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Primary ciliary dyskinesia (PCD) is characterized by impaired mucociliary clearance, recurrent respiratory infections, and progressive airway damage and obstructive lung disease. While the association of ciliary ultrastructure defect/genotype with severity of airflow obstruction has been well characterized, their association with airway abnormalities on chest computed tomography (CT) has been minimally evaluated.We sought to delineate the association of ciliary defect class/genotype with chest CT scores in children with PCD.Cross-sectional analysis of children with PCD (N=146) enrolled in a prospective multicenter observational study, stratified by defect type: ODA (outer dynein arm), ODA/IDA (outer and inner dynein arm), IDA/MTD (inner dynein arm and microtubular disorganization), and Normal/Near Normal ultrastructure with associated genotypes. CTs were scored utilizing the Melbourne-Rotterdam Annotated Grid Morphometric Analysis for PCD (MERAGMA-PCD), evaluating airway abnormalities in a hierarchical order: atelectasis, bronchiectasis, bronchial wall thickening, mucus plugging/tree in bud opacities. Volume fraction of each component was expressed as % of total lung volume. %Disease was computed as the sum of all components. Regression analyses were utilized to describe the association between clinical predictors and CT scores.Acceptable chest CTs were obtained in 141 children (71 male): 57 ODA, 20 ODA/IDA, 40 IDA/MTD, 24 Normal/Near Normal. Mean (SD) age was 8.5 (4.6) years, forced expiratory volume in 1 second (FEV1) % predicted was 82.4 (19.5), and %Disease was 4.6 (3.5). Children with IDA/MTD defects had higher %Disease compared to children with ODA defects (2.71% higher (95%CI: 1.37-4.06, p0.001)), driven by higher %Mucus plugging (2.35% higher (1.43-3.26, p0.001)). Increasing age, lower BMI, and lower FEV1 were associated with higher %Disease (0.23%, 95%CI: 0.11-0.35, p0.001; 0.03%, 95%CI: 0.01-0.04, p=0.008; and 0.05%, 95%CI: 0.01-0.08, p=0.011, respectively).Children with IDA/MTD defects had significantly greater airway disease on CT, primarily mucus plugging, compared to children with ODA defects.

The association between organ laterality abnormalities and ciliary ultrastructural defect or genotype in primary ciliary dyskinesia is poorly understood.To determine if there is an association between presence/type of laterality abnormality and ciliary ultrastructural defect and genotype.Participants with primary ciliary dyskinesia in a multicenter, prospective study were grouped based on ciliary ultrastructural defect or genotype. In a retrospective analysis of this data, the association of ciliary ultrastructural defect or genotype and likelihood of a laterality abnormality was evaluated by logistic regression adjusted for presence of two loss-of-function versus one or more not-loss-of-function variants.Of 559 participants, 286 (51.2%), 215 (38.5%), and 58 (10.4%) were identified as having situs solitus, situs inversus totalis, and situs ambiguus, respectively; heterotaxy, defined as situs ambiguus with complex cardiovascular defects, was present in 14 (2.5%). Compared to group with inner dynein arm defects with microtubular disorganization, laterality defects were more likely in the outer dynein arm defects group (OR 2.07, 95% CI 1.21-3.54, P0.01) and less likely in the normal/near normal ultrastructure group (OR 0.04, 95% CI 0.013-0.151, P0.01). Heterotaxy was present in 11 of 242 (4.5%) in the outer dynein arm defects group but zero of 96 in the inner dynein arm defects with microtubular disorganization group (P=0.038).In primary ciliary dyskinesia, risk of a laterality abnormality differs by ciliary ultrastructure defect. Pathophysiologic mechanisms underlying these differences require further exploration.

BACKGROUND: Organ laterality defects in primary ciliary dyskinesia (PCD) are common, ranging from complete mirror image organ arrangement, situs inversus totalis (SIT), to situs ambiguus (SA), which falls along the spectrum of situs solitus (SS) and SIT. Targeted investigations for organ laterality defects are not universally recommended in PCD consensus statements. Without investigations beyond chest radiography (CXR), clinically significant defects may go undetected leading to increased morbidity. We hypothesize that clinically significant SA defects remain undetected on CXR and targeted investigations are needed to detect various laterality defects associated with morbidity. METHODS: This retrospective study collected data from PCD clinics at two Canadian children’s hospitals from 2012 to 2020. Participants

OBJECTIVE. This project aims to prospectively and objectively assess otolaryngological manifestations and quality of life of children with primary ciliary dyskinesia (PCD) and compare these findings with healthy pediatric controls. STUDY DESIGN. Cross-sectional. SETTING. Two high-volume pediatric PCD specialty centers. METHODS. Standardized clinical assessment; Sino-Nasal Outcome Test 22 (SNOT-22); Hearing Environment and Reflection Quality of Life (HEAR-QL); Reflux Symptom Index (RSI); standardized physical examination of the sinonasal, laryngeal, and otological systems; and investigations including pure-tone audiograms (PTAs) and sinonasal cultures were collected. RESULTS. Forty-seven children with PCD and 25 control participants were recruited. Children with PCD had more upper airway symptoms than healthy children. They had significantly higher scores in both SNOT-22 and RSI, indicating worse sinonasal and reflux symptoms, with worse quality of life on the HEAR-QL index compared to healthy children (P < .05). Fifty-two percent of children with PCD-related hearing loss were not aware of their hearing deficit that was present on audiological assessment, and only 23% of children who had ventilation tubes had chronic otorrhea, most of which was easily controlled with ototopic drops. Furthermore, although all children with PCD had chronic rhinosinusitis, only 36% of them were using topical nasal treatment. The most common bacteria cultured from the middle meatus were Staphylococcus aureus in 11 of 47 (23%), followed by Streptococcus pneumoniae in 10 of 47 (21%). CONCLUSION. This multisite cohort highlights the importance of otolaryngology involvement in the management of children with PCD. More rigorous otolaryngological management may lead to reductions in overall morbidity and improve quality of life for children with PCD.

Mutations in SPAG1, a dynein axonemal assembly factor (DNAAF) that facilitates the assembly of dynein arms in the cytoplasm before their transport into the cilium, result in primary ciliary dyskinesia (PCD), a genetically heterogenous disorder characterized by chronic oto-sino-pulmonary disease, infertility and laterality defects. To further elucidate the role of SPAG1 in dynein assembly, we examined its expression, interactions and ciliary defects in control and PCD human airway epithelia. Immunoprecipitations showed that SPAG1 interacts with multiple DNAAFs, dynein chains and canonical components of the R2TP complex. Protein levels of dynein heavy chains (DHCs) and interactions between DHCs and dynein intermediate chains (DICs) were reduced in SPAG1 mutants. We also identified a previously uncharacterized 60 kDa SPAG1 isoform, through examination of PCD subjects with an atypical ultrastructural defect for SPAG1 variants, that can partially compensate for the absence of full-length SPAG1 to assemble a reduced number of outer dynein arms. In summary, our data show that SPAG1 is necessary for axonemal dynein arm assembly by scaffolding R2TP-like complexes composed of several DNAAFs that facilitate the folding and/or binding of the DHCs to the DIC complex.

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.

Background Primary ciliary dyskinesia (PCD) is a genetically diverse disease which causes impaired mucociliary clearance, and results in pulmonary, otologic, and rhinologic disease in affected patients. Genetic mutations in multiple genes impair the ability of patients to clear mucous from the lungs, middle ear, and sinonasal cavity and lead to chronic pulmonary and sinonasal symptoms. Methods We identified 17 PCD patients who had available CT scans. Volumes for bilateral maxillary, sphenoid, and frontal sinuses were calculated. A control population of patients who had preoperative CT scans for endoscopic endonasal resection of skull base pathology without sinonasal cavity involvement was also identified. Results The mean age of PCD was 33 and ranged from 13 to 54 years. Patients were age- and gender-matched to a control group that underwent resection of anterior skull-base tumors and had a mean age of 35 that ranged between 17–53 years old. The volumes for all thee sinus cavities were significantly smaller (p Conclusions Overall sinus volumes were smaller in patients with PCD compared to our control population. Future studies will be aimed at understanding defects in sinus development as a function of specific genetic mutations in PCD patients. Ultimately, a better understanding of the underlying pathophysiology of PCD will allow us to identify the optimal treatment practices for this unique patient group.

Nasal nitric oxide concentrations are extremely low in primary ciliary dyskinesia (PCD), and measurement of this nasal gas is recommended as a PCD diagnostic test in cooperative patients aged 5 years and older. However, nasal nitric oxide measurements must be performed with chemiluminescence analyzers using a standardized protocol to ensure proper results, because nasal nitric oxide values can be influenced by various internal and external factors. Repeat nasal nitric oxide testing on separate visits is required to ensure that low diagnostic values are persistent and consistent with PCD. This technical paper presents the standard operating procedures for nasal nitric oxide measurement used by the PCD Foundation Clinical and Research Centers Network at various specialty centers across North America. Adherence to this document ensures reliable nasal nitric oxide testing and high diagnostic accuracy when employed in a population with appropriate clinical phenotypes for PCD.

Primary ciliary dyskinesia (PCD) is a rare lung disease caused by mutations that impair the function of motile cilia, resulting in chronic upper and lower respiratory disease, reduced fertility, and a high prevalence of situs abnormalities. The disease is genetically and phenotypically heterogeneous, with causative mutations in50 genes identified, and clinical phenotypes ranging from mild to severe. Absence of

Primary ciliary dyskinesia (PCD) is a rare disorder that affects the biogenesis or function of motile cilia resulting in chronic airway disease. PCD is genetically and phenotypically heterogeneous, with causative mutations identified in over 40 genes; however, the genetic basis of many cases is unknown. Using whole-exome sequencing, we identified three affected siblings with clinical symptoms of PCD but normal ciliary structure, carrying compound heterozygous loss-of-function variants in CFAP221. Computational analysis suggests that these variants are the most damaging alleles shared by all three siblings. Nasal epithelial cells from one of the subjects demonstrated slightly reduced beat frequency (16.5 Hz vs 17.7 Hz, p = 0.16); however, waveform analysis revealed that the CFAP221 defective cilia beat in an aberrant circular pattern. These results show that genetic variants in CFAP221 cause PCD and that CFAP221 should be considered a candidate gene in cases where PCD is suspected but cilia structure and beat frequency appear normal.

Rationale Having developed the first disease‐specific, health‐related quality of life (HRQoL) instruments for children with primary ciliary dyskinesia (PCD), we aimed to assess the psychometric performance of quality of life (QOL)‐PCD child, adolescent, and parent‐proxy versions in terms of reliability and validity across cross‐cultural settings and caring for patients with this rare disease. Methods Children (n = 71), adolescents (n = 85), and parents (n = 68) from multiple centers in the UK and North America completed age‐appropriate QOL‐PCD and generic QOL measures: pediatric QOL inventory, COPD assessment test (CAT), and Sino‐Nasal Outcome Test 20. Total of 13 children, 13 parents, and 17 adolescents repeated QOL‐PCD 10 to 14 days later to assess test‐retest reliability. Multitrait analysis evaluated how the items loaded to hypothesized scales: physical, emotional & social functioning, treatment burden, role, vitality, upper and lower respiratory symptoms, and ears and hearing symptoms. Examination of item‐to‐total correlations led to removal of three, five, and six items, respectively in the prototype child, adolescent and parent‐proxy versions; the validated measures now comprise between 34 and 38 items. Results The QOL‐PCD scales had good internal consistency; Cronbach's α for QOL‐PCD parent‐proxy ranged 0.62 to 0.86. Test‐retest reliability demonstrated stability across all scales; for example QOL‐PCD adolescent intraclass correlation coefficients ranged 0.71 to 0.89. Significant relationships were found between QOL‐PCD scales and similar constructs on generic questionnaires, for example, QOL‐PCD adolescent lower respiratory symptoms and the CAT score (r = .64, P

Primary ciliary dyskinesia is an incurable, rare, inherited, chronic condition. Treatment includes regular clearing of airway mucus, aggressive treatment of infections and management of hearing loss. Caregiver burden has not been explored, hence we interviewed 18 English speaking mothers and 6 English speaking fathers of children under 6 years who were diagnosed with PCD around the world. The parents described how the child’s diagnosis, treatment regimen, and health status impacted their life. They discussed the impact of the COVID-19 pandemic and they talked about the different ways they cope with challenges that arise. The need for integrated social care is discussed.

Motile cilia are highly complex hair-like organelles of epithelial cells lining the surface of various organ systems. Genetic mutations (usually with autosomal recessive inheritance) that impair ciliary beating cause a variety of motile ciliopathies, a heterogeneous group of rare disorders. The pathogenetic mechanisms, clinical symptoms and severity of the disease depend on the specific affected genes and the tissues in which they are expressed. Defects in the ependymal cilia can result in hydrocephalus, defects in the cilia in the fallopian tubes or in sperm flagella can cause female and male subfertility, respectively, and Malfunctional motile monocilia of the left–right organizer during early embryonic development can lead to laterality defects such as situs inversus and heterotaxy. If muco-ciliary clearance in the respiratory epithelium is severely impaired, the disorder is referred to as primary ciliary dyskinesia (PCD), the most common motile ciliopathy. No single test can confirm a diagnosis of motile ciliopathy, which is based on a combination of tests including nasal nitric oxide measurement; TEM, immunofluorescence and genetic analyses; and high-speed video microscopy. With the exception of azithromycin, there is no evidence-based treatment for PCD; therapies aim at relieving symptoms and reduce the effects of reduced ciliary motility.

Rare diseases are collectively common, affecting an estimated 6.2% of the world's population [1], but each rare disease affects fewer than 4 to 5 in 10 000 individuals in Europe or less than 200 000 individuals in the USA [2]. Patients with rare diseases are often disadvantaged by late diagnosis and off-label prescribing of medicines [3]. Primary ciliary dyskinesia (PCD) is a genetic disease of impaired motile ciliary function that does not have a unique International Classification of Diseases (ICD)-10 code or licensed treatments, although Q34.8 denoting “other specified malformations of the respiratory tract” including nasopharyngeal atresia has also been applicable to PCD since 2017. The disease is characterised by mucus stagnation leading to chronic airway infection, bronchiectasis, chronic rhinosinusitis, reduced fertility and abnormalities of organ laterality with an associated increased risk of complex congenital heart disease [4]. The estimated prevalence of PCD in Europe is around 1 in 10 000 to 1 in 20 000 [5]. The international PCD cohort (iPCD) includes over 3800 PCD patients ranging in age from under 12 months to over 80 years, from Europe, Northern and Southern America, Australia and Western Asia [6]. Under-diagnosis of PCD is due to a lack of awareness among the general public and physicians in general, as well as a lack of diagnostic expertise in some countries [7]. Tools to help physicians identify patients needing testing (e.g. PICADAR) [8] and the European Respiratory Society (ERS) guidelines for diagnostic testing [9] aim to improve this. In contrast to cystic fibrosis (CF), a monogenic disease, PCD is caused by mutations in one of at least 45 identified genes for which there is no effective mutation-specific therapy; this is likely to be a long way off for most patients [10]. Thus, treatment aims to prevent and manage disease complications. Even then, the lack of an evidence base for supportive treatment in PCD means that treatment recommendations are based on expert opinion and extrapolated from CF despite differing pathophysiology [11]., Primary ciliary dyskinesia, a rare disease causing bronchiectasis, lacks a sound evidence base for treatment. @beatpcd proposes 1) forming a PCD European clinical trial network to address this situation and 2) conducting n-of-1 trials to access medication. https://bit.ly/3j5blfM

Primary ciliary dyskinesia (PCD) is a heterogeneous genetic condition. European and North American diagnostic guidelines recommend transmission electron microscopy (TEM) as one of a combination of tests to confirm a diagnosis. However, there is no definition of what constitutes a defect or consensus on reporting terminology. The aim of this project was to provide an internationally agreed ultrastructural classification for PCD diagnosis by TEM.A consensus guideline was developed by PCD electron microscopy experts representing 18 centres in 14 countries. An initial meeting and discussion were followed by a Delphi consensus process. The agreed guideline was then tested, modified and retested through exchange of samples and electron micrographs between the 18 diagnostic centres.The final guideline a) provides agreed terminology and a definition of Class 1 defects which are diagnostic for PCD; b) identifies Class 2 defects which can indicate a diagnosis of PCD in combination with other supporting evidence; c) describes features which should be included in a ciliary ultrastructure report to assist multidisciplinary diagnosis of PCD; and d) defines adequacy of a diagnostic sample.This tested and externally validated statement provides a clear guideline for the diagnosis of PCD by TEM which can be used to standardise diagnosis internationally. ispartof: EUROPEAN RESPIRATORY JOURNAL vol:55 issue:4 ispartof: location:England status: published

Hydrocephalus is one of the most prevalent form of developmental central nervous system (CNS) malformations. Cerebrospinal fluid (CSF) flow depends on both heartbeat and body movement. Furthermore, it has been shown that CSF flow within and across brain ventricles depends on cilia motility of the ependymal cells lining the brain ventricles, which play a crucial role to maintain patency of the narrow sites of CSF passage during brain formation in mice. Using whole-exome and whole-genome sequencing, we identified an autosomal-dominant cause of a distinct motile ciliopathy related to defective ciliogenesis of the ependymal cilia in six individuals. Heterozygous de novo mutations in FOXJ1, which encodes a well-known member of the forkhead transcription factors important for ciliogenesis of motile cilia, cause a motile ciliopathy that is characterized by hydrocephalus internus, chronic destructive airway disease, and randomization of left/right body asymmetry. Mutant respiratory epithelial cells are unable to generate a fluid flow and exhibit a reduced number of cilia per cell, as documented by high-speed video microscopy (HVMA), transmission electron microscopy (TEM), and immunofluorescence analysis (IF). TEM and IF demonstrate mislocalized basal bodies. In line with this finding, the focal adhesion protein PTK2 displays aberrant localization in the cytoplasm of the mutant respiratory epithelial cells.

Primary Ciliary Dyskinesia (PCD) is a heterogeneous genetic condition. European and North American diagnostic guidelines recommend transmission electron microscopy as one of a combination of tests to confirm a diagnosis. However, there is no definition of what constitutes a defect or consensus on reporting terminology. The aim of this project was to provide an internationally agreed ultrastructural classification for PCD diagnosis by transmission electron microscopy. A consensus guideline was developed by PCD electron microscopy experts representing 18 centres in 13 countries. An initial meeting and discussion was followed by a Delphi consensus process. The agreed guideline was then tested, modified and retested through exchange of samples and electron micrographs between the 18 diagnostic centres. The final guideline a) Provides agreed terminology and definition of class 1 defects which are diagnostic for PCD b) Identifies class 2 defects which indicate a diagnosis of PCD in combination with other supporting evidence c) Describes features which should be included in a ciliary ultrastructure report to assist multidisciplinary diagnosis of PCD and d) Defines adequacy of a diagnostic sample. This tested and validated consensus statement provides a clear guideline for the diagnosis of PCD by transmission electron microscopy which can be used to standardise diagnosis internationally.

Background The diagnosis of primary ciliary dyskinesia (PCD) is difficult and requires a combination of clinical features, nasal nitric oxide testing, cilia ultrastructural analysis by electron microscopy (EM), and genetics. A recently described cytoplasmic ultrastructural change termed "ciliary inclusions" was reported to be diagnostic of PCD; however, no supporting evidence of PCD was provided. In this study, we sought to confirm, or refute, the diagnosis of PCD in subjects with "ciliary inclusions" on EM. Methods Six subjects from five families with previous lab reports of "ciliary inclusions" on EMs of ciliated cells were identified and evaluated at a Genetic Disorders of Mucociliary Clearance Consortium site. We performed a detailed clinical history, nasal nitric oxide measurement, genetic testing including whole-exome sequencing (WES), and when possible, repeat ciliary EM study. Results Only one of six subjects had multiple and persistent clinical features congruent with PCD. No subject had situs inversus. Only one of six subjects had a very low nasal nitric oxide level. No "ciliary inclusions" were found in three subjects who had a repeat ciliary EM, and ciliary axonemal ultrastructures were normal. Genetic testing, including WES, was negative for PCD-causing genes, and for pathogenic variants in gene pathways that might cause "ciliary inclusions," such as ciliary biogenesis. Conclusion "Ciliary Inclusions", in isolation, are not sufficient to diagnosis PCD. If seen, additional studies should be done to pursue an accurate diagnosis.

Primary ciliary dyskinesia (PCD) is a recessive genetically heterogeneous disorder of motile cilia with chronic otosinopulmonary disease and organ laterality defects in ∼50% of cases. The prevalence of PCD is difficult to determine. Recent diagnostic advances through measurement of nasal nitric oxide and genetic testing has allowed rigorous diagnoses and determination of a robust clinical phenotype, which includes neonatal respiratory distress, daily nasal congestion, and wet cough starting early in life, along with organ laterality defects. There is early onset of lung disease in PCD with abnormal airflow mechanics and radiographic abnormalities detected in infancy and early childhood.

In primary ciliary dyskinesia, factors leading to disease heterogeneity are poorly understood.To describe early lung disease progression in primary ciliary dyskinesia and identify associations between ultrastructural defects and genotypes with clinical phenotype.This was a prospective, longitudinal (5 yr), multicenter, observational study. Inclusion criteria were less than 19 years at enrollment and greater than or equal to two annual study visits. Linear mixed effects models including random slope and random intercept were used to evaluate longitudinal associations between the ciliary defect group (or genotype group) and clinical features (percent predicted FEVA total of 137 participants completed 732 visits. The group with absent inner dynein arm, central apparatus defects, and microtubular disorganization (IDA/CA/MTD) (n = 41) were significantly younger at diagnosis and in mixed effects models had significantly lower percent predicted FEVParticipants with IDA/MTD/CA defects, which included individuals with CCDC39 or CCDC40 mutations, had worse lung function and growth indices compared with those with outer dynein arm defects and DNAH5 mutations, respectively. The only group with a significant lung function decline over time were participants with IDA/MTD/CA defects.

The most common pathogen in pediatric cystic fibrosis (CF) patients is Staphylococcus aureus, and drug-resistant species are associated with negative outcomes. Methicillin-resistant Staphylococcus aureus (MRSA) is notoriously hard to treat because many antibiotics are not FDA approved for children and drug allergies or intolerances can prohibit the use of others. Telavancin is currently indicated for hospital-acquired pneumonia and ventilator-associated pneumonia caused by MRSA, but it has not been studied in patients with CF or in pediatrics. As a semi-synthetic derivative of vancomycin, it is unknown if cross-reactivity with telavancin occurs in patients with vancomycin hypersensitivity or intolerance. In this case series, we describe three adolescent patients with CF and previous intolerance to vancomycin who received telavancin for bronchopulmonary exacerbations.

Background Primary ciliary dyskinesia (PCD) and cri du chat syndrome (CdCS) are distinct disorders that can co-occur due to a common genetic locus on chromosome 5p. Chronic respiratory symptoms associated with PCD can occur in CdCS and are typically attributed to hypotonia, dysphagia, and aspiration. The prevalence of PCD among individuals with CdCS is not known. Methods An online survey assessing common features of PCD was distributed to members of the 5P Minus Society, a cri du chat patient advocacy group. Respondents who met criteria for elevated risk of PCD (at least 3 symptoms or other features highly suggestive of PCD) were offered PCD genetic testing. Results For the 123 respondents (median age 10.1 years with IQR 5.5-17.3 years; from 33 U.S. states and 10 other countries) chronic respiratory symptoms associated with PCD were prevalent, including unexplained neonatal respiratory distress, year-round nasal congestion beginning in infancy, and year-round, wet cough beginning in infancy in 35%, 32%, and 20% of respondents, respectively. Fifteen respondents (12%) met criteria for elevated risk for PCD and completed genetic analysis; however, none were diagnostic for PCD. A PCD clinical center evaluated an additional subject with CdCS who met criteria for likely PCD and had negative genetics, but had diagnostic electron microscopy of the respiratory cilia (missing outer dynein arms). Conclusion Clinicians should be aware of the genetic connection between CdCS and PCD. Non-informative genetic testing does not rule out PCD. CdCS patients with chronic respiratory symptoms may benefit from referral to specialized PCD diagnostic centers.

Background: This document presents the American Thoracic Society clinical practice guidelines for the diagnosis of primary ciliary dyskinesia (PCD). Target Audience: Clinicians investigating adult and pediatric patients for possible PCD. Methods: Systematic reviews and, when appropriate, meta-Analyses were conducted to summarize all available evidence pertinent to our clinical questions. Evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for diagnosis and discussed by amultidisciplinary panelwith expertise in PCD. Predetermined conflict-of-interest management strategies were applied, and recommendations were formulated, written, and graded exclusively by the nonconflicted panelists. Three conflicted individuals were also prohibited from writing, editing, or providing feedback on the relevant sections of the manuscript. Results: After considering diagnostic test accuracy, confidence in the estimates for each diagnostic test, relative importance of test results studied, desirable and undesirable direct consequences of each diagnostic test, downstream consequences of each diagnostic test result, patient values and preferences, costs, feasibility, acceptability, and implications for health equity, the panel made recommendations for or against the use of specific diagnostic tests as compared with using the current reference standard (transmission electron microscopy and/or genetic testing) for the diagnosis of PCD. Conclusions: The panel formulated and provided a rationale for the direction as well as for the strength of each recommendation to establish the diagnosis of PCD.

Summary Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, rare lung disease resulting in chronic oto‐sino‐pulmonary disease in both children and adults. Many physicians incorrectly diagnose PCD or eliminate PCD from their differential diagnosis due to inexperience with diagnostic testing methods. Thus far, all therapies used for PCD are unproven through large clinical trials. This review article outlines consensus recommendations from PCD physicians in North America who have been engaged in a PCD centered research consortium for the last 10 years. These recommendations have been adopted by the governing board of the PCD Foundation to provide guidance for PCD clinical centers for diagnostic testing, monitoring, and appropriate short and long‐term therapeutics in PCD patients. Pediatr Pulmonol. 2016;51:115–132. © 2015 The Authors. Pediatric Pulmonology Published by Wiley Periodicals, Inc.

Primary ciliary dyskinesia (PCD) is characterised by chronic suppurative lung disease, rhino-sinusitis, hearing impairment and sub-fertility. We have developed the first multidimensional measure to assess health-related quality of life (HRQoL) in adults with PCD (QOL–PCD). Following a literature review and expert panel meeting, open-ended interviews with patients investigated the impact of PCD on HRQoL in the UK and North America (n=21). Transcripts were content analysed to derive saturation matrices. Items were rated for relevance by patients (n=49). Saturation matrices, relevance scores, literature review, evaluation of existing measures, and expert opinion contributed to development of a preliminary questionnaire. The questionnaire was refined following cognitive interviews (n=18). Open-ended interviews identified a spectrum of issues unique to adults with PCD. Saturation matrices confirmed comprehensive coverage of content. QOL–PCD includes 48 items covering the following seven domains: Physical Functioning, Emotional Functioning, Treatment Burden, Respiratory and Sinus Symptoms, Ears and Hearing, Social Functioning, and Vitality and Health Perceptions. Cognitive testing confirmed that content was comprehensive and the items were well-understood by respondents. Content validity and cognitive testing supported the items and structure. QOL–PCD has been translated into other languages and is awaiting psychometric testing., QOL–PCD: quality of life measure for primary ciliary dyskinesia is ready for multi-national psychometric testing http://ow.ly/KAYyG

Primary ciliary dyskinesia (PCD) is a genetic disorder causing chronic oto-sino-pulmonary disease. No single diagnostic test will detect all PCD cases. Transmission electron microscopy (TEM) of respiratory cilia was previously considered the gold standard diagnostic test for PCD, but 30% of all PCD cases have either normal ciliary ultrastructure or subtle changes which are non-diagnostic. These cases are identified through alternate diagnostic tests, including nasal nitric oxide measurement, high-speed videomicroscopy analysis, immunofluorescent staining of axonemal proteins, and/or mutation analysis of various PCD causing genes. Autosomal recessive mutations in DNAH11 and HYDIN produce normal TEM ciliary ultrastructure, while mutations in genes encoding for radial spoke head proteins result in some cross-sections with non-diagnostic alterations in the central apparatus interspersed with normal ciliary cross-sections. Mutations in nexin link and dynein regulatory complex genes lead to a collection of different ciliary ultrastructures; mutations in CCDC65, CCDC164, and GAS8 produce normal ciliary ultrastructure, while mutations in CCDC39 and CCDC40 cause absent inner dynein arms and microtubule disorganization in some ciliary cross-sections. Mutations in CCNO and MCIDAS cause near complete absence of respiratory cilia due to defects in generation of multiple cellular basal bodies; however, the scant cilia generated may have normal ultrastructure. Lastly, a syndromic form of PCD with retinal degeneration results in normal ciliary ultrastructure through mutations in the RPGR gene. Clinicians must be aware of these genetic causes of PCD resulting in non-diagnostic TEM ciliary ultrastructure and refrain from using TEM of respiratory cilia as a test to rule out PCD.

Introduction: Nasal NO is recommended to be used in the diagnostic work-up of PCD. Objective: To determine whether nNO measurements using portable electrochemical device NIOX VERO ® could distinguish subjects with PCD from healthy subjects. The primary endpoint was mean nNO measurements in subjects with at least 2 measurements. Method: A multi-center, single visit, non-randomised study involved subjects ≥5 years with known PCD vs. age matched healthy controls (HC). Subjects attempted nNO using both tidal breathing method (TB-nNO) and expiration against resisitance method (ER-nNO). Descriptive analyses were performed, including a Receiver Operating Characteristic curve analysis to assess optimal cut-off values. Results: In this study, 98.1% (49 PCD [mean age 17.5 (SD 11.66)/105 HC 19.4 (SD 14.22)] completed at least one measurement in both methods; 96.8% completed at least two measurements from one nostril using either method. Mean TB-nNO values were 50.7 (SD 50.28) ppb and 575.3 (SD 236.88) ppb in PCD vs HC and mean ER-nNO values were 80.5 (SD 101.73) ppb and 915.9 (SD 391.68) ppb in PCD vs HC. In subjects with two measurements from both nostrils using either method, opitimal cut-off values were 171 ppb (51.3 nL/min) for TB-nNO (AUC 99.8%; specificity 100%; sensitivity 98.0%) and 356 ppb (106.8 nL/min) for ER-nNO (AUC 98.7%; specificity 96.3%; sensitivity 97.8%). Conclusions: The new NIOX VERO ® nasal application can be used to differentiate patients with PCD from healthy individuals. The obtained cut-off TB-nNO and ER-nNO values show that both methods in NIOX VERO ® can be used in children and adult patients as part of the diagnostic work-up of PCD.

Rationale: The standard approach to diagnosis of primary ciliary dyskinesia (PCD) in the United Kingdom consists of assessing ciliary function by high-speed microscopy and ultrastructure by election microscopy, but equipment and expertise is not widely available internationally. The identification of biallelic disease-causing mutations is also diagnostic, but many disease-causing genes are unknown, and testing is not widely available outside the United States. Fluorescent antibodies to ciliary proteins are used to validate research genetic studies, but diagnostic utility in this disease has not been systematically evaluated.

RATIONALE: Primary ciliary dyskinesia (PCD) is a rare disorder causing chronic otosinopulmonary disease, generally diagnosed through evaluation of respiratory ciliary ultrastructure and/or genetic testing. Nasal nitric oxide (nNO) measurement is used as a PCD screening test because patients with PCD have low nNO levels, but its value as a diagnostic test remains unknown. OBJECTIVES: To perform a systematic review to assess the utility of nNO measurement (index test) as a diagnostic tool compared with the reference standard of electron microscopy (EM) evaluation of ciliary defects and/or detection of biallelic mutations in PCD genes. DATA SOURCES: Ten databases were searched for reference sources from database inception through July 29, 2016. DATA EXTRACTION: Study inclusion was limited to publications with rigorous nNO index testing, reference standard diagnostic testing with EM and/or genetics, and calculable diagnostic accuracy information for cooperative patients (generally >5 yr old) with high suspicion of PCD. SYNTHESIS: Meta-analysis provided a summary estimate for sensitivity and specificity and a hierarchical summary receiver operating characteristic curve. The Quality Assessment of Diagnostic Accuracy Studies-2 tool was used to assess study quality, and Grading of Recommendations Assessment, Development, and Evaluation was used to assess the certainty of evidence. In 12 study populations (1,344 patients comprising 514 with PCD and 830 without PCD), using a reference standard of EM alone or EM and/or genetic testing, summary sensitivity was 97.6% (92.7-99.2) and specificity was 96.0% (87.9-98.7), with a positive likelihood ratio of 24.3 (7.6-76.9), a negative likelihood ratio of 0.03 (0.01-0.08), and a diagnostic odds ratio of 956.8 (141.2-6481.5) for nNO measurements. After studies using EM alone as the reference standard were excluded, the seven studies using an extended reference standard of EM and/or genetic testing showed a summary sensitivity of nNO measurements of 96.3% (88.7-98.9) and specificity of 96.4% (85.1-99.2), with a positive likelihood ratio of 26.5 (5.9-119.1), a negative likelihood ratio of 0.04 (0.01-0.12), and a diagnostic odds ratio of 699.3 (67.4-7256.0). Certainty of the evidence was graded as moderate. CONCLUSIONS: nNO is a sensitive and specific test for PCD in cooperative patients (generally >5 yr old) with high clinical suspicion for this disease. With a moderate level of evidence, this meta-analysis confirms that nNO testing using velum closure maneuvers has diagnostic accuracy similar to EM and/or genetic testing for PCD when cystic fibrosis is ruled out. Thus, low nNO values accompanied by an appropriate clinical phenotype could be used as a diagnostic PCD test, though EM and/or genetics will continue to provide confirmatory information.

Background: Quality of life (QOL)-primary ciliary dyskinesia (PCD) is the first disease-specific, health-related QOL instrument for PCD. Psychometric validation of QOL-PCD assesses the performance of this measure in adults, including its reliability, validity and responsiveness to change. Methods: Seventy-two adults (mean (range) age: 33 years (18–79 years); mean (range) FEV1% predicted: 68 (26–115)) with PCD completed the 49-item QOL-PCD and generic QOL measures: Short-Form 36 Health Survey, Sino-Nasal Outcome Test 20 (SNOT-20) and St George Respiratory Questionnaire (SGRQ)-C. Thirty-five participants repeated QOL-PCD 10–14 days later to measure stability or reproducibility of the measure. Results: Multitrait analysis was used to evaluate how the items loaded on 10 hypothesised scales: physical, emotional, role and social functioning, treatment burden, vitality, health perceptions, upper respiratory symptoms, lower respiratory symptoms and ears and hearing symptoms. This analysis of item-to-total correlations led to 9 items being dropped; the validated measure now comprises 40 items. Each scale had excellent internal consistency (Cronbach's α: 0.74 to 0.94). Two-week test–retest demonstrated stability for all scales (intraclass coefficients 0.73 to 0.96). Significant correlations were obtained between QOL-PCD scores and age and FEV1. Strong relationships were also found between QOL-PCD scales and similar constructs on generic questionnaires, for example, lower respiratory symptoms and SGRQ-C (r=0.72, p

Objective Pseudomonas aeruginosa has been suggested as a major determinant of poor pulmonary outcomes in cystic fibrosis (CF), although other factors play a role. Our objective was to investigate the association of early childhood Pseudomonas infection on differences in lung function in adolescence with CF. Methods Two populations of subjects with CF were studied: from the Gene Modifier Study (GMS), 346 F508del homozygotes with severe vs. mild adolescent lung disease, and from the Colorado Newborn Screen Study (NBS) 172 subjects diagnosed with CF by newborn screening. Associations of Pseudomonas infection and lung function in early childhood with lung function in adolescence were investigated using multivariate linear regression analyses. Results Among GMS subjects, those with severe adolescent lung disease had worse lung function in childhood (FEV1 25 percentage points lower) compared to subjects with mild adolescent lung disease, regardless of early childhood Pseudomonas status. Among NBS subjects, those with lowest adolescent lung function had significantly lower early childhood lung function and faster rate of decline in FEV1 than subjects with highest adolescent lung function; early Pseudomonas infection was not associated with rate of FEV1 decline. The strongest predictor of adolescent lung function was early childhood lung function. Subjects with a higher percentage of cultures positive for Pseudomonas before age 6 or a lower BMI at 2–4 years old also had lower adolescent lung function, though these associations were not as strong as with early childhood lung function. Conclusions In separate analyses of two distinct populations of subjects with CF, we found a strong correlation between lower lung function in early childhood and adolescence, regardless of early childhood Pseudomonas status. Factors in addition to early Pseudomonas infection have a strong impact on lung function in early childhood in CF. Further exploration may identify novel underlying genetic or environmental factors that predispose children with CF to early loss of lung function.

International audience; The diagnosis of primary ciliary dyskinesia is often confirmed with standard, albeit complex and expensive, tests. In many cases, however, the diagnosis remains difficult despite the array of sophisticated diagnostic tests. There is no “gold standard” reference test. Hence, a Task Force supported by the European Respiratory Society has developed this guideline to provide evidence-based recommendations on diagnostic testing, especially in light of new developments in such tests, and the need for robust diagnoses of patients who might enter randomised controlled trials of treatments. The guideline is based on pre-defined questions relevant for clinical care, a systematic review of the literature, and assessment of the evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. It focuses on clinical presentation, nasal nitric oxide, analysis of ciliary beat frequency and pattern by high-speed video-microscopy analysis, transmission electron microscopy, genotyping and immunofluorescence. It then used a modified Delphi survey to develop an algorithm for the use of diagnostic tests to definitively confirm and exclude the diagnosis of primary ciliary dyskinesia; and to provide advice when the diagnosis was not conclusive. Finally, this guideline proposes a set of quality criteria for future research on the validity of diagnostic methods for primary ciliary dyskinesia.