterogeneous condition enriched in some consanguineous populations, results from recessive mutations affecting cilia biogenesis and motility. Currently, diagnosis requires multiple expert tests.MethodsThe diagnostic utility of multigene panel next-generation sequencing (NGS) was evaluated in 161 unrelated families from multiple population ancestries.ResultsMost (82%) families had affected individuals with biallelic or hemizygous (75%) or single (7%) pathogenic causal alleles in known PCD genes. Loss-of-function alleles dominate (73% frameshift, stop-gain, splice site), most (58%) being homozygous, even in non-consanguineous families. Although 57% (88) of the total 155 diagnostic disease variants were novel, recurrent mutations and mutated genes were detected. These differed markedly between white European (52% of families carry DNAH5 or DNAH11 mutations), Arab (42% of families carry CCDC39 or CCDC40 mutations) and South Asian (single LRRC6 or CCDC103 mutations carried in 36% of families) patients, revealing a striking genetic stratification according to population of origin in PCD. Genetics facilitated successful diagnosis of 81% of families with normal or inconclusive ultrastructure and 67% missing prior ultrastructure results.ConclusionsThis study shows the added value of high-throughput targeted NGS in expediting PCD diagnosis. Therefore, there is potential significant patient benefit in wider and/or earlier implementation of genetic screening.

Lung Clearance Index, measured using the multiple breath washout (MBW) technique, may be a useful test in infants with Cystic Fibrosis (CF). However, the requirement for specialised equipment and a number of important technical and methodological considerations relevant to testing in infants have complicated matters, and to date prevented its widespread translatability in this age group. Areas covered: We review the current status of infant MBW testing in CF, focusing on Lung Clearance Index. This includes a review of recent developments in the field relevant to testing methodology in the infant population, use in evaluating lung disease in CF in infancy, and the associated challenges which remain. Expert commentary: The challenges of infant MBW are not limited to those associated with testing equipment, but also gaps in our understanding regarding the interpretation of MBW indices in infants. This includes their relationship to underlying physiology and pathology, and tracking over time. Recent advances in understanding and improving the infant MBW test set up (including both hardware and software) relevant to infants will greatly progress the field.

SummaryBackground The bronchodilator response (BDR) is frequently used to support diagnostic and therapeutic decision-making for children who wheeze. However, there is little evidence-based guidance describing the role of BDR testing in preschool children and it is unclear whether published cut-off values, which are derived from adult data, can be applied to this population. Methods We searched MEDLINE, EMBASE, Web of Science, and Cochrane databases (inception—September 2015) for studies reporting response to a bronchodilator in healthy preschool children, response following placebo inhalation, and the diagnostic efficacy of BDR compared with a clinical diagnosis of asthma/recurrent wheezing. Findings We included 14 studies. Thirteen studies provided BDR data from healthy preschool children. Two studies reported response to placebo in preschool children with asthma/recurrent wheezing. Twelve studies compared BDR measurements from preschool children with asthma/recurrent wheeze to those from healthy children and seven of these studies reported diagnostic efficacy. Significant differences between the BDR measured in healthy preschool children compared with that in children with asthma/recurrent wheeze were demonstrated in some, but not all studies. Techniques such as interrupter resistance, oscillometry, and plethysmography were more consistently successfully completed than spirometry. Between study heterogeneity precluded determination of an optimum technique. Interpretation There is little evidence to suggest spirometry-based BDR can be used in the clinical assessment of preschool children who wheeze. Further evaluation of simple alternative techniques is required. Future studies should recruit children in whom airways disease is suspected and should evaluate the ability of BDR testing to predict treatment response. Pediatr Pulmonol. 2016;51:1242–1250. © 2016 Wiley Periodicals, Inc.

BACKGROUND: Ivacaftor is generally safe and effective in patients aged 2 years and older who have cystic fibrosis and specific CFTR mutations. We assessed its use in children aged 12 to

BACKGROUND:Obstructive airway disease is nonuniformly distributed throughout the bronchial tree, although the extent to which this occurs can vary among conditions. The multiple-breath washout (MBW) test offers important insights into pediatric lung disease, not available through spirometry or resistance measurements. The European Respiratory Society/American Thoracic Society inert gas washout consensus statement led to the emergence of validated commercial equipment for the age group 6 years and above; specific recommendations for preschool children were beyond the scope of the document. Subsequently, the focus has shifted to MBW applications within preschool subjects (aged 2-6 yr), where a "window of opportunity" exists for early diagnosis of obstructive lung disease and intervention.METHODS:This preschool-specific technical standards document was developed by an international group of experts, with expertise in both custom-built and commercial MBW equipment. A comprehensive review of published evidence was performed.RESULTS:Recommendations were devised across areas that place specific age-related demands on MBW systems. Citing evidence where available in the literature, recommendations are made regarding procedures that should be used to achieve robust MBW results in the preschool age range. The present work also highlights the important unanswered questions that need to be addressed in future work.CONCLUSIONS:Consensus recommendations are outlined to direct interested groups of manufacturers, researchers, and clinicians in preschool device design, test performance, and data analysis for the MBW technique

International audience; Motile cilia move body fluids and gametes and the beating of cilia lining the airway epithelial surfaces ensures that they are kept clear and protected from inhaled pathogens and consequent respiratory infections. Dynein motor proteins provide mechanical force for cilia beating. Dynein mutations are a common cause of primary ciliary dyskinesia (PCD), an inherited condition characterized by deficient mucociliary clearance and chronic respiratory disease coupled with laterality disturbances and subfertility. Using next-generation sequencing, we detected mutations in the ciliary outer dynein arm (ODA) heavy chain gene DNAH9 in individuals from PCD clinics with situs inversus and in one case male infertility. DNAH9 and its partner heavy chain DNAH5 localize to type 2 ODAs of the distal cilium and in DNAH9-mutated nasal respiratory epithelial cilia we found a loss of DNAH9/DNAH5-containing type 2 ODAs that was restricted to the distal cilia region. This confers a reduced beating frequency with a subtle beating pattern defect affecting the motility of the distal cilia portion. 3D electron tomography ultrastructural studies confirmed regional loss of ODAs from the distal cilium, manifesting as either loss of whole ODA or partial loss of ODA volume. Paramecium DNAH9 knockdown confirms an evolutionarily conserved function for DNAH9 in cilia motility and ODA stability. We find that DNAH9 is widely expressed in the airways, despite DNAH9 mutations appearing to confer symptoms restricted to the upper respiratory tract. In summary, DNAH9 mutations reduce cilia function but some respiratory mucociliary clearance potential may be retained, widening the PCD disease spectrum.

SummaryIntroduction Interstitial lung disease (ILD) in infants is rare. Clinical and radiological features are often non-specific, and overlap with growth disorders and infection. In infants with severe respiratory compromise, lung biopsy is often necessary to guide acute management, but the risk and diagnostic yield of this procedure is incompletely understood. Aims To retrospectively review infants undergoing open lung biopsy for suspected ILD at a large referral center; to determine morbidity and mortality related to the procedure; and to describe subsequent diagnosis and outcome. Methods Lung biopsies performed in infants (aged

This statement summarizes the information available on specific exercise test protocols and outcome parameters used in patients with cystic fibrosis (CF) and provides expert consensus recommendations for protocol and performance of exercise tests and basic interpretation of results for clinicians. The conclusions were reached employing consensus meetings and a wide-band Delphi process. Although data on utility are currently limited, standardized exercise testing provides detailed information on physiological health, allows screening for exercise-related adverse reactions and enables exercise counselling. The Godfrey Cycle Ergometer Protocol with monitoring of oxygen saturation and ventilatory gas exchange is recommended for exercise testing in people 10 years and older. Cycle ergometry only with pulse oximetry using the Godfrey protocol or treadmill exercise with pulse oximetry - preferably with measurement of gas exchange - are second best options. Peak oxygen uptake, if assessed, and maximal work rate should be reported as the primary measure of exercise capacity. The final statement was reviewed by the European Cystic Fibrosis society and revised based on the comments received. The document was endorsed by the European Respiratory Society.

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.

Background The Quanjer et al. Global Lung Function Initiative (GLI)-2012 multi-ethnic all-age reference equations for spirometry are endorsed by all major respiratory societies and are the new gold standard. Before the GLI equations are implemented for use in CF patients, the impact of changing equations from those currently used needs to be better understood. Methods Annual review data submitted to the UK CF Trust Registry between 2007 and 2011 were used to calculate %predicted FEV 1 , FVC and FEV 1 /FVC using three widely used reference equations (Wang–Hankinson and Knudson) and the new GLI-2012 equations. Results Overall, Knudson and Wang equations overestimated %predicted values in paediatric patients, such that a greater proportion of patients had lung function values in the normal range. Within individual patients, the impact of switching equations varied greatly depending on the patients' age, and which equations were used. Conclusions A unified approach to interpreting spirometric lung function measurements would help facilitate more appropriate comparison both within and between centres and countries. Interpretation of longitudinal measurements using a continuous reference equation across all-ages, like the GLI, may further improve our understanding of CF lung disease.

Educational aims To understand which techniques are available to monitor early lung disease in cystic fibrosis, recognise difficulties inherent to each measure, and describe the use of tests in clinical practice or interventional trials. Summary It is a particular challenge to detect and monitor lung disease in children younger than 6 years old. Various methods exist that can reveal abnormality in young children, but each technique presents difficulties on performing the test or interpreting results. Most children with cystic fibrosis are now diagnosed shortly after birth, but it is still unclear how to evaluate new therapies, or at what age to initiate them. This review summarises current options for monitoring early disease, limitations of individual techniques and how evidence to date influences their use in research and clinical practice. Key points Lung disease remains the major cause of morbidity and mortality in cystic fibrosis Despite clear improvements in outcomes such as nutrition, the benefit of early diagnosis by newborn screening on pulmonary health in cystic fibrosis has yet to be proven. Early lung disease is challenging to detect and monitor in young children with cystic fibrosis, but there is an urgent requirement to define useful outcome measures in this population, particularly as new treatments emerge. Many techniques are available, but difficulties with measurement or interpretation must be recognised when appraising past studies, considering their use in practice or as endpoints in clinical trials. There is no superior monitoring test at present, but emerging evidence from longitudinal studies in children with cystic fibrosis will help define which are most useful.

BackgroundAt our hospital the current model of care for children with moderate–severe CF is focused on intensive inpatient intervention, regular outpatient clinic review and specialist outreach care as required. An alternative model providing more regular physiotherapy and dietetic outreach support, in addition to these specialist services, may be more effective.Methods16 children (4 male; 12 female; mean age 10.9±2.93; range 4–15years) who required >40days of IV antibiotics in the 12-months pre-intervention were enrolled. Physiotherapy included weekly-supervised exercise sessions, alongside regular review of home physiotherapy regimens. Dietetic management included 1–2 monthly monitoring of growth, appetite, intake and absorption, and nutrition education sessions.ResultsThere was a 23% reduction in inpatient IV antibiotic requirement and 20% reduction in home IV antibiotic requirement during the intervention year. Cost–benefit analyses showed savings of £113,570. VO2Peak increased by 4.9ml·kg·min−1 (95%CI 1.01 to 8.71; p=0.02), and 10m-MSWT distance and increment achieved increased by 229m (95%CI 109 to 350; p

Cystic Fibrosis Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK Portex Respiratory Medicine Unit, University College London Institute of Child Health, London, UK *Author for correspondence: Tel.: +44 207 905 2178; Fax: +44 207 813 8514; sean.ledger@gosh.nhs.uk “...recent pilot studies in subjects with more advanced disease, where the exercise intervention runs over a longer period, have implied marked improvements in a variety of outcomes...”

Cystic fibrosis (CF) lung disease starts early in life and progresses even in the absence of clinical symptoms. Therefore, sensitive outcome measures to quantify and track these early abnormalities in infants and young children are needed; both for clinical care and interventional trials. Currently, the efficacy of most therapeutic interventions in CF has not been tested in children under the age of 6 years and drug development programmes have focused on assessing safety rather than efficacy in this age group. This article summarises the current status for outcome measures that can be utilised in clinical trials in infants and children with CF. Two methodologies are specifically highlighted in this review; chest computed tomography to assess structural damage of the lung and multiple breath washout as a technique to quantify ventilation inhomogeneity. While not all questions regarding the utility of these outcome measures in infants and young children have been resolved, significant advances have been made and it now appears feasible to design and conduct adequately powered efficacy studies in this age group. This could be a crucial step to further improve outcomes in CF patients as initiating effective treatment early is considered essential to prevent permanent lung damage.

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.

Introduction: Commercial N 2 -WO systems need modifications for use in young children and must be validated before widespread use. Aim: To compare LCI and FRC from Eco Medics Exhalyzer-D N 2 -WO to a custom-built AMIS 2000 Mass Spectrometer sulphur hexafluoride washout (SF 6 -WO) in preschool (3-6y)controls and patients with cystic fibrosis(CF) Methods: Washouts were performed on the same day. SF 6 -WO to standard lab protocol, N 2 -WO with a low deadspace filter and modified capnostat. A face mask with putty was used for all tests Results: 42 children were tested (25 CF). Mean age 5.1y CF, 4.8y, mean height and weight no difference CF vs. control . SF 6 -WO was not possible in 2 children, N 2 -WO was not possible in 6 Figure: Bland Altman (BA) plots for CF (black), Control (red), FRC (top) and LCI (bottom) FRC N2 was significantly higher than FRC SF6 in both groups. LCI N2 -LCI SF6 in controls showed good agreement. LoA were wider for children with CF, but there was no significant group difference (table 1). In children with CF only the BA plots suggest increased FRC N2 -FRC SF6 with increasing FRC, and decreased LCI N2 -LCI SF6 with increasing LCI (figure) Conclusion: Device specific reference values are needed for FRC and LCI in preschool children with CF.

Mycobacterium abscessus is associated with poor outcome following lung transplantation. We investigated whether outcome was related to subspecies and genetic cluster. CF patients transplanted at GOSH from 2004 – 2016 were retrospectively examined. Medical notes, microbiology, radiology databases and operative notes were reviewed. All M. abscessus isolates identified to subspecies level by PCR sequencing and genetic cluster determined by variable number tandem repeat (VNTR) profiling and whole genome sequencing. 11 patients with chronic M. abscessus infection (AAFB smear positive) underwent bilateral lung transplantation. Outcomes are shown in table. Dramatically worse outcomes were seen in patients infected with M. abscessus subspecies abscessus, genetic clusters VNTR I and II, compared with other strains. We have reported for the first time an association between lung transplant outcome in CF patients and M. abscessus genetic cluster and advise great caution in transplanting patients infected with genetic clusters VNTR I or II. However, patients infected with other M. abscessus strains appear to have acceptable outcomes.

Introduction: Although mean lung function (LF) is stable to two years in NBS CF infants (1), the extent to which LF varies within individuals over time is unknown. Aim: To investigate within-subject change in LF during the first two years. Methods: Forced Expiratory Volume (FEV 0.5 ), Lung Clearance Index (LCI) and plethysmographic Functional Residual Capacity (FRC) were measured in CF infants and controls at ∼ 3mth, 1 and 2yrs. Results: Of 58 NBS CF infants, 10 had an abnormal (≥1.96 z-scores) LCI at 1yr, 8 of whom had a 2yr LCI within the normal range (Fig). Of 9 infants with abnormal 2yr results, only 2 had abnormal 1yr results. In contrast to controls, there was no association between zLCI at 2yrs with either 3mth or 1yr results. No child had abnormal zFEV 0.5 at both 1 and 2yr tests. Despite significant associations between zFRCat 2yrs and either 3mths or 1yr, most infants (6/9; 67%) with abnormal 1yr FRC had normal 2yr results. The mean (95% range) within-subject change in zLCI among 31 controls with paired results at 1 and 2yrs was -0.1 (-1.8 to 1.5). 11 infants with CF had a significant increase (> 1.5 z scores) in LCI between 1 and 2yrs although only 6 of these also had an abnormal zLCI at 2yr (Fig). Conclusions: LF outcomes are highly variable over time in individual NBS CF infants, presenting challenges for interventional trial design and clinical decision making. Ref: (1) Thia et al ERJ 2013(S57).

Objectives: Long term effects of exercise on FEV1, LCI, VO2Peak, 10m-MSWT and CFQ-R. Methods: Children aged 10±3 (mean±SD, range 6-15) yrs with average FEV1 of 86.6±15.3%pred were randomised by minimisation into control (n=34) or intervention groups (n=37). Both received specialist CF care. The intervention group also received weekly supervised exercise for 24-months. Results: Data for 68/71 were available. There was an average annual FEV1 decline of 1.7%pred in both groups and a 15% increase in VO2Peak, but no between-group differences. Significant between-group differences in 10m-MSWT favoured the intervention group. Perception of treatment burden reduced significantly in the intervention group. Increased physical and total-CFQ domains approached significance, with no between-groups differences in other CFQ-R domains. Conclusion: Despite modest deterioration in lung function over 2yrs, weekly supervised exercise significantly improved functional exercise capacity in the intervention group with quality of life benefits.

The lung clearance index (LCI) is more sensitive than spirometry in detecting abnormal lung function in children with cystic fibrosis. LCI is thought to be independent of age, but recent evidence suggests that the upper limit of normal is higher in infants and preschool children than in older subjects. This study examines whether LCI remains independent of body size throughout childhood. Multiple-breath washout data from healthy children and adolescents were collated from three centres using the mass spectrometer system and the inert gas sulfur hexafluoride. Reference equations for LCI and functional residual capacity (FRC) were constructed using the LMS (lambda-mu-sigma) method. Data were available from 497 subjects (2 weeks to 19 years of age) tested on 659 occasions. LCI was dependent on body size, decreasing in a nonlinear pattern as height increased. Changes were particularly marked in the first 5 years of life. Height, age and sex were all independent predictors of FRC. Minimal between-centre differences allowed unified reference equations to be developed. LCI is not independent of body size. Although a constant upper normal limit would suffice for cross-sectional clinical assessments from 6 years of age, appropriate reference equations are essential for accurate interpretation of results during early childhood.