The ciliary transition zone (TZ) regulates ciliary proteome composition, yet its molecular architecture, protein content, and contribution to motile ciliopathies remain poorly defined. We applied in situ cryo-electron tomography and subtomogram averaging to human multiciliated epithelial cells. This approach resolved TZ-specific doublet microtubules at subnanometer resolution and identified nine constituent proteins. We identified that ECT2L and DZANK1 form the major linker complexes between adjacent TZ doublet microtubules. Biallelic loss-of-function variants in either gene cause primary ciliary dyskinesia. ECT2L and DZANK1 deficiency disrupted TZ architecture, caused microtubular abnormalities and abnormal bulbous ciliary tips, and impaired mucociliary clearance. These findings establish a direct genetic link between TZ defects and human motile ciliopathy, and illustrate how in situ structural biology can uncover mechanisms of human disease.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder leading to destructive airway disease with severe bronchiectasis and chronic lung failure in adulthood. Pathogenic variants in CCDC40 are associated with a more severe reduction of lung function compared to most other PCD types. Currently, no therapies correcting the underlying disease mechanism are available. Here, we investigate the efficacy of lipidoid nanoparticle-formulated mRNA encoding human CCDC40 (LNP-CCDC40-mRNA) as a corrective measure for structural and functional defects in vitro (human cells) and in vivo (zebrafish). Human nasal respiratory epithelial cells cultured at an air-liquid interface from 5 CCDC40-deficient individuals and a newly generated vertebrate animal model (ccdc40-/- zebrafish) were treated with LNP-CCDC40-mRNA. CCDC40-deficient cells were analyzed by high-speed video microscopy and immunofluorescence microscopy. ccdc40-/- zebrafish olfactory pit cilia were analyzed by high-speed video microscopy and fluid flow assays. Topical application of exogenous LNP-CCDC40-mRNA to CCDC40-deficient cells results in endogenous CCDC40 expression (10%-74% of ciliated cells), enabling axonemal integration of CCDC40-associated proteins (CCDC39, GAS8/DRC4, DNALI1). Consistently, ciliary beat frequencies were significantly increased in treated CCDC40-deficient cells and were comparable to those of healthy control cells. Further, we showed improved ciliary transport of fluorescent particles. Injection or topical application of human LNP-CCDC40-mRNA to ccdc40-/- zebrafish significantly increased ciliary motility and established directional flow in olfactory pits. We provide structural and functional evidence in vitro and in vivo for the biological efficacy of LNP-CCDC40-mRNA in CCDC40-deficient respiratory cells and zebrafish. Based on our results, an in vivo human study (Phase 1 trial) is planned in individuals with pathogenic variants in CCDC40.

Background: Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by deficient mucociliary clearance and development of chronic lung disease. Pulmonary exacerbations (PEx) in chronic lung diseases increase morbidity and lung function decline, but their frequency in PCD has been understudied. We aimed to prospectively determine the annual frequency of PEx in PCD and identify related risk factors. Methods: In a multicentre, observational study conducted in 11 centres from seven countries, we prospectively collected data from a well-described patient cohort with genetically confirmed PCD over a year via monthly telephone questionnaires and clinical visits. We assessed the annual PEx frequency using three definitions: i) clinical definition 1 (Def-1) when three out of seven clinical items were positive; clinical definition 2 (Def-2) if the patient started or changed antibiotic treatment; self-reported PEx by the patient. For paired statistical comparisons we used the Friedman test and the Wilcoxon matched-pairs test and tested their agreement (Cohen's kappa statistics). We also determined related risk factors using a mixed-effects model. Results: We recruited 271 individuals with PCD of all ages. Among patients with complete annual records (n = 248), approximately 80% experienced at least one PEx per year, as assessed by the three definitions used. Self-reported PEx per year (median 2, interquartile range (IQR) 1-5) were higher (p < 0.0001) than the PEx assessed by Def-1 (median 2, IQR 0-4) and Def-2 (median 1, IQR 0.25-3). Self-reported PEx had a substantial agreement with Def-1 [kappa (SE) = 0.61 (0.05)] and a moderate agreement with Def-2 [kappa (SE) = 0.51 (0.05)]. Female sex and autumn season were associated with higher number of PEx, independent of the definition used. Increasing age was correlated with higher annual PEx frequency by Def-1. Conclusion: In this multicentre study, we prospectively assessed the annual PEx frequency in patients genetically diagnosed with PCD, demonstrating the importance of the definition used in capturing the exacerbation burden of PCD, as well as the influence of sex, age and season on exacerbation frequency.

Abstract Background Upper airway disease is common in primary ciliary dyskinesia (PCD), but management evidence is limited. We aimed to describe management practices and identify factors influencing management decisions. Methods Using data from the Ear-Nose-Throat (ENT) Prospective International Cohort of patients with PCD (EPIC-PCD) and an ENT-specialist survey across participating centres, we described management practices recorded at routine follow-up. We assessed clinical factors associated with practices via mixed-effects logistic regression models. In a subgroup of patients, we assessed factors associated with initiation or discontinuation of practices. Results We included 579 patients: median age 15 years, 46% female. Nasal rinsing (54%) and nasal corticosteroids (22%) were most frequently prescribed. Among 466 patients with available data, 47 had grommets (10%) and 42 hearing aids (9%). Nasal corticosteroids and rinsing were more frequently prescribed in patients with polyps (odds ratio [OR] 3.74, 95% confidence interval [CI] 1.80-7.76; OR 3.39, 95% CI 1.37-8.37) or turbinate hypertrophy (OR 1.89, 95% CI 1.03-3.47; OR 2.89, 95% CI 1.55-5.38), and upper airway nebulisation in patients with frequent nasal symptoms (OR 2.86, 95% CI 1.11-7.39). Management practices differed between centres, as seen also by the specialists’ survey responses. In 177 patients with multiple visits, initiation of nasal rinsing was associated with frequent nasal symptoms (OR 3.18, 95% CI 1.24-8.18) and turbinate hypertrophy (OR 3.21, 95% CI 1.20-8.59). Conclusion Upper airway disease management in PCD varies and is partly guided by symptom burden and clinical findings. This variation across centres highlights the need for care standardisation and PCD-specific management guidelines.

STUDY QUESTION:Are pathogenic variants in homeodomain-interacting protein kinase (HIPK4) associated with sperm head abnormalities that cause male infertility? SUMMARY ANSWER:HIPK4 is a novel candidate gene associated with sperm head defects and human male infertility. WHAT IS KNOWN ALREADY:Numerous genes have been described in which pathogenic variants cause male infertility due to multiple morphological abnormalities of the sperm flagella (MMAF), but the genetic basis of sperm head defects is less well understood. STUDY DESIGN SIZE DURATION:This study included four infertile brothers displaying varying degrees of quantitatively and/or qualitatively impaired spermatogenesis, their parents, and their fertile brother. We also queried the Male Reproductive Genomics (MERGE) cohort comprising exome/genome sequencing data of >3300 men. PARTICIPANTS/MATERIALS SETTING METHODS:We performed exome sequencing in all five brothers and their parents. To characterize sperm phenotypes, we carried out standard semen analysis, immunofluorescence staining, and transmission electron microscopy (TEM). Further, we evaluated the impact of the HIPK4 variant in cell culture experiments using HEK293T cells. MAIN RESULTS AND THE ROLE OF CHANCE:By analysing the exome data, we could not identify a common genetic cause in all four affected brothers. However, one of the affected brothers was compound heterozygous for two loss-of-function variants in DNAH17 (c.1076_1077dup p.(Lys360*) and c.7752+2T>A p.?), associated with markedly reduced sperm motility and MMAF. The variants' pathogenicity was further validated by TEM of flagellar cross sections revealing an outer dynein arm defect and axonemal disruption. In contrast, his three infertile brothers were homozygous for the start-loss variant c.1A>G in HIPK4. This gene is expressed during spermiogenesis and is reportedly involved in sperm head shaping in mice. Heterologous expression of (partial) HIPK4 variant cDNA showed that translation was being initiated at an alternative in-frame start codon located 35 amino acids downstream, resulting in an N-terminally truncated protein p.(Met1_Glu35del). The truncated HIPK4 protein lacks parts of its kinase domain and shows reduced protein stability. Corresponding with published mouse models, all three brothers displayed 100% abnormal sperm head morphology with variable defects. Importantly, one brother affected by HIPK4 variants fathered a child after successful ICSI, demonstrating a successful treatment option for HIPK4-related teratozoospermia. No further men from the MERGE cohort were affected by biallelic HIPK4 variants. Taken together, HIPK4 is an autosomal recessive candidate gene in which pathogenic variants are associated with sperm head defects and male infertility. LARGE-SCALE DATA:The reported variants in DNAH17 and HIPK4 have been published in ClinVar. LIMITATIONS REASONS FOR CAUTION:Independent replication is required to assess the phenotypic spectrum and the reproductive outcome associated with biallelic HIPK4 variants and to formally establish the gene-disease relationship for male infertility. WIDER IMPLICATIONS OF THE FINDINGS:This study raises awareness of the significant genetic heterogeneity of male infertility. The described family highlights that distinct genetic causes may underlie a seemingly similar phenotype. Exome sequencing of families is helpful to efficiently disentangle individual causes among affected family members. FUNDING:N.N., J.R., H.O., S.L., C.F., and F.T. were supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) within the Clinical Research Unit 'Male Germ Cells' (CRU326, project number 329621271). R.T.-W., N.N., J.R., H.O., and F.T. were supported by the Federal Ministry of Research, Technology and Space (BMFTR) as part of the project ReproTrack.MS (grant 01GR2303). S.A.K. was supported by the DFG Clinician Scientist programme CareerS Münster (project number 493624047). A.S.G. was supported by the Medical Faculty Münster via an Innovative Medical Research (IMF) grant (GA-122104). DISCLOSURES:The authors declare no conflicts of interest.

Rationale: Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by progressive lung disease. Pseudomonas aeruginosa is a major pathogen in this disease and is known to impact lung function. Previous genotype-phenotype studies have been limited by cross-sectional designs, isolated adult or pediatric populations, small numbers, or short follow-up durations. Objectives: We aimed to explore long-term lung function in PCD grouped by genotypes and ultrastructural defects, considering the influence of P. aeruginosa. Methods: In this retrospective observational study, we analyzed 43 years of spirometry and 20 years of microbiology data. Using linear mixed-effects models, we estimated forced expiratory volume in 1 second z-score trends and compared them at ages 10, 25, and 50 years, whereas generalized estimating equations were used to assess P. aeruginosa prevalence between groups. In a secondary analysis, we matched spirometry and microbiology samples to evaluate the influence of P. aeruginosa on lung function. Results: We included 127 genotyped patients, 6,691 spirometry measurements, and 10,082 microbiology samples. CCDC39 and CCDC40 variants showed early-onset and sustained decline in lung function, whereas DNAH11 and HYDIN variants demonstrated relative stability. Lung function in the proximity of positive P. aeruginosa cultures was on average 0.06 z-score lower. Despite this, differences between groups remained largely unaffected by P. aeruginosa. Conclusions: Long-term lung function in PCD follows discrete genotype-specific profiles and appears independent of P. aeruginosa infection. We confirm and extend previous findings of CCDC39 and CCDC40 as variants associated with early-onset severe lung function impairment persisting in the long term.

BackgroundThe Primary Ciliary Dyskinesia Rule (PICADAR) is a diagnostic predictive tool currently recommended by the European Respiratory Society (ERS) to assess the likelihood of a primary ciliary dyskinesia (PCD) diagnosis. Despite its recommendation according to the current ERS PCD diagnostic guideline, the performance of the PICADAR remains insufficiently studied.MethodsWe evaluated the sensitivity of PICADAR in 269 individuals with genetically confirmed PCD. Using an initial question, PICADAR rates all individuals without daily wet cough negative for PCD. PICADAR evaluates seven questions in the daily wet cough group. We here calculated test sensitivity based on the proportion of individuals scoring ≥5 points as recommended. Subgroup analyses examined the impact of laterality defects and predicted hallmark ultrastructural defects.Results18 individuals (7%) reported no daily wet cough ruling out PCD according to PICADAR. The median PICADAR score was 7 (IQR: 5–9), with an overall sensitivity of 75% (202/269). Sensitivity was higher in individuals with laterality defects (95%; median score: 10; IQR 8–11) compared to those with situs solitus (61%, median score: 6; IQR 4–8; p*<0.0001). Further stratification by associated ciliary ultrastructure showed higher sensitivity in individuals with hallmark defects (83%) versus those without (59%, p*<0.0001).ConclusionThe PICADAR has limited sensitivity, particularly in individuals without laterality defects (61%) or absent hallmark ultrastructural defects (59%). Therefore, PICADAR should not be the only factor to initiate diagnostic work-up for PCD. Alternative predictive tools are needed, particularly for PCD individuals with normal body composition and normal ultrastructure.

Background Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by dysfunction of motile cilia. Symptoms include recurrent and chronic airway infections which can lead to deteriorating lung function and inflammatory destructive lung disease in the form of persistent atelectasis and bronchiectasis. Routine blood testing may be used as a tool for disease monitoring and management. However, currently there are no consensus-based guidelines within the field of PCD. BEAT-PCD together with the ERN-LUNG PCD-Clinical Trial Network aimed to develop an international expert consensus statement on which routine blood tests should be conducted in patients with PCD. Methods An international panel of 33 PCD experts from 17 countries was established to generate consensus on routine blood testing in PCD. A modified Delphi technique with three e-survey rounds was used to reach consensus, which was defined as ≥80% agreement for each statement. Two patient representatives were included in the consensus process. Results The expert panel reached consensus on 51 out of 101 statements (50%) on routine blood testing in children and adults with PCD to be performed at diagnosis, annually and on exacerbation. The statements include biomarkers for inflammation, haemoglobin, iron status, vitamin D, immune function, inhalant allergies, liver and kidney function, and allergic bronchopulmonary aspergillosis. Conclusions This is the first international consensus on routine blood testing in PCD. It highlights blood tests that may be relevant to perform at diagnosis, annually and on exacerbation in people with PCD. Further research on the clinical usefulness of routine blood testing in PCD is needed.

Die Primäre Ciliäre Dyskinesie (PCD) ist eine Multisystemerkrankung, die durch eine Dysfunktion motiler Zilien entsteht. Charakteristisch ist eine chronische Sekretretention der oberen und unteren Atemwege, die zu einer destruierenden Lungenerkrankung mit Ausbildung von Bronchiektasen führt. Es gibt kaum evidenzbasierte Therapien für Patientinnen und Patienten mit PCD, die meisten Behandlungskonzepte sind an andere Atemwegserkrankungen angelehnt oder beruhen auf der Meinung von Expertinnen und Experten. Der vorliegende Artikel befasst sich mit der physiotherapeutischen Versorgung von Menschen mit PCD und gibt eine Übersicht über Empfehlungen aus der vorhandenen Literatur sowie über langjährige Erfahrung in der physiotherapeutischen Behandlung von Patientinnen und Patienten mit PCD. Da es aktuell keine kurative Therapie für die PCD gibt, ist die symptomatische Behandlung mit dem Fokus auf dem Sekretmanagement von großer Bedeutung. Diese umfasst v.a. Inhalation, Sekretmobilisation, körperliche Aktivität und die gezielte Verwendung von Hilfsmitteln sowie Rehabilitation. Eine Anleitung und Steuerung der Physiotherapie sollten nach Möglichkeit durch speziell ausgebildete Therapeutinnen und Therapeuten erfolgen.

Rare and complex diseases can have a significant impact on family life, and managing the reproductive aspects of patients of childbearing age with rare diseases is often difficult and complex. A European Reference Network (ERN) Transversal Working Group (WG) on Pregnancy and Family Planning was created to join forces to promote and address issues on these topics in rare and low-prevalence diseases. To outline the challenges and the good practices related to pregnancy and family planning in rare and complex diseases for healthcare professionals (HCPs). A survey on state of the art and unmet needs was created by a co-design group of both clinicians and patients’ representatives from 20 ERNs. The survey was uploaded in English on the online platform “EU Survey” and disseminated by respective ERNs and learned societies. Seven transversal domains were explored in the survey by using closed and open-ended questions: fertility preservation, pre-conceptional counselling, family planning counselling, pre-implantation diagnosis, prenatal diagnosis, pregnancy monitoring and post pregnancy monitoring, lactation monitoring/counselling and newborn management. The questions investigated for each topic were the following: level of importance, activities performed by the centre, clinical challenges, good practice and educational activities. A total of 197 answers were collected from 24 different countries. Unmet needs for HCPs included: the need to improve communication between different HCPs, the lack of predefined organizational pathways, the lack of availability of expert HCPs for some pregnancy-related issues and the need to streamline the care provided among different countries. In addition, the survey underlined the need to improve the educational activities provided to rare disease patients. Physicians and patients need to be educated on the emerged unmet needs in order to standardize the information for both HCPs and patients with rare diseases. Educational activities should be considered to help to disseminate information.

Primary ciliary dyskinesia (PCD) is a multisystem disease caused by dysfunction of motile cilia. It is characterized by chronic mucus retention of the upper and lower airways. This results in a destructive lung disease with the development of bronchiectasis. There are a very few evidence-based therapies for patients with PCD. Most treatment concepts are based on other respiratory diseases or expert opinion. This article is about the physiotherapy care of patients with PCD and provides an overview of recommendations from the current literature as well as many years of experience in the physiotherapy treatment of patients with PCD. Currently, no curative therapy for PCD exists. Symptomatic treatment with a focus on mucus management is relevant. This includes inhalation, mobilization of mucus, physical activity and the targeted use of medical aids for chest clearance as well as rehabilitation. Whenever possible, specialized therapists should provide guidance for physiotherapy.

Background Despite advances in primary ciliary dyskinesia (PCD) research, many questions remain; diagnosis is complex and no disease-specific therapies exist. Using a mixed-methods approach, we aimed to identify priorities for clinical and epidemiological research and explore barriers to research. Methods To obtain rich, relevant, diverse data, we performed in-depth semi-structured interviews with PCD specialists selected using purposive sampling. We transcribed, coded and analysed interview data using thematic analysis. Based on interview themes that we identified, we developed an anonymous survey and circulated it widely through the BEAT-PCD network. Results We interviewed 28 participants from 15 countries across different disciplines and expertise levels. The main themes identified as priorities for PCD research were improving diagnosis; understanding prevalence and disease course; phenotypic variability; disease monitoring; treatment strategies; clinical trial end-points; and poorly researched areas. In total, 136 participants (49% paediatric pulmonologists) from 36 countries completed the survey. Most commonly reported barriers for research were low awareness about PCD and difficulties securing funding - in more than one-third of cases, participants reported undertaking predominantly unfunded research. Research questions ranked highest included priorities related to further improving diagnosis, treating PCD, managing upper and lower airway problems, and studying clinical variability and disease prognosis. Conclusion We need to overcome barriers of limited funding and low awareness and promote collaborations between centres, disciplines, experts and patients to address identified PCD priorities effectively. Our results contribute to the ongoing efforts of guiding the use of existing limited research resources and setting up a roadmap for future research activities.

Primary ciliary dyskinesia (PCD) is a rare genetic disorder with a variable clinical phenotype that is accompanied by reduced motility of the cilia in the respiratory tract and numerous other organs. This leads to various characteristic symptoms and disease manifestations, primarily affecting the lungs (chronic persistent productive cough, bronchiectasis), the nose and paranasal sinuses (chronic persistent rhinitis or rhinosinusitis) as well as the middle ear (chronic otitis media, middle ear effusion). Moreover, PCD is associated with impaired fertility or lateralization defects (situs anomalies, congenital heart defects). The diagnostics of PCD are complex and require a combination of several sophisticated instrument-based diagnostic procedures. Through thorough history taking and evaluation, suspected cases can be comparatively well identified based on typical clinical features and referred to further diagnostics. In recent years, molecular genetic analysis through panel diagnostics or whole exome and whole genome sequencing, has gained in importance as this enables affected individuals to participate in disease-specific and genotype-specific clinical trials. Although the current treatment is purely symptomatic, the earliest possible diagnosis is crucial for connecting patients to specialized PCD centers, which can have a significant impact on the clinical course of the affected individuals.

Rationale: Bronchiectasis is a pathological dilatation of the bronchi in the respiratory airways associated with environmental or genetic causes (e.g., cystic fibrosis, primary ciliary dyskinesia, and primary immunodeficiency disorders), but most cases remain idiopathic. Objectives: To identify novel genetic defects in unsolved cases of bronchiectasis presenting with severe rhinosinusitis, nasal polyposis, and pulmonary Pseudomonas aeruginosa infection. Methods: DNA was analyzed by next-generation or targeted Sanger sequencing. RNA was analyzed by quantitative PCR and single-cell RNA sequencing. Patient-derived cells, cell cultures, and secretions (mucus, saliva, seminal fluid) were analyzed by Western blotting and immunofluorescence microscopy, and mucociliary activity was measured. Blood serum was analyzed by electrochemiluminescence immunoassay. Protein structure and proteomic analyses were used to assess the impact of a disease-causing founder variant. Measurements and Main Results: We identified biallelic pathogenic variants in WAP four-disulfide core domain 2 (WFDC2) in 11 individuals from 10 unrelated families originating from the United States, Europe, Asia, and Africa. Expression of WFDC2 was detected predominantly in secretory cells of control airway epithelium and also in submucosal glands. We demonstrate that WFDC2 is below the limit of detection in blood serum and hardly detectable in samples of saliva, seminal fluid, and airway surface liquid from WFDC2-deficient individuals. Computer simulations and deglycosylation assays indicate that the disease-causing founder variant p.Cys49Arg structurally hampers glycosylation and, thus, secretion of mature WFDC2. Conclusions: WFDC2 dysfunction defines a novel molecular etiology of bronchiectasis characterized by the deficiency of a secreted component of the airways. A commercially available blood test combined with genetic testing allows its diagnosis.

Background Primary ciliary dyskinesia is a genetic disorder caused by aberrant motile cilia function that results in defective ciliary airway clearance and subsequently leads to recurrent airway infections and bronchiectasis. We aimed to determine: how many functional multiciliated airway cells are sufficient to maintain ciliary airway clearance? Methods To answer this question we exploited the molecular defects of the X-linked recessive primary ciliary dyskinesia variant caused by pathogenic variants in DNAAF6 (PIH1D3), characterised by immotile cilia in affected males. We carefully analysed the clinical phenotype and molecular defect (using immunofluorescence and transmission electron microscopy) and performed in vitro studies ( particle tracking in air-liquid interface cultures) and in vivo studies (radiolabelled tracer studies) to assess ciliary clearance of respiratory cells from female individuals with heterozygous and male individuals with hemizygous pathogenic DNAAF6 variants. Results Primary ciliary dyskinesia male individuals with hemizygous pathogenic DNAAF6 variants displayed exclusively immotile cilia, absence of ciliary clearance and severe primary ciliary dyskinesia symptoms. Owing to random or skewed X-chromosome inactivation in six female carriers with heterozygous pathogenic DNAAF6 variants, 54.3 +/- 10% (range 38-70%) of multiciliated cells were defective. Nevertheless, in vitro and in vivo assessment of the ciliary airway clearance was normal or slightly abnormal. Consistently, heterozygous female individuals showed no or only mild respiratory symptoms. Conclusions Our findings indicate that having 30-62% of multiciliated respiratory cells functioning can generate either normal or slightly reduced ciliary clearance. Because heterozygous female carriers displayed either no or subtle respiratory symptoms, complete correction of 30% of cells by precision medicine could improve ciliary airway clearance in individuals with primary ciliary dyskinesia, as well as clinical symptoms.

Introduction Nearly all patients with primary ciliary dyskinesia (PCD) report ear–nose–throat (ENT) symptoms. However, scarce evidence exists about how ENT symptoms relate to pulmonary disease in PCD. We explored possible associations between upper and lower respiratory disease among patients with PCD in a multicentre study. Methods We included patients from the ENT Prospective International Cohort (EPIC-PCD). We studied associations of several reported ENT symptoms and chronic rhinosinusitis (defined using patient-reported information and examination findings) with reported sputum production and shortness of breath, using ordinal logistic regression. In a subgroup with available lung function results, we used linear regression to study associations of chronic rhinosinusitis and forced expiratory volume in 1 s (FEV 1 ) accounting for relevant factors. Results We included 457 patients (median age 15 years, interquartile range 10–24 years; 54% males). Shortness of breath associated with reported nasal symptoms and ear pain of any frequency, often or daily hearing problems, headache when bending down (OR 2.1, 95% CI 1.29–3.54) and chronic rhinosinusitis (OR 2.3, 95% CI 1.57–3.38) regardless of polyp presence. Sputum production associated with daily reported nasal (OR 2.2, 95% CI 1.20–4.09) and hearing (OR 2.0, 95% CI 1.10–3.64) problems and chronic rhinosinusitis (OR 2.1, 95% CI 1.48–3.07). We did not find any association between chronic rhinosinusitis and FEV 1 . Conclusion Reported upper airway symptoms and signs of chronic rhinosinusitis associated with reported pulmonary symptoms, but not with lung function. Our results emphasise the assessment and management of upper and lower respiratory disease as a common, interdependent entity among patients with PCD.