Primary Ciliary Dyskinesia Patients Research Articles

Novel pathogenic variants of DNAH5 associated with clinical and genetic spectra of primary ciliary dyskinesia in an Arab population

Introduction: Primary ciliary dyskinesia (PCD) is caused by the dysfunction of motile cilia resulting in insufficient mucociliary clearance of the lungs. This study aimed to map novel PCD variants and determine their pathogenicity in PCD patients in Kuwait.Methods: Herein, we present five PCD individuals belonging to a cohort of 105 PCD individuals recruited from different hospitals in Kuwait. Genomic DNAs from the family members were analysed to screen for pathogenic PCD variants. Transmission electron microscopy (TEM) and immunofluorescence (IF) analyses were performed on the nasal biopsies to detect specific structural abnormalities within the ciliated cells.Results: Genetic screening and functional analyses confirmed that the five PCD individuals carried novel pathogenic variants of DNAH5 causing PCD in three Arabic families. Of these, one multiplex family with two affected individuals showed two novel homozygous missense variants in DNAH5 causing PCD with situs inversus; another multiplex family with two affected individuals showed two newly identified compound heterozygous variants in DNAH5 causing PCD with situs solitus. In addition, novel heterozygous variants were identified in a child with PCD and situs solitus from a singleton family with unrelated parents. TEM analysis demonstrated the lack of outer dynein arms (ODAs) in all analysed samples, and IF analysis confirmed the absence of the dynein arm component of DNAH5 from the ciliary axoneme.Conclusion: The newly identified pathogenic variants of DNAH5 are associated with PCD as well as variable pulmonary clinical manifestations in Arabic families.

Alexithymia in primary ciliary dyskinesia.

Recent evidence suggests that alexithymic deficits in emotional processing may also affect physical health, and alexithymia may also be associated with organic disorders. The emotional well-being of patients with primary ciliary dyskinesia (PCD) is often negatively affected by uncertainty about the prognosis, lack of ongoing medical care, and lack of symptom control. This study aims to evaluate the frequency of alexithymia and its possible impact on the management of childhood PCD. Subjects were recruited from patients with PCD and healthy volunteers aged 8-18 years. The questionnaire included sociodemographic characteristics and self-report scales. Data were compared between patient and control groups. In the >14 years of age group, the total Toronto Alexithymia Scale (TAS-20) score was significantly higher in the patients (56.60 ± 13.01) compared to the control group (46.47 ± 7.50) (p = .007). There were 6 (30) patients with a TAS-20 score ≥61. There was a significant correlation between TAS-20 and Pediatric Quality of Life (PedsQL) score (child), but no correlation between TAS-20 and Kovacs Children Depression Inventory (CDI) and PedsQL score (parents). The TAS-20 score was significantly higher in patients with bronchiectasis (p = .035), nasal polyps (p = .045), and siblings with PCD (p = .001). Furthermore, the TAS-20 score had a significant negative correlation with pulmonary function tests. Although this study is based on limited data from a single center and cannot be generalized to all PCD patient communities, our results show that PCD patients are more likely to have alexithymia compared to healthy controls and highlight the need to evaluate for alexithymia in patients with PCD. It is important for pediatric pulmonologists to have a thorough knowledge of the alexithymic features associated with PCD and to refer patients to pediatric psychiatry when necessary, especially in patients who are noncompliant with treatment protocols.

Antigen stasis and airway nitrosative stress in human primary ciliary dyskinesia.

Nasal nitric oxide (nNO) is low in most patients with primary ciliary dyskinesia (PCD). Decreased ciliary motion could lead to antigen stasis, increasing oxidant production and NO oxidation in the airways. This could both decrease gas phase NO and increase nitrosative stress. We studied primary airway epithelial cells from healthy controls (HCs) and patients with PCD with several different genotypes. We measured antigen clearance in fenestrated membranes exposed apically to the fluorescently labeled antigen Dermatophagoides pteronyssinus (Derp1-f). We immunoblotted for 3-nitrotyrosine (3-NT) and for oxidative response enzymes. We measured headspace NO above primary airway cells without and with a PCD-causing genotype. We measured nNO and exhaled breath condensate (EBC) H2O2 in vivo. Apical Derp1-f was cleared from HC better than from PCD cells. DUOX1 expression was lower in HC than in PCD cells at baseline and after 24-h Derp1-f exposure. HC cells had less 3-NT and NO3- than PCD cells. However, NO consumption by HC cells was less than that by PCD cells; NO loss was prevented by superoxide dismutase (SOD) and by apocynin. nNO was higher in HCs than in patients with PCD. EBC H2O2 was lower in HC than in patients with PCD. The PCD airway epithelium does not optimally clear antigens and is subject to oxidative and nitrosative stress. Oxidation associated with antigen stasis could represent a therapeutic target in PCD, one with convenient monitoring biomarkers.NEW & NOTEWORTHY The PCD airway epithelium does not optimally clear antigens, and antigen exposure can lead to NO oxidation and nitrosative stress. Oxidation caused by antigen stasis could represent a therapeutic target in PCD, and there are convenient monitoring biomarkers.

Redox Imbalance in Nasal Epithelial Cells of Primary Ciliary Dyskinesia Patients.

Background: Primary Ciliary Dyskinesia (PCD) represents a rare condition marked by an abnormal mobility pattern of cilia and flagella, resulting in impaired mucociliary clearance. This deficiency leads to recurrent infections and persistent inflammation of the airways. While previous studies have indicated heightened oxidative stress levels in the exhaled breath condensate of pediatric PCD patients, the assessment of oxidative stress within the affected respiratory tissue remains unexplored. Aims: To assess the oxidative status of human nasal epithelial cells (NECs) in PCD patients. Methods: Thirty-five PCD patients and thirty-five healthy control subjects were prospectively included in the study. Levels of reactive oxygen species (ROS), reactive nitrogen species (RNS), glutathione (GSH), intracellular Ca2+, plasma membrane potential, and oxidative damage in lipids and proteins were measured. In addition, apoptosis and mitochondrial function were analyzed by flow cytometry in NECs. Results: NECs from PCD patients showed reduced levels of apoptosis (p = 0.004), superoxide anion (O2-, p = 0.018), peroxynitrite (ONOO-, p = 0.007), nitric oxide (NO, p = 0.007), mitochondrial hydrogen peroxide (mtH2O2, p < 0.0001), and mitochondrial superoxide anion (mtO2-, p = 0.0004) and increased mitochondrial mass (p = 0.009) compared to those from healthy individuals. No significant differences were observed in oxidized proteins (p = 0.137) and the oxidized/reduced lipid ratio (p = 0.7973). The oxidative profile of NEC cells in PCD patients, according to their ciliary motility, recurrent otitis, recurrent pneumonia, atelectasis, bronchiectasis, and situs inversus, showed no statistically significant differences in the parameters studied. Conversely, patients with chronic rhinosinusitis exhibited lower levels of ONOO- than PCD patients without this condition, with no significant differences related to other symptoms. Conclusions: Our findings strongly suggest the presence of a redox imbalance, specifically leaning toward a reductive state, in PCD patients.

The genetic framework of primary ciliary dyskinesia assessed by soft computing analysis.

International guidelines disagree on how best to diagnose primary ciliary dyskinesia (PCD), not least because many tests rely on pattern recognition. We hypothesized that quantitative distribution of ciliary ultrastructural and motion abnormalities would detect most frequent PCD-causing groups of genes by soft computing analysis. Archived data on transmission electron microscopy and high-speed video analysis from 212 PCD patients were re-examined to quantitate distribution of ultrastructural (10 parameters) and functional ciliary features (4 beat pattern and 2 frequency parameters). The correlation between ultrastructural and motion features was evaluated by blinded clustering analysis of the first two principal components, obtained from ultrastructural variables for each patient. Soft computing was applied to ultrastructure to predict ciliary beat frequency (CBF) and motion patterns by a regression model. Another model classified the patients into the five most frequent PCD-causing gene groups, from their ultrastructure, CBF and beat patterns. The patients were subdivided into six clusters with similar values to homologous ultrastructural phenotype, motion patterns, and CBF, except for clusters 1 and 4, attributable to normal ultrastructure. The regression model confirmed the ability to predict functional ciliary features from ultrastructural parameters. The genetic classification model identified most of the different groups of genes, starting from all quantitative parameters. Applying soft computing methodologies to PCD diagnostic tests optimizes their value by moving from pattern recognition to quantification. The approach may also be useful to evaluate atypical PCD, and novel genetic abnormalities of unclear disease-producing potential in the future.

Pulmonary functions, nasal symptoms, and quality of life in patients with primary ciliary dyskinesia (PCD).

Several factors may influence quality of life (QOL) for patients with primary ciliary dyskinesia (PCD). We aimed to evaluate the association between pulmonary functions, nasal symptoms and QOL in PCD patients. A prospective single center study. Patients performed spirometry, whole body plethysmography, forced oscillation technique (FOT), lung clearance index (LCI), 6-min walk test (6MWT), and filled two questionnaires: a specific PCD QOL questionnaire (PCD-QOL) and Sino-nasal outcome test (SNOT-22) questionnaire, assessing symptoms of chronic rhinosinusitis and health related QOL. Twenty-seven patients (56% females), age 19.4 ± 10.5 years were included; their, FEV1 was 74.6 ± 22.7%, and RV/TLC was (157.3 ± 39.3% predicted). Health perception and lower respiratory symptoms domains of PCD-QOL had the lowest score (median [IQR]: 50 [33.3-64.6] and 57.1 [38.9-72.2], respectively). FOT parameters correlated with several PCD-QOL domains. R5 z-score (indicating total airway resistance) and AX z-score (indicating airway reactance) correlated negatively with physical domain (r = -0.598, p = .001, and r = -0.42, p = .03, respectively); R5 z-score also correlated negatively with hearing domain (r = -0.57, p = .002). R5-20 z-score (indicating small airway resistance) correlated negatively with role domain (r = -0.49, p = .03). SNOT-22 score correlated negatively with several PCD-QOL domains (lower respiratory symptoms r = -0.77, p < .001; physical r = -0.72, p < .001; upper respiratory symptoms r = -0.66, p < .001). No correlations were found between spirometry values, LCI, 6MWT, and PCD-QOL. FOT suggested small airway dysfunction, and correlated negatively with several PCD-QOL domains. Nasal symptoms had strong negative correlations with PCD-QOL. Larger longitudinal studies will further elucidate factors affecting QOL in PCD.

Device comparison study to measure nasal nitric oxide in relation to primary ciliary dyskinesia

Primary ciliary dyskinesia (PCD) is a genetic respiratory disease characterized by chronic cough, recurrent respiratory infections, and rhinosinusitis. The measurement of nasal nitric oxide (nNO) against resistance has been suggested as a sensitive screening method. However, current recommendations argue for the use of expensive, chemiluminescence devices to measure nNO. This study aimed to compare nNO measurement using three different devices in distinguishing PCD patients from healthy controls and cystic fibrosis (CF) patients and to evaluate their diagnostic precision. The study included 16 controls, 16 PCD patients, and 12 CF patients matched for age and sex. nNO measurements were performed using a chemiluminescence device (Eco Medics CLD 88sp), and two devices based on electrochemical sensors (Medisoft FeNO+ and NIOX Vero) following standardized guidelines. Correlation estimation, Bland–Altman, ROC curve, and one-way ANOVA were used to assess device differences and diagnostic performance. Significantly lower nNO output values were observed in PCD and CF patients compared to controls during exhalation against resistance. The correlation analysis showed high agreement among the three devices. ROC curve analysis demonstrated 100% sensitivity and specificity at different cut-off values for all devices in distinguishing PCD patients from controls (optimal cut-offs: EcoMedics 73, Medisoft 92 and NIOX 87 (nl min−1 )). Higher nNO output values were obtained with the Medisoft and NIOX devices as compared to the EcoMedics device, with a bias of−19 nl min−1 (95% CI: −73–35) and −21 nl min−1 (−73–31) accordingly. These findings indicate that all three tested devices can potentially serve as diagnostic tools for PCD if device specific cut-off values are used. This last-mentioned aspect warrants further studies and consideration in defining optimal cut-offs for individual device.

Changes in Sleep in Children and Adults with Cystic Fibrosis and Primary Ciliary Dyskinesia over Time and after CFTR Modulator Therapy.

Cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) are associated with sleep disturbances affecting quality of life (QOL) in both children and adults. However, little is known about the progression of these complaints over time, and the effect of CFTR modulator (CFTRm) therapies. Participants completed sleep quality (SDSC, PSQI) and quality of life questionnaires (PedQL, QOL-BE) as well as the Epworth sleepiness scale (ESS) at baseline and after 4 years. Medical records were reviewed for clinical data and correlations were sought between sleep, QOL, and clinical parameters. A total of 67 patients (33 pediatric), 37 pancreatic insufficient CF (CF-PI), 15 pancreatic sufficient CF (CF-PS), and 15 PCD patients, completed the study. In adults, global sleep quality decreased from 85.8% (76.2-90.5) to 80.9% (71.4-85.7); (p = 0.009). Analysis by disease cohort showed a significant deterioration only in the CF-PS group. In adults off CFTRm, sleep quality decreased from 85.7% (78.6-88.2) to 80.9% (71.4-87.3); (p = 0.021) and from 85.8% (76.2-92.9) to 76.2% (71.4-85.8); (p = 0.078) in people on CFTRm. Changes in sleep quality and changes in QOL over time were strongly associated with each other. In conclusion sleep quality deteriorates over time, correlates with QOL, and is driven primarily by adults and CF-PS patients. CFTRm has a possible effect on sleep initiation; however, results are mixed, and further long-term studies are required.

Sleep Respiratory Disorders in Children and Adolescents with Cystic Fibrosis and Primary Ciliary Dyskinesia.

Cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) are genetic respiratory diseases featured by chronic upper and lower airway inflammation and infection, mainly due to impaired mucociliary clearance due to genetic mutations. Sleep is crucial to healthy children's normal physical and psychological development and has an important value in chronic respiratory diseases. Impaired sleep quality, such as sleep deprivation or insufficient sleep during the night, and sleep respiratory disorders (SRDs) are common in 5% to 30% of the general population. Sleep disruption leads to attention deficits, daytime sleepiness, fatigue and mood disorders and correlates to a worsened quality of life. Furthermore, sleep respiratory disorders (SRSs) are under-recognized comorbidities in CF and PCD patients. SRSs include a spectrum of symptoms ranging from primary snoring through upper airway resistance to obstructive sleep apnea (OSA), nocturnal hypoventilation and hypoxemia occurring in people with moderate to severe lung disease and damaging the disease-related outcomes and quality of life. Effective screening during sleep with polysomnography is very important for the timely initiation of efficacious treatments and to prevent worsened respiratory, metabolic and cardiovascular outcomes. However, the impact of SRDs on health and quality of life is still underinvestigated.

Pulmonary radioaerosol mucociliary clearance assessment: searching for genotype-specific differences and potential as an outcome measure in primary ciliary dyskinesia

BackgroundPulmonary radioaerosol mucociliary clearance (PRMC) is a reliable method for assessingin vivowhole lung mucociliary clearance and has been used at the Danish PCD Centre as a supplementary diagnostic test for primary ciliary dyskinesia (PCD) for more than two decades. This study aimed to investigate genotype-specific differences in PRMC measures and evaluate its potential as an outcome parameter.Material and methodsThe study was based on a retrospective analysis of PRMC tests performed over a 24-year period (1999–2022) in individuals referred for PCD work-up and included patients with genetically confirmed PCD and non-PCD controls. Patients inhaled nebulised technetium-albumin-colloid before static and dynamic imaging was obtained. Three parameters were evaluated: 1-h lung retention (LR1), tracheobronchial velocity (TBV) and cough clearance.ResultsThe study included 69 patients from the Danish PCD cohort, representing 26 different PCD genotypes. Mucociliary clearance by PRMC was consistently absent in most PCD patients, regardless of genotype. However, a single patient with aCCDC103mutation, preserved ciliary function and normal nasal nitric oxide levels exhibited normal LR1 and low TBV values. Voluntary cough significantly improved clearance, with a median improvement of 11% (interquartile range 4–24%).ConclusionAbsent mucociliary clearance by PRMC should be expected in PCD regardless of genotype but residual ciliary function could result in measurable PRMC. This indicates a potential for PRMC to detect improvements in ciliary function if this can be restored. Addressing involuntary cough and peripheral deposition of radioaerosol is important if PRMC is to be used as an outcome measure in future clinical PCD trials.

A clinical case of primary ciliary dyskinesia in a child under one year old with a pathogenic genetic variant of the DNAH5 gene described for the first time

Relevance: primary ciliary dyskinesia (PCD) is a rare hereditary autosomal recessive disease from the group of ciliopathies, which is based on a defect in the ultrastructure of the cilia of the epithelium of the respiratory tract and similar structures, leading to a violation of their motor function. It is characterized by the defeat of all parts of the respiratory tract with the formation of a chronic inflammatory process and bronchiectasis. About half of patients with PCD have a complete or incomplete reverse arrangement of internal organs with various variants of heterotaxy (situs inversus). Primary ciliary dyskinesia should be differentiated from cystic fibrosis, primary immunodeficiency conditions, congenital anomalies of the structure of the bronchial tree, bronchiectasis of other origin, bronchial asthma, congenital anomalies of the cardiovascular system. Objective: describe the clinical case of a PCD patient with the first-described pathogenic variant of the nucleotide sequence (chr5:13700862CCATAGA&gt;C) of the DNAH5 gene to familiarize doctors with the clinical features of the disease and modern diagnostic capabilities. Materials and methods: the data from the patient’s medical history, transmission electron microscopy to detect anomalies in the structure of cilia in the biopsy of the nasal mucosa and the results of molecular genetic diagnostics were used. Results. The patient was admitted for 8 months for examination and treatment in June 2022. A child from the 1st pregnancy, the first birth at 43 weeks. From anamnesis: suffered intrauterine pneumonia, otitis media without hearing loss, obstructive bronchitis, episodes of apnea. Neonatal screening for cystic fibrosis is negative. According to the PICADOR scale, 12 points were obtained. On high-speed video microscopy of cilia, there is a violation of the movements of the cilia. On computed tomography of the chest organs, the reverse location of the internal organs was noted, there were no pathological changes in the lungs. The total absence of external and internal dynein handles on transmission electron microscopy was revealed. Exome sequencing revealed the previously described variant of the nucleotide sequence in exon 68 of the DNAH5 gene (chr5:13735348G&gt; A) in a heterozygous state. Also, a previously undescribed variant of the nucleotide sequence (chr5:13700862CCATAGA&gt; C) in a heterozygous state was detected in exon 78 of the DNAH5 gene. Conclusion: modern possibilities of PCD diagnostics are demonstrated by the example of clinical observation. It is noted that patients with suspected PCD need a comprehensive examination. A pathogenic variant of the nucleotide sequence (chr5:13700862CCATAGA&gt;C) of the DNAH5 gene in a heterozygous state has been described for the first time, leading to the deletion of two amino acids without shifting the reading frame (c.13604_13609del p. (Val4535_Tyr4536del); NM_001369.3), which will help for the diagnosis of PCD in the future.

Airway microbiota correlated with pulmonary exacerbation in primary ciliary dyskinesia patients.

Primary ciliary dyskinesia (PCD) is characterized by symptoms such as productive cough, rhinitis, and recurrent infections in both the upper and lower airways, which can lead to chronic infection, bronchiectasis, and decreased pulmonary function. Our study aimed to analyze the diversity and composition of the microbiota in the respiratory tract and investigate the correlation of the microbiota with pulmonary exacerbation in PCD patients. This study employed 16S rRNA amplicon sequencing to explore the microbiota present in both bronchoalveolar lavage fluid (BALF) and sputum samples collected from PCD patients. Eighty-five airway samples (17 BALF and 68 sputum samples) were collected from 72 patients aged 2 months to 60 years. Significantly lower sputum microbiota diversity and richness were found in the pulmonary exacerbation group than in the pulmonary stabilization group; additionally, the relative abundance of Pseudomonas increased when pulmonary exacerbation occurred. There was a positive correlation between pulmonary exacerbation and the relative abundance of Pseudomonas, while Streptococcus, Moraxella, and Haemophilus showed a negative correlation. Although there was no significant difference in the sputum microbiota diversity and composition in children aged 6-18 years with pulmonary exacerbation, Pseudomonas increased during pulmonary exacerbation. BALF samples of pediatric patients with pulmonary exacerbation had a lower microbiota diversity and richness; furthermore, Pseudomonas had a higher abundance and a moderate distinguishing effect. We found that microbiota beta diversity and dominance were decreased during pulmonary exacerbation. Additionally, Pseudomonas had a higher abundance and moderate distinguishing effect in pediatric patients with pulmonary exacerbation. IMPORTANCE PCD is a rare disease characterized by productive cough, rhinitis, and recurrent infections of the upper and lower airways. Because the diagnosis of PCD is often delayed, patients receive more antibiotics, experience a heavier financial burden, and have a worse prognosis; thus, it is very important to identify the pathogeny and use the correct antibiotic. In this large single-center study of PCD microbiota, we identified an outline of the bacterial microbes from the respiratory tract; furthermore, we found that the microbiota diversity in pediatric sputum was richer than that in pediatric BALF through sequencing, indicating a heterogeneous community structure. The microbiota diversity and richness were lower during pulmonary exacerbation than during pulmonary stabilization. A significantly higher abundance of Pseudomonas had a moderate distinguishing effect for lung exacerbation, which attracted more attention for the study of Pseudomonas therapy in pediatric patients with PCD.

The effect of inspiratory muscle training in PCD and CF patients: A pilot study.

Effective work of breathing and bronchial hygiene requires synergy of inspiratory and expiratory muscles. Inspiratory muscle training (IMT) is a part of pulmonary rehabilitation in chronic obstructive pulmonary disease (COPD). There is some evidence of its efficacy in cystic fibrosis (CF) and, recently, in long COVID-19. We are not aware of studies on IMT in primary ciliary dyskinesia (PCD). Our aim was to assess the effect of IMT on respiratory muscle strength and pulmonary function in PCD and CF patients. A single center pilot study. Spirometry, lung clearance index (LCI), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) were measured at baseline (visit 1), after a month of IMT with ®POWERbreathe (visit 2), and at follow-up (visit 3). The cohort included 27 patients (19 PCD, 8 CF); mean age 18.4 ± 9.8 years. After a month of IMT, there was a significant increase in MIP and MIP% (6.19-7.44, p = .015; and 81.85%-100.41%, p = .046, respectively), which was sustained at visit 3. Compliance ≥90% led to higher improvement in MIP. In sub-group analysis, improvement in MIP and MIP% remained significant for PCD patients (p = .026 and p = .049, respectively). No significant changes were found in spirometry, MEP or LCI. IMT was well-tolerated and led to improved inspiratory muscle strength in PCD patients. The clinical implication of improved MIP should be further investigated. Larger, long-term studies are needed to evaluate long-term effects of IMT on pulmonary function, respiratory muscle strength, pulmonary exacerbations, and quality of life.

Primary ciliary dyskinesia: An update on contemporary diagnosis.

Primary ciliary dyskinesia (PCD) is a complex diagnosis without a universal diagnostic test Clinicians must have some skepticism of historic diagnoses of PCD Clinicians should consider a diagnosis of PCD in patients with recalcitrant disease.

A novel mutation in PCD-associated gene DNAAF3 causes male infertility due to asthenozoospermia.

Primary ciliary dyskinesia (PCD) is a rare autosomal-recessive disease manifested with recurrent infections of respiratory tract and infertility. DNAAF3 is identified as a novel gene associated with PCD and different mutations in DNAAF3 results in different clinical features of PCD patients, such as situs inversus, sinusitis and bronchiectasis. However, the sperm phenotypic characteristics of PCD males are generally poorly investigated. Our reproductive medicine centre received a case of PCD patient with infertility, who presented with sinusitis, recurrent infections of the lower airway and severe asthenozoospermia; However, no situs inversus was found in the patient. A novel homozygous mutation in DNAAF3(c.551T>A; p.V184E) was identified in the PCD patient by whole-exome sequencing. Subsequent Sanger sequencing further confirmed that the DNAAF3 had a homozygous missense variant in the fifth exon. Transmission electron microscopy and immunostaining analysis of the sperms from the patient showed a complete absence of outer dynein arms and partial absence of inner dynein arms, which resulted in the reduction in sperm motility. However, this infertility was overcome by intracytoplasmic sperm injections, as his wife achieved successful pregnancy. These findings showed that the PCD-associated pathogenic mutation within DNAAF3 also causes severe asthenozoospermia and male infertility ultimately due to sperm flagella axoneme defect in humans. Our study not only contributes to understand the sperm phenotypic characteristics of patients with DNAAF3 mutations but also expands the spectrum of DNAAF3 mutations and may contribute to the genetic diagnosis and therapy for infertile patient with PCD.

Ear and upper airway clinical outcome measures for use in primary ciliary dyskinesia research: a scoping review.

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by pulmonary, otological and sino-nasal manifestations. Well-defined clinical outcome measures are needed in such rare diseases research to improve follow-up and treatments. Pulmonary outcome measures have recently been described. The aim of this study was to identify ear and upper airway outcome measures that could be used for longitudinal follow-up of individuals with PCD. A scoping review was performed by systematically searching MEDLINE, Embase and Cochrane Database of Systematic Reviews online databases for studies published from January 1996 to March 2022 that included at least 10 adult or paediatric PCD patients and reported ear and upper airway outcomes. 33 studies (1794 patients) were included. 10 ear and upper airway outcomes were reported. 17 studies reported audiometry, 16 reported otoscopic findings, and 13 reported rhinoscopic findings and sinus imaging. Health-related quality of life questionnaires were performed in seven studies. There was a high variability in definitions and measurement of outcomes between studies. This scoping review highlights the lack of data regarding ear and upper airway outcomes in PCD. It also reports a high heterogeneity in outcome definitions or measures. We provide well-founded specific suggestions to standardise ear and upper airway outcome definitions and reporting for future PCD research studies.

Evaluation of otorhinolaryngological manifestations in patients with primary ciliary dyskinesia

Primary ciliary dyskinesia (PCD) is a genetic disease characterized by congenital impairment of mucociliary clearance causing recurrent respiratory tract infections. Pulmonary manifestations of PCD are well-known whereas adequate data on otorhinolaryngological complications is lacking. The aim of this study was to investigate clinical features, course and related factors of otorhinolaryngologic domains in PCD patients. Patients with a diagnosis of PCD who were on follow-up in the ear-nose-throat (ENT) department of our center between 2000 and 2021 were enrolled. Demographic and clinical data, frequency of sinonasal and otological complaints, examination findings and possible risk factors associated with otorhinolaryngological diseases were obtained via electronic medical charts retrospectively. Of the 121 patients, 53% were male, median age at PCD diagnosis was 7 years (1 month - 20yrs). The most common ENT manifestation was otitis media with effusion (OME) (66.1%, n=80), followed by acute otitis media (43.8%, n=53), acute rhinosinusitis (ARS) (28.9%, n=35), chronic rhinosinusitis (CRS) (27.3%, n=33) and chronic otitis media (10.7%, n=13). Patients with ARS and CRS were significantly older than patients who did not have ARS and CRS (p=0.045 and p=0.028, respectively). The annual number of ARS attacks also correlated with age of patients positively (r=0.170, p=0.06). Of the 45 patients with pure-tone audiometry, most common finding was conductive hearing loss (CHL) in 57,8% (n=26). Presence of OME significantly increased tympanic membrane injury which was observed as sclerosis, perforation, retraction or changes due to ventilation tube insertion (VTI). (OR: 8.6, 95% CI: 3.6-20.3, p<0.001). Otorhinolaryngologic diseases are common, variable and complicated in PCD patients, consequently ENT physicians' awareness should be improved through shared experiences. ARS and CRS seem to appear in older PCD patients. Presence of OME is the most important risk factor for tympanic membrane damage.

PO-05-014 SUCCESSFUL IMPLANTATION OF A MICRA LEADLESS PACEMAKER THROUGH THE LEFT SUBCLAVIAN VEIN IN A PATIENT WITH SITUS AMBIGUOUS

Primary ciliary dyskinesia patients often have situs ambiguous, a congenital condition with abnormal arrangement of visceral organs in the abdomen and chest. It is associated with an increased risk of congenital heart defects and anomalous venous connections. As a result, placement of the leadless pacemaker through the femoral approach may not be viable in these patients. Herein we describe a successful placement of a leadless pacemaker through the left subclavian approach in a patient with primary ciliary dyskinesia with associated interrupted IVC, right internal jugular (RIJ) thrombus, failed epicardial pacers, and extraction of infected transvenous pacer. N/A A 36-year-old female with primary ciliary dyskinesia, situs ambiguous, RIJ thrombus, and azygous venous connection presents with paroxysmal atrial fibrillation, sinus node dysfunction and syncope (A); History of multiple pacemakers, including failed epicardial pacer, substance abuse and recurrent bacteremia with multiple transvenous pacer infections requiring extractions. Ultrasound access was gained in the left subclavian vein via the modified Seldinger technique. Access was serially dilated until a 23Fr dilator. A manual curve was applied to the tip of the Micra-introducer sheath and the long 27Fr hydrophilic micra-introducer sheath was advanced over a Lunderquist wire, using a stiff rail, into middle of the right atrium (B). The 105 cm Micra delivery catheter was inserted into the sheath, and advanced with fluoroscopic guidance into the right atrium. The introducer sheath was pulled back into the SVC and the delivery catheter was counter-clocked, flexed downward and advanced across the tricuspid valve. The pacemaker was directed to the midseptal position. Contrast was injected to verify positioning against the myocardium (C). The device was deployed with satisfactory parameters noting R waves of 12mV and threshold less than 1V at 0.24 msec pulse with. The pacer was then released with tugging testing confirming adequate deployment. (D). The patient was discharged safely home 2 days later. The left subclavian vein is a viable and safe approach for placing the Micra leadless pacemaker.

Sinonasal disease among patients with primary ciliary dyskinesia: an international study

Sinonasal symptoms are a common feature of primary ciliary dyskinesia (PCD); however, literature about their severity and frequency, particularly during the life course, is scarce. Using baseline data from the Ear, nose and throat (ENT) Prospective International Cohort of PCD patients, we describe sinonasal disease in PCD. We included participants who had a routine sinonasal examination during which they completed a symptoms questionnaire. We compared frequency of reported symptoms and examination findings among children and adults, and identified characteristics potentially associated with higher risk of sinonasal disease using ordinal regression. 12 centres contributed 384 participants; median age was 16 years (IQR 9-22), and 54% were male. Chronic nasal problems were the most common feature, reported by 341 (89%). More adults (33; 24%) than children (10; 4%) described hyposmia. Quality of life was moderately affected by rhinosinusitis among 136 participants with completed SNOT-22 questionnaires (median score 31; IQR 23-45). Examinations revealed nasal polyps among 51 of 345 participants (15%) and hypertrophic inferior nasal turbinates among 127 of 341 participants (37%). Facial pain was detected in 50 of 342 participants (15%). Nasal polyps, hypertrophic turbinates, deviated septum and facial pain were found more commonly in adults than children. The only characteristic associated with higher risk of sinonasal disease was age 10 years and older. Based on our findings, regular sinonasal examinations are relevant for patients with PCD of all ages. There is a need for improved management of sinonasal disease supported by evidence-based guidelines.

Characteristic genetic spectrum of primary ciliary dyskinesia in Japanese patients and global ethnic heterogeneity: population-based genomic variation database analysis.

Primary ciliary dyskinesia (PCD) is a hereditary disease caused by pathogenic variants in genes associated with motile cilia. Some variants responsible for PCD are reported to be ethnic-specific or geographical-specific. To identify the responsible PCD variants of Japanese PCD patients, we performed next-generation sequencing of a panel of 32 PCD genes or whole-exome sequencing in 26 newly identified Japanese PCD families. We then combined their genetic data with those from 40 Japanese PCD families reported previously, for an overall analysis of 66 unrelated Japanese PCD families. We conducted Genome Aggregation Database and TogoVar database analyses to reveal the PCD genetic spectrum of the Japanese population and compare with other ethnic groups worldwide. We identified 22 unreported variants among the 31 patients in the 26 newly identified PCD families, including 17 deleterious variants estimated to cause lack of transcription or nonsense-mediated mRNA decay and 5 missense mutations. In all 76 PCD patients from the 66 Japanese families, we identified 53 variants on 141 alleles in total. Copy number variation in DRC1 is the most frequent variant in Japanese PCD patients, followed by DNAH5 c.9018C>T. We found 30 variants specific to the Japanese population, of which 22 are novel. Furthermore, 11 responsible variants in the Japanese PCD patients are common in East Asian populations, while some variants are more frequent in other ethnic groups. In conclusion, PCD is genetically heterogeneous between different ethnicities, and Japanese PCD patients have a characteristic genetic spectrum.