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Background: The denomination of noncystic fibrosis bronchiectasis (NCFB) includes several causes, and differences may be expected between the patient subgroups regarding age, comorbidities, and clinical and functional evolution. This study sought to identify the main causes of NCFB in a cohort of stable adult patients and to investigate whether such conditions would be different in their clinical, functional, and quality of life aspects., Methods: Between 2017 and 2019, all active patients with NCFB were prospectively evaluated searching for clinical data, past medical history, dyspnea severity grading, quality of life data, microbiological profile, and lung function (spirometry and six-minute walk test)., Results: There was a female predominance; mean age was 54.7 years. Causes were identified in 82% of the patients, the most frequent being postinfections ( n = 39), ciliary dyskinesia (CD) ( n = 32), and chronic obstructive pulmonary disease (COPD) ( n = 29). COPD patients were older, more often smokers (or former smokers) and with more comorbidities; they also had worse lung function (spirometry and oxygenation) and showed worse performance in the six-minute walk test (6MWT) (walked distance and exercise-induced hypoxemia). Considering the degree of dyspnea, in the more symptomatic group, patients had higher scores in the three domains and total score in SGRQ, besides having more exacerbations and more patients in home oxygen therapy., Conclusions: Causes most identified were postinfections, CD, and COPD. Patients with COPD are older and have worse pulmonary function and more comorbidities. The most symptomatic patients are clinically and functionally more severe, besides having worse quality of life., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2024 Ádria Cristina da Silva et al.)

Motile cilia and flagella beat rhythmically on the surface of cells to power the flow of fluid and to enable spermatozoa and unicellular eukaryotes to swim. In humans, defective ciliary motility can lead to male infertility and a congenital disorder called primary ciliary dyskinesia (PCD), in which impaired clearance of mucus by the cilia causes chronic respiratory infections 1 . Ciliary movement is generated by the axoneme, a molecular machine consisting of microtubules, ATP-powered dynein motors and regulatory complexes 2 . The size and complexity of the axoneme has so far prevented the development of an atomic model, hindering efforts to understand how it functions. Here we capitalize on recent developments in artificial intelligence-enabled structure prediction and cryo-electron microscopy (cryo-EM) to determine the structure of the 96-nm modular repeats of axonemes from the flagella of the alga Chlamydomonas reinhardtii and human respiratory cilia. Our atomic models provide insights into the conservation and specialization of axonemes, the interconnectivity between dyneins and their regulators, and the mechanisms that maintain axonemal periodicity. Correlated conformational changes in mechanoregulatory complexes with their associated axonemal dynein motors provide a mechanism for the long-hypothesized mechanotransduction pathway to regulate ciliary motility. Structures of respiratory-cilia doublet microtubules from four individuals with PCD reveal how the loss of individual docking factors can selectively eradicate periodically repeating structures., (© 2023. The Author(s).)

Background: Primary ciliary dyskinesia is a rare genetic disorder characterized by recurrent sinopulmonary infections and worsening obstructive lung disease. Kidney and brain involvement is less common and is associated with overlapping ciliopathies/syndromes. The lungs are impacted early in the course of the disease, so it is vital to monitor lung function and recognize any decline by doing appropriate lung function tests. This systematic review compares different lung function tests and analyzes which one becomes abnormal earlier in the disease., Methods: A systematic review was conducted following the methodology in the "Cochrane Handbook on Systematic Reviews for diagnostic tests." The Preferred Reporting Items for Systematic Review and Meta-Analyses were used to report the results. The risk of bias assessment was done using "The Cochrane Handbook for Systematic Reviews tool for interventional studies." A meta-analysis was not performed due to the small sample size. All studies were analyzed by using Joanna Briggs Institute's critical appraisal tool., Results: After screening for the duplication of results and applying inclusion and exclusion criteria, 14 studies were assessed by reading the full texts. Out of these, eight were finally included in this systematic review. The total sample size from all studies was 165, including 80 males. All the studies used spirometry as a lung function test, whereas multiple breath washout was used in five studies. Other tests used for comparison were computed tomography (CT), magnetic resonance imaging (MRI), cardiopulmonary exercise testing, 6-min walk test, DLCO, maximal inspiratory pressure, maximal expiratory pressure, and PaO 2 . Lung clearance index (LCI) by multiple breath washout had a stronger association with the structural changes on CT/MRI than spirometry indices like forced expiratory volume in 1 s (FEV1) and forced expiratory flow at 25% to 75% of lung volume (FEF 25-75)., Conclusions: Based on the evidence from this systematic review, LCI becomes abnormal earlier than FEV1 or FEF 25-75 and positively correlates with the findings on high-resolution CT. It has limitations like the lack of reference values and a complex technique to perform the test., (© 2022 Wiley Periodicals LLC.)

Zebrafish is a vertebrate teleost widely used in many areas of research. As embryos, they develop quickly and provide unique opportunities for research studies owing to their transparency for at least 48 h post fertilization. Zebrafish have many ciliated organs that include primary cilia as well as motile cilia. Using zebrafish as an animal model helps to better understand human diseases such as Primary Ciliary Dyskinesia (PCD), an autosomal recessive disorder that affects cilia motility, currently associated with more than 50 genes. The aim of this study was to validate zebrafish motile cilia, both in mono and multiciliated cells, as organelles for PCD research. For this purpose, we obtained systematic high-resolution data in both the olfactory pit (OP) and the left-right organizer (LRO), a superficial organ and a deep organ embedded in the tail of the embryo, respectively. For the analysis of their axonemal ciliary structure, we used conventional transmission electron microscopy (TEM) and electron tomography (ET). We characterised the wild-type OP cilia and showed, for the first time in zebrafish, the presence of motile cilia (9 + 2) in the periphery of the pit and the presence of immotile cilia (still 9 + 2), with absent outer dynein arms, in the centre of the pit. In addition, we reported that a central pair of microtubules in the LRO motile cilia is common in zebrafish, contrary to mouse embryos, but it is not observed in all LRO cilia from the same embryo. We further showed that the outer dynein arms of the microtubular doublet of both the OP and LRO cilia are structurally similar in dimensions to the human respiratory cilia at the resolution of TEM and ET. We conclude that zebrafish is a good model organism for PCD research but investigators need to be aware of the specific physical differences to correctly interpret their results.

Background: Lung clearance index (LCI) is a promising lung function outcome in individuals with primary ciliary dyskinesia (PCD). The impact of events clinically important for individuals with PCD, such as pulmonary exacerbations, on LCI is unknown., Methods: We conducted an international, multicentre, observational cohort study to assess the association of LCI and risk of pulmonary exacerbation, specific changes in LCI during pulmonary exacerbation and global variability of LCI across four visits every 4 months. Ninety individuals with PCD, aged 3-41 years, underwent nitrogen multiple-breath washout (MBW) and spirometry measurements. The association of LCI and pulmonary exacerbations was assessed by Cox proportional hazards and random-effects regression models., Results: We obtained 430 MBW and 427 spirometry measurements. In total, 379 person-years at risk contributed to the analysis. Per one unit increase (deterioration) in LCI, the risk of future pulmonary exacerbation increased by 13%: HR (95% CI), 1.13 (1.04 to 1.23). If LCI changed from a range of values considered normal to abnormal, the risk of future pulmonary exacerbations increased by 87%: 1.87 (1.08 to 3.23). During pulmonary exacerbations, LCI increased by 1.22 units (14.5%). After pulmonary exacerbations, LCI tended to decline. Estimates of variability in LCI suggested lower variation within individuals compared with variation between individuals. Findings were comparable for forced expiratory volume in 1 s., Conclusion: On a visit-to-visit basis, LCI measurement may add to the prediction of pulmonary exacerbations, the assessment of lung function decline and the potential lung function response to treatment of pulmonary exacerbations., Competing Interests: Competing interests: Relevant financial activities for this work: AS reports grant from Ruhr-University Bochum, payment to institution. MB reports postdoctoral grant KOOR from UZLeuven, payment to institution. Relevant financial activities outside the work: FS has grants/grants pending from LungenLiga Bern, CFCH, and payment for lectures from Vertex, Novartis. MB is a member of the European Reference Network for Rare Respiratory Diseases (ERN-LUNG) Project ID No 739546. She has grants/grants pending from Horizon 2020, MyCyFAPP., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Case Presentation: A 14-year old girl presented with history of productive cough since the age of 3 years. For the past 6 years, she complained of chest tightness and wheezing. There was also nasal stuffiness and discharge for the past 6 years. She denied history of hemoptysis, ear discharge, or chest pain. There was no history of respiratory distress at the time of birth. Her brother also suffered from productive cough and wheezing since the age of 3 years. However, both her parents were asymptomatic., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Primary cilia are specialized sensory organelles that protrude from the apical surface of most cell types. During the past 2 decades, they have been found to play important roles in tissue development and signal transduction, with mutations in ciliary-associated proteins resulting in a group of diseases collectively known as ciliopathies. Many of these mutations manifest as renal ciliopathies, characterized by kidney dysfunction resulting from aberrant cilia or ciliary functions. This group of overlapping and genetically heterogeneous diseases includes polycystic kidney disease, nephronophthisis, and Bardet-Biedl syndrome as the main focus of this review. Renal ciliopathies are characterized by the presence of kidney cysts that develop due to uncontrolled epithelial cell proliferation, growth, and polarity, downstream of dysregulated ciliary-dependent signaling. Due to cystic-associated kidney injury and systemic inflammation, cases result in kidney failure requiring dialysis and transplantation. Of the handful of pharmacologic treatments available, none are curative. It is important to determine the molecular mechanisms that underlie the involvement of the primary cilium in cyst initiation, expansion, and progression for the development of novel and efficacious treatments. This review updates research progress in defining key genes and molecules central to ciliogenesis and renal ciliopathies., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: We aim to assess the anxiety and depressive symptoms related to the COVID-19 pandemic in children with chronic lung disease and their parents and also to evaluate parents' coping strategies., Methods: Parents of children aged 4-18 years, with chronic lung disease (study group n = 113) and healthy control (n = 108) were enrolled in the study. General Health Questionnaire-12, specific COVID-19 related anxiety questions, The Coping Orientation to Problems Experienced inventory, coronavirus-related psychiatric symptom scale in children-parental form were used to analyze the psychiatric effects of COVID-19. Parents were also asked about how online education affected their family life and children. All data were compared between children/parents in the study and control groups. Risk factors related with anxiety scores of children were also analyzed., Results: Talking about the pandemic, concern about coronavirus transmission, taking precaution to prevent coronavirus transmission, making pressure to protect from COVID-19 were significantly higher in parents within the study group (p < .05). Parents in the study group used more problem-focused coping than parents in the control group (p = .003). Anxiety symptoms score was higher in children of the study group (p = .007). Parents in the study group found online education more useful than parents in the control group., Conclusion: Children with chronic lung diseases and their parents have more anxiety due to COVID-19 pandemic and these parents use more mature coping strategies to manage the stress of the pandemic. Longitudinal and larger studies should be done in all aspects of online education in children with chronic lung diseases., (© 2020 Wiley Periodicals LLC.)

Background: Chest physiotherapy (CP) is a recommended treatment modality in primary ciliary dyskinesia (PCD)., Objective: Primary aim was to compare the efficacy and safety of the conventional chest physiotherapy (CCP) and oscillatory positive expiratory pressure therapy (OPEPT). Secondary aims were to compare the exacerbation rate, time until the first exacerbation, patient compliance and comfort between the two CP methods., Methods: This is a 6 month randomized, controlled crossover trial. Patients >6 years of age with PCD were randomized into two groups, first group was assigned to OPEPT (Acapella®) for 3 months while second group was assigned to CCP. Groups were crossed over to the other modality after a 15-day washout period. Pulmonary function tests (PFTs) and compliance were monitored by monthly clinic visits., Results: There was a significant increase in FEV 1 , FEF 25-75 , and PEF values (p = .018, p = .020, and p = .016, respectively) in the OPEPT group and in FVC values (p = .007) in CCP group compared to baseline. However PFT increase at 3rd month was not superior to each other with both physiotherapy methods. Median acute pulmonary exacerbation rate and time period until the first exacerbation were similar in both groups (p = .821, p = .092, respectively). Comfort and effectiveness of OPEPT was higher than CCP according to patients (p = .029 and p = .042, respectively). There were no adverse effects with either therapy., Conclusions: OPEPT was as effective as CCP in PCD patients. OPEPT was more comfortable and effective than CCP according to patients. OPEPT might be an efficient alternative method for airway cleareance in PCD patients., (© 2020 Wiley Periodicals LLC.)

Primary Ciliary Dyskinesia (PCD) is a genetic motile ciliopathy, leading to significant otosinopulmonary disease. PCD diagnosis is often missed or delayed due to challenges with different diagnostic modalities. Ciliary videomicroscopy, using Digital High-Speed Videomicroscopy (DHSV), one of the diagnostic tools for PCD, is considered the optimal method to perform ciliary functional analysis (CFA), comprising of ciliary beat frequency (CBF) and beat pattern (CBP) analysis. However, DHSV lacks standardized, published operating procedure for processing and analyzing samples. It also uses living respiratory epithelium, a significant infection control issue during the COVID-19 pandemic. To continue providing a diagnostic service during this health crisis, the ciliary videomicroscopy protocol has been adapted to include adequate infection control measures. Here, we describe a revised protocol for sampling and laboratory processing of ciliated respiratory samples, highlighting adaptations made to comply with COVID-19 infection control measures. Representative results of CFA from nasal brushing samples obtained from 16 healthy subjects, processed and analyzed according to this protocol, are described. We also illustrate the importance of obtaining and processing optimal quality epithelial ciliated strips, as samples not meeting quality selection criteria do now allow for CFA, potentially decreasing the diagnostic reliability and the efficiency of this technique.

Background: Primary ciliary dyskinesia (PCD) is generally likened to cystic fibrosis (CF) due to similarities in impaired mucociliary clearance and some other symptoms. The aim of our study was to investigate pulmonary and extrapulmonary characteristics of children with CF and PCD since no studies have addressed respiratory muscle strength in children with PCD and to compare the results to those obtained from healthy age-matched controls., Methods: Pulmonary and extrapulmonary characteristics were assessed by 6-min walk test, spirometry, maximum inspiratory and expiratory pressure measurements, and knee extensor strength test in the children with CF, PCD, and healthy controls., Results: Children with PCD and CF had similar PFT results, except forced expiratory flow between 25% and 75% of vital capacity (FEF 25-75 ) which was lower in PCD (p = .04). Maximum inspiratory pressure (MIP) value was lower in the children with CF compared with the healthy controls (p = .016), MEP value of the children with PCD was worse than those with CF and healthy controls (p = .013 and p = .013), respectively. 6-min walk test (6MWT) distance of the children with CF was lower than their healthy counterparts (p = .003). Knee extensor muscle strength differed among the children with PCD, CF, and healthy control groups, but post hoc test failed to show statistical significance (p = .010)., Conclusion: Children with CF and PCD had some impairments in pulmonary functions, respiratory muscle strength, functional capacity, and peripheral muscle strength compared with healthy children. However, the unique characteristics of each disease should be considered during physiotherapy assessment and treatment. The clinicians may especially focus on the respiratory and peripheral muscle strength of the children with PCD., (© 2020 Wiley Periodicals LLC.)

Objective: To report detailed knowledge about the clinical manifestations, ciliary phenotypes, genetic spectrum as well as phenotype/genotype correlation in primary ciliary dyskinesia (PCD) in Chinese children., Study Design: We recruited 50 Chinese children with PCD. Extensive clinical assessments, nasal nitric oxide, high-speed video analysis, transmission electron microscopy, and genetic testing were performed to characterize the phenotypes and genotypes of these patients., Results: Common clinical features included chronic wet cough (85.4%), laterality defects (70.0%), and neonatal respiratory distress (55.8%). A high prevalence of congenital abnormalities (30.2%, 13/43), observed in patients who underwent comprehensive examination for comorbidities, included thoracic deformity (11.6%, 5/43), congenital heart disease (9.3%, 4/43), and sensorineural deafness (2.3%, 1/43). For 24 children age >6 years, the mean predicted values of forced expiratory volume in 1 second were 87.2%. Bronchiectasis evident on high-resolution computed tomography was reported in 38.1% of patients (16/42). Biallelic mutations (81 total; 57 novel) were identified in 13 genes: DNAAF3, DNAAF1, DNAH5, DNAH11, CCDC39, CCDC40, CCDC114, CCDC103, HYDIN, CCNO, DNAI1, OFD1, and SPAG1. Overall, ciliary ultrastructural and beat pattern correlated well with the genotype. However, variable phenotypes were also observed in CCDC39 and DNAH5 mutant cilia., Conclusions: This large PCD cohort in China broadens the clinical, ciliary phenotypes, and genetic characteristics of children with PCD. Our findings are roughly consistent with previous studies besides some peculiarities such as high prevalence of associated abnormalities., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Rationale: In cystic fibrosis (CF), the lung clearance index (LCI), derived from multiple breath washout (MBW), is more sensitive in detecting early lung disease than FEV 1 ; MBW has been less thoroughly evaluated in young patients with primary ciliary dyskinesia (PCD). Objectives: Our objectives were 1 ) to evaluate the sensitivity of MBW and spirometry for the detection of mild lung disease in young children with PCD and CF compared with healthy control (HC) subjects and 2 ) to compare patterns of airway obstruction between disease populations. Methods: We used a multicenter, single-visit, observational study in children with PCD and CF with a forced expiratory volume in 1 second (FEV 1 ) greater than 60% predicted and HC subjects, ages 3-12 years. Nitrogen MBW and spirometry were performed and overread for acceptability. χ 2 and Kruskall-Wallis tests compared demographics and lung function measures between groups, linear regression evaluated the effect of disease state, and Spearman's rank correlation coefficient compared the LCI and spirometric measurements. Results: Twenty-five children with PCD, 49 children with CF, and 80 HC children were enrolled, among whom 17 children with PCD (68%), 36 children with CF (73%), and 53 (66%) HC children performed both acceptable spirometry and MBW; these children made up the analytic cohort. The median age was 9.0 years (interquartile range [IQR], 6.8-11.1). The LCI was abnormal (more than 7.8) in 10 of 17 (59%) patients with PCD and 21 of 36 (58%) patients with CF, whereas FEV 1 was abnormal in three of 17 (18%) patients with PCD and six of 36 (17%) patients with CF. The LCI was significantly elevated in patients with PCD and CF compared with HC subjects (ratio of geometric mean vs. HC: PCD 1.27; 95% confidence interval [CI], 1.15-1.39; and CF 1.24; 95% CI, 1.15-1.33]). Children with PCD had lower midexpiratory-phase forced expiratory flow % predicted compared with children with CF (62% [IQR, 50-78%] vs. 85% [IQR, 68-99%]; P  = 0.05). LCI did not correlate with FEV 1 . Conclusions: The LCI is more sensitive than FEV 1 in detecting lung disease in young patients with PCD, similar to CF. LCI holds promise as a sensitive endpoint for the assessment of early PCD lung disease.

Objective: In England, the National Health Service commissioned a National Management Service for children with primary ciliary dyskinesia (PCD). The aims of this study were to describe the health of children seen in this Service and compare lung function to children with cystic fibrosis (CF)., Design: Multi-centre service evaluation of the English National Management PCD Service., Setting: Four nationally commissioned PCD centres in England., Patients: 333 children with PCD reviewed in the Service in 2015; lung function data were also compared with 2970 children with CF., Results: Median age at diagnosis for PCD was 2.6 years, significantly lower in children with situs inversus (1.0 vs 6.0 years, p<0.001). Compared with national data from the CF Registry, mean (SD) %predicted forced expiratory volume in one second (FEV 1 ) was 76.8% in PCD (n=240) and 85.0% in CF, and FEV 1 was lower in children with PCD up to the age of 15 years. Approximately half of children had some hearing impairment, with 26% requiring hearing aids. Children with a lower body mass index (BMI) had lower FEV 1 (p<0.001). One-third of children had positive respiratory cultures at review, 54% of these grew Haemophilus influenzae ., Conclusions: We provide evidence that children with PCD in England have worse lung function than those with CF. Nutritional status should be considered in PCD management, as those with a lower BMI have significantly lower FEV 1 . Hearing impairment is common but seems to improve with age. Well-designed and powered randomised controlled trials on management of PCD are needed to inform best clinical practice., Competing Interests: Competing interests: JL reports grants, personal fees and non-financial support from Aerocrine/ Circassia, grants and personal fees from Vertex, grants from Parion, outside the submitted work. SC reports grants, personal fees and non-financial support from Vertex Pharmaceuticals, grants and other from Chiesi Pharmaceuticals, other from Pharmaxis Pharmaceuticals, personal fees from Actavis Pharmaceuticals, other from Profile Pharma, outside the submitted work., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Bronchial epithelial reticular basement membrane (RBM) thickening occurs in diseases with both eosinophilic (allergic bronchial asthma [BA]) and neutrophilic (cystic fibrosis [CF] and primary ciliary dyskinesia [PCD]) chronic airway inflammation; however, the lung function and airway remodeling relation remains unclear. The aim of this study was to test whether ventilation inhomogeneity is related to RBM thickening., Methods: Multiple breath washout test, endobronchial biopsy, and BAL were performed in 24 children with CF, 11 with PCD, 15 with BA, and in 19 control subjects. Lung clearance index at 2.5% (1/40th) of starting nitrogen concentration (LCI 2.5 ), RBM thickness, and lavage fluid cytology were quantified; their mutual associations were studied by using Spearman rank correlations (r)., Results: In asthma, ventilation inhomogeneity (mean ± SD) was mild (LCI 2.5 , 9.3 ± 1.4 vs 7.9 ± 0.9 in control subjects; P = .0391), and the RBM thickened (5.26 ± 0.98 μm vs 3.12 ± 0.62 μm in control subjects; P < .0001). No relation between RBM thickness and ventilation inhomogeneity or lavage cytology was found. In CF and PCD, RBM thickness was similar to that in asthma (4.54 ± 0.66 μm and 5.27 ± 1.11 μm, respectively), but ventilation inhomogeneity was significantly higher (LCI 2.5 , 12.5 ± 2.4 and 11.8 ± 2.5). Both in CF and PCD, RBM thickness correlated with LCI 2.5 (r = 0.594, P = .015; r = 0.821, P = .023). In PCD only, RBM thickness was also related to the number of neutrophils in lavage fluid (r = 0.821; P = .023)., Conclusions: Lung function impairment in relation to RBM thickness was milder in BA than in CF and PCD. In asthma, ventilation inhomogeneity did not correlate with RBM thickness, whereas it did in CF and PCD. This outcome suggests a different structure-function relation in these diseases., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: Nitric oxide (NO) is a gas synthesized by the inducible NO synthase enzyme in airway cells and it is thought to make important functions in the airway inflammation of several respiratory diseases., Evidence Acquisition: This current study is a review of the literature from 1990 to present about NO and its use in clinical practice. The databases used were PubMed, Scopus, and Cochrane Library., Evidence Synthesis: At the respiratory level there are three different measurements sites of NO: nNO (nasal nitric oxide), FeNO (exhaled fraction of nitric oxide), CaNO (alveolar nitric oxide). Each of them is produced at different levels of the respiratory tract and is involved in various diseases. nNO finds its use, principally, in the allergic rhinitis in fact it can be used as a measure of therapeutic efficacy, but not for the evaluation of the severity; also in primary ciliary dyskinesia (PCD), where high levels exclude the disease, and in chronic rhinosinusitis, but it is not currently used as a diagnostic or prognostic marker. FeNO has a greatest use in bronchial asthma, particularly, it is considered a non-invasive biomarker to identify and to monitor airway inflammation but currently, there is not a consensus on the use of the FeNO in the management of asthma treatment. Finally, CaNO is the least used in clinical practice, because lack of standardization of measurement techniques., Conclusions: Nitric oxide is a sensitive indicator of the presence of airway inflammation and ciliary dysfunction, although some studies have shown varying or conflicting results.

Primary ciliary dyskinesia is an inherited disorder in which respiratory cilia are stationary, or beat in a slow or dyskinetic manner, leading to impaired mucociliary clearance and significant sinopulmonary disease. One diagnostic test is ciliary functional analysis using digital high-speed video microscopy (DHSV), which allows real-time analysis of complete ciliary function, comprising ciliary beat frequency (CBF) and ciliary beat pattern (CBP). However, DHSV lacks standardization. In this paper, the current knowledge of DHSV ciliary functional analysis is presented, and recommendations given for a standardized protocol for ciliary sample collection and processing. A proposal is presented for a quantitative and qualitative CBP evaluation system, to be used to develop international consensus agreement, and future DHSV research areas are identified., (© 2019 Wiley Periodicals, Inc.)

Introduction: Primary ciliary dyskinesia (PCD) is a rare, heterogeneous genetic disorder where impaired mucociliary clearance is caused by dysfunctional motile cilia leading to bronchiectasis. There is limited evidence characterising the nutritional status of children with PCD, although lower body mass index (BMI) z-score has been associated with worse lung function (FEV 1 )., Methods: All children (n = 43) with PCD, aged <16 years, from a single tertiary centre were prospectively enrolled. Information on clinical phenotype and nutritional status including bioelectrical impedance spectroscopy (BIS) phase-angle was collected., Results: There was a weak positive association between height-for-age z-score (HAZ) and FEV 1 z-score (n = 28, r = 0.4, p = 0.049). Those with a low fat free mass index (<-2 z scores) had a lower BMI z score (-1.3 ± 1.2 vs. 0.8 ± 0.7, p = 0.0002). BIS phase angle identified more patients at nutritional risk than using moderate malnutrition cut-offs of either HAZ or BMI ≤ -2 z scores alone (21% vs. 4.6% vs. 6.9% respectively). PCD patients had a higher incidence of vitamin D insufficiency (<50 nmoL/L) (54%) and deficiency (<30 nmoL/L) (26%) than healthy children., Conclusions: We have characterised the nutritional phenotype of a cohort of children with PCD. Monitoring vitamin D levels is important in PCD patients. There is a weak association between lung function and nutritional status, and measures of BIS phase-angle. The use of BIS phase-angle may allow for early identification of at risk children and may therefore be of benefit for nutritional assessments in the clinical setting. These findings will help inform a future nutritional intervention strategy in children with PCD., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Primary ciliary dyskinesia (PCD) is a hereditary defect of motile cilia in humans and several domestic animal species. Typical clinical findings are chronic recurrent infections of the respiratory tract and fertility problems. We analyzed an Alaskan Malamute family, in which two out of six puppies were affected by PCD. The parents were unaffected suggesting autosomal recessive inheritance. Linkage and homozygosity mapping defined critical intervals comprising ~118 Mb. Whole genome sequencing of one case and comparison to 601 control genomes identified a disease associated frameshift variant, c.43delA, in the NME5 gene encoding a sparsely characterized protein associated with ciliary function. Nme5-/- knockout mice exhibit doming of the skull, hydrocephalus and sperm flagellar defects. The genotypes at NME5:c.43delA showed the expected co-segregation with the phenotype in the Alaskan Malamute family. An additional unrelated Alaskan Malamute with PCD and hydrocephalus that became available later in the study was also homozygous mutant at the NME5:c.43delA variant. The mutant allele was not present in more than 1000 control dogs from different breeds. Immunohistochemistry demonstrated absence of the NME5 protein from nasal epithelia of an affected dog. We therefore propose NME5:c.43delA as the most likely candidate causative variant for PCD in Alaskan Malamutes. These findings enable genetic testing to avoid the unintentional breeding of affected dogs in the future. Furthermore, the results of this study identify NME5 as a novel candidate gene for unsolved human PCD and/or hydrocephalus cases., Competing Interests: The authors have declared that no competing interests exist.

Previous reports suggested links between respiratory ciliary dysfunction and primary ciliopathies such as X-linked retinitis pigmentosa (XLRP). To investigate if patients with XLRP have abnormal airway ciliary structure or function, we assessed respiratory ciliary beat pattern and ultrastructure, including ciliary orientation, in 12 patients with XLRP without respiratory disease and 10 control subjects. Patients with XLRP had normal ciliary ultrastructure but significantly (p=0.004) increased mean ciliary deviation (33.8°±9.4°) compared with normal subjects (14.8°±5.4°). Altered orientation was associated with impaired ciliary beat pattern in six patients with XLRP. These findings indicate that XLRP mutations, affecting non-motile cilia of the photoreceptors in the retina, can have effects on motile cilia in the respiratory tract. The observation of disrupted ciliary orientation in patients with XLRP is suggestive of a defect in planar cell polarity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Primary ciliary dyskinesia (PCD) is a congenital lung disease that leads to recurrent and chronic lung infection. The resulting inflammation causes lung damage and declines in lung function. Mannose-binding lectin (MBL) is a first line host defense protein of importance for the innate immunity. Polymorphisms in the MBL gene named MBL2 result in unstable and low functional levels MBL proteins. MBL insufficiency is linked to an increased risk of lung infection and to declines in lung function in patients with cystic fibrosis. We investigated whether there is a similar link in patients with PCD., Methods: This retrospective longitudinal study included 85 patients with PCD. Diagnostics and age at diagnosis were recorded, complete spirometry data starting at diagnosis, and Pseudomonas aeruginosa infection status over the last 2 years were collected, and the patients were grouped according to MBL2 genotype status (MBL2-sufficient or MBL2-deficient)., Results: MBL-deficient patients were diagnosed almost 3 years earlier than MBL-sufficient patients (median 6.1 vs 8.9 years, P  < 0.05). There were no differences in the first measured spirometry values, but MBL-deficient patients showed greater declines in forced expiratory volume in one sec (FEV 1 ) than patients with MBL sufficiency (z-score: -0.049 per year [95% CI, -0.075; -0.021] vs -0.009 per year [95% CI, -0.033; 0.015]; P = 0.023). No differences were found in forced vital capacity (FVC), FEV 1 /FVC, or infection status., Conclusion: MBL-deficiency, which is associated with MBL2 mutations, was associated with a lower age at diagnosis and with steeper declines in FEV 1 in patients with PCD. This suggests that the MBL genotype might be a disease modifier in PCD., (© 2019 Wiley Periodicals, Inc.)

Primary ciliary dyskinesia (PCD) causes a broad spectrum of disease. This study aims to explore the developmental, behavioral, and social-emotional aspects of preschool-aged children with PCD. Fourteen PCD, 17 cystic fibrosis (CF) patients and 15 healthy subjects were enrolled. Developmental features of the participants were evaluated with Ages and Stages Questionnaire. Parents of participants filled out the Child Behavior Checklist (CBCL). The number of children screened positive for developmental delay was statistically higher in the PCD group. Higher numbers of children with PCD were screened positive for developmental delay in communication and problem-solving domains. Delay in fine motor skill domain was more common in children with PCD and CF compared to healthy subjects. There was no difference among the three groups in terms of gross motor and personal-social development. None of the children in all three groups was shown to have social-emotional problems. In CBCL, patients with CF had higher internalizing problem scores. Externalizing and total problem scores did not differ between the three groups. However, among PCD patients, children with developmental delay on more than one domain had higher externalizing and total problem scores.Conclusion: The current study revealed that positive screening for developmental delay is more common in preschool-aged PCD patients compared to patients with CF and healthy children. What is Known: • Intelligence scores of school-aged PCD patients are similar to healthy subjects despite their higher internalizing problem scores on Child Behavior Checklist (CBCL). • School-aged PCD patients exhibit higher hyperactivity and inattention findings. What is New: • Positive screening for developmental delay in communication, problem-solving and fine motor skills is more common in preschool-aged PCD patients. • Preschool-aged PCD patients screened positive for developmental delay in more than one domain have higher externalizing and total problem scores on CBCL.

Background: Primary Ciliary Dyskinesia (PCD) diagnosis relies on a combination of tests which may include (a) nasal Nitric Oxide (nNO), (b) High Speed Video Microscopy (HSVM) and (c) Transmission Electron Microscopy (TEM). There is variability in the availability of these tests and lack of universal agreement whether diagnostic tests should be performed in sequence or in parallel. We assessed three combinations of tests for PCD diagnosis and estimated net sensitivity and specificity as well as cost-effectiveness (CE) and incremental cost-effectiveness (ICE) ratios., Methods and Results: A hypothetical initial population of 1000 referrals (expected 320 PCD patients) was followed through a probabilistic decision analysis model which was created to assess the CE of three diagnostic algorithms (a) nNO + TEM in sequence, (b) nNO + HSVM in sequence and (c) nNO/HSVM in parallel followed, in cases with conflicting results, by confirmatory TEM (nNO/HSVM+TEM). Number of PCD patients identified, CE and ICE ratios were calculated using Monte Carlo simulations. Out of 320 expected PCD patients, 313 were identified by nNO/HSVM+TEM, 274 with nNO + HSVM and 198 with nNO + TEM. The nNO/HSVM+TEM had the highest mean annual cost (€209 K) followed by nNO + TEM (€150 K) and nNO + HSVM (€136 K). The nNO + HSVM algorithm dominated the nNO + TEM algorithm (less costly and more effective). The ICE ratio for nNO/HSVM+TEM was €2.1 K per additional PCD patient identified., Conclusions: The diagnostic algorithm (nNO/HSVM+TEM) with parallel testing outperforms algorithms with tests in sequence. These findings, can inform the dialogue on the development of evidence-based guidelines for PCD diagnostic testing. Future research in understudied aspects of the disease, such as PCD-related quality of life and PCD-associated costs, is needed to help the better implementation of these guidelines across various healthcare systems.

Primary ciliary dyskinesia (PCD) is a genetic disorder that is typically inherited in an autosomal recessive manner. It is clinically characterized by recurrent respiratory infections. However, its repercussions for patient quality of life should not be overlooked. Studies have shown that PCD has a significant impact on the lives of patients, although there are as yet no PCD-specific markers of quality of life. To address that problem, researchers in the United Kingdom developed a quality-of-life questionnaire for patients with PCD. The present communication focuses on the process of translating that questionnaire into Brazilian Portuguese, through a partnership between researchers in Brazil and those in the United Kingdom, as well as its subsequent application in patients in Brazil.

Introduction: Nasal nitric oxide (nNO) is extremely low in individuals with primary ciliary dyskinesia (PCD) and is recommended as part of early workup. We investigated whether tidal breathing sampling for a few seconds was as discriminative between PCD and healthy controls (HC) as conventional tidal breathing sampling (cTB-nNO) for 20-30 s., Methods: We performed very rapid sampling of tidal breathing (vrTB-nNO) for 2, 4 and 6 s, respectively. Vacuum sampling with applied negative pressure (vrTB-nNO vac ; negative pressure was applied by pinching the sampling tube) for < 2 s resulted in enhanced suction of nasal air during measurement. Feasibility, success rate, discriminatory capacity, repeatability and agreement were assessed for all four sampling modalities., Results: We included 13 patients with PCD, median (IQR) age of 21.8 (12.2-27.7) years and 17 HC, 25.3 (14.5-33.4) years. Measurements were highly feasible (96.7% success rate). Measured NO values with vrTB-nNO modalities differed significantly from TB-nNO measurements (HC: p < 0.001, PCD: p < 0.05). All modalities showed excellent discrimination. The vacuum method gave remarkably high values of nNO in both groups (1865 vs. 86 ppb), but retained excellent discrimination. vrTB-nNO 4sec , vrTB-nNO 6sec and vrTB-nNO vac showed identical specificity to cTB-nNO (all: 1.0, 95% CI 0.77-1.0)., Conclusion: vrTB-nNO sampling requires only a few seconds of probe-in-nose time, is feasible, and provides excellent discrimination between PCD and HC. Rapid TB-nNO sampling needs standardisation and further investigations in infants, young children and patients referred for PCD workup.

Primary ciliary dyskinesia (PCD) is a genetic disorder in which impaired ciliary function leads to chronic airway disease. Exome sequencing of a PCD subject identified an apparent homozygous frameshift variant, c.887&#95;890delTAAG (p.Val296Glyfs ∗ 13), in exon 5; this frameshift introduces a stop codon in amino acid 308 of the growth arrest-specific protein 2-like 2 (GAS2L2). Further genetic screening of unrelated PCD subjects identified a second proband with a compound heterozygous variant carrying the identical frameshift variant and a large deletion (c.867&#95; ∗ 343+1207del; p.?) starting in exon 5. Both individuals had clinical features of PCD but normal ciliary axoneme structure. In this research, using human nasal cells, mouse models, and X.laevis embryos, we show that GAS2L2 is abundant at the apical surface of ciliated cells, where it localizes with basal bodies, basal feet, rootlets, and actin filaments. Cultured GAS2L2-deficient nasal epithelial cells from one of the affected individuals showed defects in ciliary orientation and had an asynchronous and hyperkinetic (GAS2L2-deficient = 19.8 Hz versus control = 15.8 Hz) ciliary-beat pattern. These results were recapitulated in Gas2l2 -/- mouse tracheal epithelial cell (mTEC) cultures and in X. laevis embryos treated with Gas2l2 morpholinos. In mice, the absence of Gas2l2 caused neonatal death, and the conditional deletion of Gas2l2 impaired mucociliary clearance (MCC) and led to mucus accumulation. These results show that a pathogenic variant in GAS2L2 causes a genetic defect in ciliary orientation and impairs MCC and results in PCD., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Objectives: Oxygen tension affects the biology of aerobic and denitrifying organisms. Using a novel, fast-response sensor, we developed a noninvasive procedure to measure pO 2 in distal human airways. We hypothesized that distal pO 2 would be low in cystic fibrosis (CF) airways., Materials and Methods: We measured the fraction of expired oxygen (F EO2 ) in real time using a fast laser diode analyzer in healthy subjects and in patients with CF, asthma, and primary ciliary dyskinesia (PCD). Subjects slowly exhaled to residual volume (RV), where the nadir of F EO2 (NFO) was recorded. Values were compared to peripheral oxygen saturation (S a O 2 ), expired CO 2 at RV, FEV 1 , FEV 1 /FVC, and FEF 25-75 . We also measured the effect of supplemental oxygen on F EO2 ., Results: Seventy-four subjects completed the study. Seven additional subjects could not perform the maneuver. Mean (±SD) NFO values for controls (n = 29), CF patients (n = 23), asthma patients (n = 15), and PCD patients (n = 7) were 13.4 ± 1.1%, 12.4 ± 1.2%, 13.3 ± 1.1%, 14.4 ± 0.6%, respectively. NFO in CF was lower than in controls (P = 0.0162), and NFO in PCD was higher than in CF (P = 0.0007). Asthma results were heterogeneous. Oxygen caused a dose-dependent increase in NFO (P < 0.0005; n = 3; r 2  = 0.91). NFO values were positively associated with FEV 1 (P = 0.0009), FEV 1 /FVC (P = 0.0019) and FEF 25-75 (P = 0.0155), but there was no association with S a O 2 ., Conclusions: Distal airway pO 2 is lower in CF than in controls. This may reflect absorption of oxygen in partially plugged acinar units, and/or increased epithelial oxygen consumption. Distal airway pO 2 can be precisely titrated to treat infections., (© 2018 Wiley Periodicals, Inc.)

Background: The present study aimed to develop an automated computed tomography (CT) score based on the CT quantification of high-attenuating lung structures, in order to provide a quantitative assessment of lung structural abnormalities in patients with Primary Ciliary Dyskinesia (PCD)., Methods: Adult (≥18 years) PCD patients who underwent both chest CT and spirometry within a 6-month period were retrospectively included. Commercially available lung segmentation software was used to isolate the lungs from the mediastinum and chest wall and obtain histograms of lung density. CT-density scores were calculated using fixed and adapted thresholds based on various combinations of histogram characteristics, such as mean lung density (MLD), skewness, and standard deviation (SD). Additionally, visual scoring using the Bhalla score was performed by 2 independent radiologists. Correlations between CT scores, forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) were evaluated., Results: Sixty-two adult patients with PCD were included. Of all histogram characteristics, those showing good positive or negative correlations to both FEV 1 and FVC were SD (R = - 0.63 and - 0.67; p < 0.001) and Skewness (R = 0.67 and 0.67; p < 0.001). Among all evaluated thresholds, the CT-density score based on MLD + 1SD provided the best negative correlation with both FEV 1 (R = - 0.68; p < 0.001) and FVC (R = - 0.71; p < 0.001), close to the correlations of the visual score (R = - 0.60; p < 0.001 for FEV 1 and R = - 0.62; p < 0.001, for FVC)., Conclusions: Automated CT scoring of lung structural abnormalities lung in primary ciliary dyskinesia is feasible and may prove useful for evaluation of disease severity in the clinic and in clinical trials.

Rationale: Primary ciliary dyskinesia (PCD) is an inherited disorder characterized by heterogeneous airway disease. Traditional lung function techniques (e.g., spirometry) may underestimate severity and complexity of PCD., Objectives: We assessed lung impairment in individuals with PCD using structural and functional magnetic resonance imaging (MRI) and different lung function techniques., Methods: A total of 30 study participants with PCD (median, 13.4 yr; range, 5-28 yr) underwent structural and functional MRI, spirometry, and multiple breath washout (MBW) on the same day. Primary endpoints included structural MRI morphology scores, relative ventilation, and perfusion impairment from functional MRI, forced expiratory volume in 1 second (FEV 1 ) from spirometry, and lung clearance index (LCI) from MBW., Results: Severity and complexity of PCD lung disease varied significantly between individuals. Structural lung disease was detected in all subjects with a median (interquartile range) extent score of 10.3 (7-19; maximum score = 60). Functional MRI ventilation impairment was present in 52% of subjects, affecting 24.2% (21.1 to 25.2%) of the lung. Relative perfusion impairment was detected in 78% of individuals affecting 21.1% (19.4 to 25.9%) of the lung. LCI was abnormal in 83% (median, 8.3 [2.6 to 13.2] z-scores) and FEV 1 was abnormal in 27% (-0.5 [-1.6 to 0.3] z-scores) of individuals. Concordance between spirometry and imaging outcomes was poor, with 52% of patients showing both abnormal MRI and LCI values, but normal FEV 1 ., Conclusions: Discordance between lung function and imaging outcomes in patients with PCD supports the use of both imaging and lung function, such as MBW, for surveillance of this heterogeneous disease.

Primary ciliary dyskinesia (PCD) has been considered a relatively mild disease, especially compared to cystic fibrosis (CF), but studies on lung function in PCD patients have been few and small.This study compared lung function from spirometry of PCD patients to normal reference values and to published data from CF patients. We calculated z-scores and % predicted values for forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) using the Global Lung Function Initiative 2012 values for 991 patients from the international PCD Cohort. We then assessed associations with age, sex, country, diagnostic certainty, organ laterality, body mass index and age at diagnosis in linear regression models. Lung function in PCD patients was reduced compared to reference values in both sexes and all age groups. Children aged 6-9 years had the smallest impairment (FEV 1 z-score -0.84 (-1.03 to -0.65), FVC z-score -0.31 (-0.51 to -0.11)). Compared to CF patients, FEV 1 was similarly reduced in children (age 6-9 years PCD 91% (88-93%); CF 90% (88-91%)), but less impaired in young adults (age 18-21 years PCD 79% (76-82%); CF 66% (65-68%)). The results suggest that PCD affects lung function from early in life, which emphasises the importance of early standardised care for all patients., Competing Interests: Conflict of interest: N. Schwerk reports personal fees for lecturing from Novartis, Allergopharma and Infectopharm, and grants from FP7-ChILD EU, outside the submitted work. Conflict of interest: P. Yiallouros reports grants from European Union's Seventh Framework Programme under EG-GA (number 35404 BESTCILIA), during the conduct of the study. Conflict of interest: P. Latzin reports personal fees from Gilead, Novartis, Polyphor, Roche, Santhera, Schwabe, Vertex, Vifor and Zambon, outside the submitted work. Conflict of interest: H. Mazurek reports grants from Bestcilia, during the conduct of the study., (Copyright ©ERS 2018.)

Bronchiectasis is characterized by deregulated inflammatory response and recurrent bacterial infection resulting in progressive lung damage and an irreversible dilatation of bronchi and bronchioles. Generally accepted model of the development of bronchiectasis is the "vicious cycle hypothesis" that proposes compromising of the mucociliary clearance by an initial event, which leads to the infection of the respiratory tract followed by further impairment of mucociliary function, bacterial proliferation, and more inflammation. Bronchiectasis is a very common symptom in patients with cystic fibrosis (CF), while bronchiectasis unrelated to CF is heterogeneous pathology of unknown cause with a large number of potential contributory factors and poorly understood pathogenesis. It is presumed that bronchiectasis unrelated to CF is a multifactorial condition predisposed by genetic factors. Different molecules have been implicated in the onset and development of idiopathic bronchiectasis, as well as modulation of the disease severity and response to therapy. Most of these molecules are involved in the processes that contribute to the homeostasis of the lung tissue, especially mucociliary clearance, protease-antiprotease balance, and immunomodulation. Evaluation of the studies performed towards investigation of the role these molecules play in bronchiectasis identifies genetic variants that may be of potential importance for clinical management of the disease, and also of interest for future research efforts. This review focuses on the molecules with major roles in lung homeostasis and their involvement in bronchiectasis unrelated to CF.

Purpose of Review: Impaired mucociliary clearance has been implicated in chronic upper and lower airway inflammatory diseases (i.e., allergic and non-allergic rhinitis, chronic rhinosinusitis with or without nasal polyps and asthma). How motile ciliary disorders (impaired ciliogenesis, ciliary beating and ultrastructural defects) are implicated in chronic airway inflammatory diseases is not fully understood. Elaboration of the role of motile ciliary disorders may serve as therapeutic targets for improving mucociliary clearance, thereby complementing contemporary disease management., Recent Findings: We have summarized the manifestations of motile ciliary disorders and addressed the underlying associations with chronic airway inflammatory diseases. A panel of established and novel diagnostic tests and therapeutic interventions are outlined. Physicians should be vigilant in screening for motile ciliary disorders, particularly in patients with co-existing upper and lower airway inflammatory diseases. Proper assessment and treatment of motile ciliary disorders may have added value to the management and prevention of chronic airway inflammatory diseases.

Background: Peak oxygen uptake (VO 2peak ) is associated with morbidity and mortality in health and disease, and provides important information of global physical health not achieved from standard pulmonary function tests. Primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) are genetically determined diseases involving different basic defects, but both showing impaired mucociliary clearance leading to chronic infections and pulmonary destruction early in life. PCD is generally considered a milder disease than CF and it is hypothesized that children with CF would have consistently lower VO 2peak and pulmonary function than children with PCD., Methods: We performed a prospective, observational single-center, clinical cohort study of VO 2peak and pulmonary function in age and gender matched schoolchildren, at two occasions 12 months apart., Results: VO 2peak was persistently (at baseline and after 12 months) and significantly reduced in the 22 patients with PCD (z-score = -0.89 and -1.0) and 24 with CF (z-score = -0.94 and -1.1), included in the study. Abnormal VO 2peak was detected in a larger proportion of children with PCD (≈30%) than CF (≈13%). Moreover, children with PCD exhibited persistently lower FEV 1 (p < 0.0001 at first visit and p = 0.001 at second visit) while FEF 25-75 and FVC differed only at baseline. Indeed, a retrospective analysis comparing lung function over the last year in our entire PCD and CF populations between 6 and 18 years of age, revealed lower values in patients with PCD (FEV 1 z-score, p = 0.0004, FVC z-score p < 0.0001, FEF 25-75 z-score p = 0.008)., Conclusion: This is the first report indicating that cardiopulmonary fitness is equally and consistently reduced in both children with PCD and CF along with a consistent lower pulmonary function in PCD compared with CF. A certain reservation for possible selection bias and the small number of patients is necessary. However, increased focus on early diagnosis, evidence-based treatment regimens and close clinical monitoring in PCD are warranted., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: Primary ciliary dyskinesia (PCD) is characterised by repeated upper and lower respiratory tract infections, neutrophilic airway inflammation and obstructive airway disease. Different ultrastructural ciliary defects may affect lung function decline to different degrees. Lung clearance index (LCI) is a marker of ventilation inhomogeneity that is raised in some but not all patients with PCD. We hypothesised that PCD patients with microtubular defects would have worse (higher) LCI than other PCD patients., Methods: Spirometry and LCI were measured in 69 stable patients with PCD. Age at testing, age at diagnosis, ethnicity, ciliary ultrastructure, genetic screening result and any growth of Pseudomonas aeruginosa was recorded., Results: Lung clearance index was more abnormal in PCD patients with microtubular defects (median 10.24) than those with dynein arm defects (median 8.3, p = 0.004) or normal ultrastructure (median 7.63, p = 0.0004). Age is correlated with LCI, with older patients having worse LCI values (p = 0.03, r = 0.3)., Conclusion: This study shows that cilia microtubular defects are associated with worse LCI in PCD than dynein arm defects or normal ultrastructure. The patient's age at testing is also associated with a higher LCI. Patients at greater risk of obstructive lung disease should be considered for more aggressive management. Differences between patient groups may potentially open avenues for novel treatments.

Objectives: Few studies have examined the potentially therapeutic effect of increasing the production of endogenous nitric oxide (NO) in Primary Ciliary Dyskinesia (PCD) and other chronic respiratory conditions. Nasal NO is low in PCD and has been found to correlate with compromised Ciliary Beat Frequency (CBF). In this study we assessed the effect of increasing l-Arginine, as the substrate of NO synthases, on CBF in biopsies of human respiratory ciliated epithelium., Methodology: A total of 28 suspect cases with chronic respiratory manifestations referred for PCD diagnostic testing and 8 healthy controls underwent nasal brushing. Obtained epithelial cells were divided between three culture medium 199 solutions, containing different levels of l-Arginine (0.33 mM as baseline, 1 mM and 10 Mm as increased levels). CBF measurements were obtained at 37 °C and 25 °C at 1, 3 and 24 h after sample acquisition., Results: Among a total of 36 recruited subjects, 8 had PCD confirmed (PCD n = 8), 20 had PCD excluded (non-PCD n = 20) and 8 were healthy controls (Healthy Controls = 8). Among PCD subjects, ciliary motility was characterized by rotational (n = 5) or dyskinetic (n = 3) beating. At 37 °C, compared to baseline, higher levels of l-Arginine resulted in up to 9% CBF increase at 1 h (p = 0.007), up to 9% CBF increase at 3 h (p < 0.001) and up to 12% CBF increase at 24 h (p = 0.002). Similar although smaller scale increases were recorded at 25 °C. The effect of l-Arginine was time dependent (interaction p = 0.002) and was similar in PCD patients, non-PCD chronic respiratory patients and healthy controls (interaction p = 0.800)., Conclusions: l-Arginine increases CBF and merits to be evaluated as a potential stimulator of mucociliary clearance in chronic respiratory conditions and congenital ciliary disorders with residual motility. Larger human studies are needed to confirm these findings., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Heterotaxy (HTX) congenital heart disease (CHD) patients with ciliary dysfunction (CD) have been shown to have increased postoperative respiratory morbidity. We hypothesized that non-HTX CHD infants with CD also will have increased postoperative morbidity, particularly respiratory complications., Methods: Sixty-three infants with non-HTX CHD undergoing cardiac surgery were enrolled. Tests commonly used to assess for CD, nasal nitric oxide (nNO) measurements and nasal epithelial ciliary motion (CM) assessment, were obtained. Baseline characteristics and postoperative outcomes were collected and analyzed., Results: Non-HTX CHD infants exhibited a high prevalence of abnormal CM (32%) and low nNO (39%). This finding was not correlated with demographics or surgical complexity. Infants with abnormal CM had increased odds of requiring noninvasive positive pressure ventilation (odds ratio [OR], 6.5; 95% confidence interval [CI], 1.5-29.4; P = .016) and respiratory medication use (OR, 4.4; 95% CI, 1.5-13.3; P = .01). In contrast, infants with low nNO showed evidence of abnormal pre- and postoperative systolic function (40% vs 4%; P = .004, and 34% vs 13%; P = .056, respectively) and had greater odds of acquiring infections (OR, 4.9; 95% CI, 1.4-17; P = .014)., Conclusions: Non-HTX CHD infants with abnormal CM showed increased postoperative morbidity associated with poor respiratory outcomes. In contrast, low nNO correlated with reduced hemodynamic function. These findings suggest screening for abnormal CM may allow perioperative interventions to reduce pulmonary morbidities. Whether low nNO may prognosticate poor hemodynamic function warrants further investigation., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

The function of normal and defective candidate genes for human genetic diseases, which are rapidly being identified in large numbers by human geneticists and the biomedical community at large, will be best studied in relevant and predictive model organisms that allow high-speed verification, analysis of underlying developmental, cellular and molecular mechanisms, and establishment of disease models to test therapeutic options. We describe and discuss the pros and cons of the frog Xenopus, which has been extensively used to uncover developmental mechanisms in the past, but which is being underutilized as a biomedical model. We argue that Xenopus complements the more commonly used mouse and zebrafish as a time- and cost-efficient animal model to study human disease alleles and mechanisms., (© 2018 S. Karger AG, Basel.)

Chronic respiratory disease can affect growth and nutrition, which can influence lung function. We investigated height, body mass index (BMI), and lung function in patients with primary ciliary dyskinesia (PCD).In this study, based on the international PCD (iPCD) Cohort, we calculated z-scores for height and BMI using World Health Organization (WHO) and national growth references, and assessed associations with age, sex, country, diagnostic certainty, age at diagnosis, organ laterality and lung function in multilevel regression models that accounted for repeated measurements.We analysed 6402 measurements from 1609 iPCD Cohort patients. Height was reduced compared to WHO (z-score -0.12, 95% CI -0.17 to -0.06) and national references (z-score -0.27, 95% CI -0.33 to -0.21) in male and female patients in all age groups, with variation between countries. Height and BMI were higher in patients diagnosed earlier in life (p=0.026 and p<0.001, respectively) and closely associated with forced expiratory volume in 1 s and forced vital capacity z-scores (p<0.001).Our study indicates that both growth and nutrition are affected adversely in PCD patients from early life and are both strongly associated with lung function. If supported by longitudinal studies, these findings suggest that early diagnosis with multidisciplinary management and nutritional advice could improve growth and delay disease progression and lung function impairment in PCD., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Primary ciliary dyskinesia (PCD) is a rare, genetic disorder of the motile cilia characterised by chronic lung disease, nasal and sinus disease, chronic ear infections with glue ear leading to possible hearing impairment, and subfertility. Half of patients have organ laterality defects. Despite symptoms being present from birth, PCD remains underdiagnosed. Early diagnosis and symptom management may reduce morbidity, improve quality of life and ensure children are adequately supported to meet their full potential. This article seeks to raise awareness of PCD in children's nurses who are well placed to identify children for referral to the national PCD diagnostic service. It examines the clinical characteristics of the disease along with the complexities and limitations of diagnostic testing. In addition, it explores the management of children with PCD within the national PCD management service for children., Competing Interests: The National Primary Ciliary Dyskinesia (PCD) centre at Southampton is commissioned and funded by NHS England. PCD research in Southampton is supported by National Institute for Health Research (NIHR) Southampton Biomedical Research Centre, NIHR Wellcome Trust Southampton Clinical Research Facility, NIHR (RfPB PB-PG-1215-20014) and The AAIR Charity (Reg. No. 1129698). Amanda Harris participates in the network of COST Action BEAT-PCD: Better Evidence to Advance Therapeutic options for PCD (BM 1407). Amanda Harris is supported by Health Education England (Wessex) Integrated Clinical Academic Internship., (©2012 RCN Publishing Company Ltd. All rights reserved. Not to be copied, transmitted or recorded in any way, in whole or part, without prior permission of the publishers.)

Among more than 5,000 human monogenic disorders with known causative genes, transposable element insertion of a Long Interspersed Nuclear Element 1 (LINE1, L1) is known as the mechanistic basis in only 13 genetic conditions. Meckel-Gruber syndrome is a rare ciliopathy characterized by occipital encephalocele and cystic kidney disease. Here, we document a boy with occipital encephalocele, post-axial polydactyly, and multicystic renal disease. A medical exome analysis detected a heterozygous frameshift mutation, c.4582&#95;4583delCG p.(Arg1528Serfs*17) in CC2D2A in the maternally derived allele. The further use of a dedicated bioinformatics algorithm for detecting retrotransposon insertions led to the detection of an L1 insertion affecting exon 7 in the paternally derived allele. The complete sequencing and sequence homology analysis of the inserted L1 element showed that the L1 element was classified as L1HS (L1 human specific) and that the element had intact open reading frames in the two L1-encoded proteins. This observation ranks Meckel-Gruber syndrome as only the 14th disorder to be caused by an L1 insertion among more than 5,000 known human genetic disorders. Although a transposable element detection algorithm is not included in the current best-practice next-generation sequencing analysis, the present observation illustrates the utility of such an algorithm, which would require modest computational time and resources. Whether the seemingly infrequent recognition of L1 insertion in the pathogenesis of human genetic diseases might simply reflect a lack of appropriate detection methods remains to be seen., (© 2017 Wiley Periodicals, Inc.)