Primary Ciliary Dyskinesia Research Articles

Understanding primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a rare, inherited disease characterized by impaired motile ciliary function leading to chronic sinopulmonary disease, persistent middle ear effusions, laterality defects, and subfertility. Over fifty PCD-associated genes have also been identified, which have provided new insights into the processes involved into ciliary assembly, structure, and function. Historically, the diagnosis of PCD was based on the presence of ultrastructural defects in the ciliary axoneme but with identification of a growing number of disease-associated genes, genetic testing has become a first-line diagnostic tool. Other approaches have also evolved, that have improved our diagnostic capabilities. Treatments for PCD have lagged, and though our growing understanding of the genetic and pathophysiological bases of the disease of PCD may yield to better therapeutic strategies.

Multiomic comparison of GLP1R analogues interaction networks

Abstract Background GLP1R analogs are drugs increasingly used in clinical practice in patients with type 2 diabetes, and obesity. Subsequent clinical trials indicate their beneficial effects, including cardioprotection, but the exact mechanisms of those actions are still not known. Aim of the study: This study aims to understand how GLP1R analogs exert cardioprotective and therapeutic effects in patients with type 2 diabetes and obesity. Through analyzing GLP1R interaction networks and associated metabolomic and lipidomic data, we seek to uncover the molecular mechanisms underlying these effects and their potential therapeutic implications. Methods We performed an integrative analysis of four GLP1Ri interaction networks and associated metabolomic and lipidomic datasets. Interactomics revealed 130 common genes among semaglutide, exenatide, tirzapeptide, and retatrutide, primarily associated with diabetes-related processes, including obesity and hyperglycemia. Noteworthy findings encompassed ontological terms related to cardiovascular diseases (CVDs), such as hypertension, calcium regulation in cardiac cells, and amino acid accumulation-induced mTOR activation. Additionally, enrichment in gene sets linked to longevity, less recognized terms like fatty liver disease, chemokine signaling, and sirtuin interactome, were observed. Results Specific processes for tirzepatide included behavior-related terms and hydrochloric acid secretion, while retatrutide exhibited associations with fibrosarcoma, thinking and speaking disturbances, and adipogenesis signaling. Shared processes like primary ciliary dyskinesia differed in implicated genes. Metabolomics identified shared metabolites associated with diverse pathways, including galactose metabolism and nitric oxide-related pathways. Lipidomics highlighted enriched phenotypes and pathways, such as arachidonic acid metabolism and cholesterol biosynthesis. Conclusion Integration of interaction networks with metabolomic and lipidomic data revealed top interactors and impacted metabolites, shedding light on the intricate molecular landscape of GLP1Ri. These findings contribute valuable insights into the potential therapeutic implications and broader health considerations of GLP1R drugsfig1fig2

Genetic Variants Supporting the Diagnosis of Primary Ciliary Dyskinesia in Japan.

Primary ciliary dyskinesia (PCD; OMIM 244400) is a rare genetic disorder affecting motile cilia and is characterized by impaired mucociliary clearance in the airway epithelium that leads to chronic oto-sinopulmonary manifestations. To date, over 50 PCD-causing genes have been identified, with these genes and their variants varying globally across populations. We performed targeted resequencing of 42 PCD-causative genes in 150 Japanese patients suspected of having PCD and identified pathogenic or likely pathogenic variants in 51 patients. Among these, 24 patients exhibited a homozygous deletion of DRC1 exons 1-4, the most common cause of PCD in Japan. The allele frequency of this deletion was estimated at 0.0034 (95% CI: 0.0025-0.0044), based on bioinformatic analysis of 7906 whole-genome sequences from the general Japanese population. Additionally, RNA sequencing of nasal samples supplemented in silico variant predictions, aiding in the identification of causative variants. Considering potential ethnic differences, it is essential to accumulate global data on these variants and their functional impacts.

Long-Term Lung Function and Pseudomonas aeruginosa Infection in Genotyped Primary Ciliary Dyskinesia.

Rationale: Primary ciliary dyskinesia is a rare genetic disorder characterized by progressive lung disease. Pseudomonas aeruginosa is a major pathogen in this disease, 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 primary ciliary dyskinesia 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 FEV1 z-score trends and compared them at ages 10, 25, and 50 years, while 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. Measurements and Main Results: We included 127 genotyped subjects, 6,691 spirometries and 10,082 microbiology samples. CCDC39 and CCDC40 variants showed early onset and sustained decline in lung function, while DNAH11 and HYDIN variants demonstrated relative stability. Lung function in the proximity of positive P. aeruginosa cultures were on average 0.06 z-score lower. Despite this, differences between groups remained largely unaffected by P. aeruginosa. Conclusion: Long-term lung function in primary ciliary dyskinesia follows discrete genotype specific profiles and appear 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.

Microbial Isolates and Antimicrobial Resistance Patterns in Adults with Inborn Errors of Immunity: A Retrospective Longitudinal Analysis of Sputum Cultures

Introduction: Individuals with inborn errors of immunity (IEI) are at increased risk of respiratory infection and frequently receive prolonged broad-spectrum antibiotics, leading to antibiotic resistance. The aim of this study was to identify respiratory pathogens and antibiotic resistance patterns in IEI patients. Methods: We retrospectively studied 36 IEI patients with positive bacterial growth in sputum cultures between 2014 and 2023. Data covered hospitalizations, respiratory infections, yearly antibiotic prescriptions, past sputum cultures, and antibiotic sensitivities. Patients with primary ciliary dyskinesia (PCD) and bronchiectasis served as a control group. Results: A total of 314 sputum cultures were analyzed from patients with IEI, alongside 585 cultures from individuals with PCD and 113 cultures from patients with bronchiectasis. Patients with IEI had a median age of 23.5 years, with 61% male participants. The study compared the differences in bacterial isolates from sputum cultures and antibiotic resistance between patients with IEI and the control groups. The most common bacterial isolates across all groups were Haemophilus influenzae (159 isolates in IEI vs. 314 in PCD and 26 in bronchiectasis), Pseudomonas aeruginosa, and Streptococcus pneumoniae. In IEI patients, 992 symptomatic respiratory exacerbations and 43 pneumonia-related hospitalizations were recorded. Notably, H. influenzae in IEI patients showed high resistance rates to cefuroxime (82%), amoxicillin/clavulanic acid (66%), trimethoprim/sulfamethoxazole (59%), and ampicillin/sulbactam (49%). P. aeruginosa in IEI patients displayed significant resistance to ciprofloxacin (85%), ceftazidime (42%), and aminoglycosides (23–33%). Additionally, all S. pneumoniae isolates in IEI patients were tetracycline resistant, with high resistance rates to penicillin, clindamycin, and erythromycin. It is essential to highlight the substantial resistance of common pathogens to oral antibiotics. In contrast, the control groups exhibited lower resistance rates across all bacterial isolates. Conclusion: Antimicrobial resistance is a growing concern among vulnerable IEI patients. We suggest conducting similar investigations in other regions to address this issue. The findings should inform future infection management guidelines for IEIs.

Delayed Diagnosis of Primary Ciliary Dyskinesia in Low-Middle-Income Countries: The Clinical Value of Nasal Nitric Oxide

Delayed Diagnosis of Primary Ciliary Dyskinesia in Low-Middle-Income Countries: The Clinical Value of Nasal Nitric Oxide

Primary ciliary dyskinesia in children: clinical, laboratory-instrumental and genetic characteristics

Background. Primary ciliary dyskinesia (PCD) is an orphan disease, and diagnosis is difficult because there is no gold standard for diagnosis. Aim. Clinical, laboratory-instrumental, genetic characteristics of PCD in children. Materials and methods. From 2009 to 2024, 31 patients with a genetically confirmed diagnosis of PCD were observed as part of a multicenter, open-ended, descriptive pilot longitudinal study. Examination methods: clinical and anamnestic method; X-ray examination and computed tomography of the chest organs and paranasal sinuses, tracheobronchoscopy; sputum/aspirate cultures of the tracheobroncheal tree with determination of sensitivity to antibiotics; transmission electron microscopy, high-speed video microscopy of the ciliated epithelium, cytological examination of bronchoalveolar lavage; monitoring computer pulse oximetry, echocardiography, audiometry, spirometry with bronchodilator test. Results. Respiratory symptoms in the neonatal period have 80% of children with PCD, lateralization defects – 35%, congenital heart defects – 13%, bronchiectasis – 68%, purulent endobronchitis – 62%, year-round rhinitis – 84%, hearing loss, otitis – 65%. The average age of onset of symptoms was 1 [1; 1] weeks, and the verification of diagnosis was 6 [2,5; 8] years. The main pathogens of chronic respiratory infection with PCD are Haemophilus influenzae, Pseudomonas aeruginosa, Staphylococcus aureus. The most common cause of PCD was biallelic variants of the DNAH5 gene. Conclusion. The diagnosis of PCD should be based on the application of the maximum number of diagnostic tests.

Impact of TAS2R38 polymorphisms on nasal nitric oxide and Pseudomonas infections in primary ciliary dyskinesia: relation to genotype

ObjectivePrimary ciliary dyskinesia (PCD) severity has been related to genotype and levels of nasal nitric oxide (nNO). The most common TAS2R38 haplotypes (PAV/PAV, PAV/AVI, AVI/AVI) encoding the bitter taste receptor...

Macrolide resistance through uL4 and uL22 ribosomal mutations in Pseudomonas aeruginosa

Macrolides are widely used antibiotics for the treatment of bacterial airway infections. Due to its elevated minimum inhibitory concentration in standardized culture media, Pseudomonas aeruginosa is considered intrinsically resistant and, therefore, antibiotic susceptibility testing against macrolides is not performed. Nevertheless, due to macrolides’ immunomodulatory effect and suppression of virulence factors, they are used for the treatment of persistent P. aeruginosa infections. Here, we demonstrate that macrolides are, instead, effective antibiotics against P. aeruginosa airway infections in an Air-Liquid Interface (ALI) infection model system resembling the human airways. Importantly, macrolide treatment in both people with cystic fibrosis and primary ciliary dyskinesia patients leads to the accumulation of uL4 and uL22 ribosomal protein mutations in P. aeruginosa which causes antibiotic resistance. Consequently, higher concentrations of antibiotics are needed to modulate the macrolide-dependent suppression of virulence. Surprisingly, even in the absence of antibiotics, these mutations also lead to a collateral reduction in growth rate, virulence and pathogenicity in airway ALI infections which are pivotal for the establishment of a persistent infection. Altogether, these results lend further support to the consideration of macrolides as de facto antibiotics against P. aeruginosa and the need for resistance monitoring upon prolonged macrolide treatment.

Chinese expert consensus on the etiological diagnosis of adult bronchiectasis

Bronchiectasis is a highly heterogeneous chronic airway disease for which accurate etiological diagnosis is crucial for effective management. A group of experts from the China Bronchiectasis Alliance and the Infection Assembly of the Chinese Thoracic Society conducted a comprehensive review of recent research into the etiology of bronchiectasis. Using the widely accepted Delphi methodology, the experts reached a consensus on the etiological diagnosis of bronchiectasis through multiple rounds of discussion and revision. The consensus is divided into four sections: the definition and classification of the etiology of bronchiectasis, the etiological diagnostic procedures for bronchiectasis, the treatable causes of bronchiectasis, and other causes of bronchiectasis. The ultimate goal of this consensus is to improve the diagnostic accuracy and optimize the management of bronchiectasis in China. The main recommendations of Section 1 focused on chest thin-section computed tomography (CT) for the diagnosis of bronchiectasis and the etiological classification. The main recommendations of Section 2 focused on the medical history collection for bronchiectasis and the etiological diagnostic protocol for bronchiectasis. The main recommendations of Section 3 focused on the recommendations of the diagnosis of bronchiectasis secondary to COPD, the diagnosis of bronchiectasis due to asthma, diffuse pan-bronchiolitis, allergic bronchopulmonary aspergillosis, connective tissue disease (CTD)-related bronchiectasis or gastroesophageal reflux disease (GERD)-related bronchiectasis. The main recommendations of Section 4 focused on suspected primary ciliary dyskinesia (PCD)-associated bronchiectasis, cystic fibrosis and the diagnosis of congenital airway malformations.

Comparison of Longitudinal Outcomes in Children with Primary Ciliary Dyskinesia and Cystic Fibrosis.

Primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) are both genetic diseases of mucociliary clearance resulting in progressive lung disease with onset in early life. PCD is often considered to be milder in childhood than CF, based on minimal evidence. Similar to CF, genotype-phenotype associations exist in PCD: pathogenic variants in CCDC39 and CCDC40, causing inner dynein arm/microtubular defects (IDA/MTD) are associated with more severe disease. To compare longitudinal outcomes in matched children with PCD and CF. We hypothesized that children with PCD with IDA/MTD defects would have lower lung function but better nutritional indices than matched children with CF with minimal function genotypes (i.e., those associated with pancreatic insufficiency). Children with PCD enrolled in a prospective, multicenter, observational study were matched with CF patients from the CF Foundation Patient Registry by birth cohort, age, sex, race/ethnicity and year of study visit. The association of disease group overall and by severity class (PCD-IDA/MTD versus all other defects and CF-minimal versus residual function) with longitudinal outcomes up to age 17 was evaluated with cubic spline mixed effects models. Groups included 136 children with PCD (40 IDA/MTD, 96 other) and 476 with CF (446 minimal function, 30 residual function). Below age 14, the PCD group had similar or lower estimated mean FEV1 % predicted compared to CF (e.g., at age 10, -5.4 % predicted lower (95% CI: -7.7, -3.1)). Compared to the CF-minimal function (pancreatic insufficient) group, the PCD-IDA/MTD group had similar BMI; estimated mean FEV1 % predicted was significantly lower by age 10 (mean difference -10.6% (95% CI: -14.7, -6.4), increasing to -15.7% (95% CI: -20.3, -11.2) at age 14. The CF cohort had increased prevalence of Pseudomonas aeruginosa cultured on one or more occasions compared to children with PCD (67% vs 27%, p<0.001); there was no difference in prevalence of P. aeruginosa between children with PCD-IDA/MTD and PCD-other. In childhood, average lung function abnormalities in PCD are not milder than CF, particularly for those with IDA/MTD ciliary defects. New guidelines and treatments to improve outcomes in PCD are urgently needed.

Promoter Deletion Leading to Allele Specific Expression in a Genetically Unsolved Case of Primary Ciliary Dyskinesia.

Variation in the non-coding genome represents an understudied mechanism of disease and it remains challenging to predict if single nucleotide variants, small insertions and deletions, or structural variants in non-coding genomic regions will be detrimental. Our approach using complementary RNA-seq and targeted long-read DNA sequencing can prioritize identification of non-coding variants that lead to disease via alteration of gene splicing or expression. We have identified a patient with primary ciliary dyskinesia with a pathogenic coding variant on one allele of the SPAG1 gene, while the second allele appears normal by whole exome sequencing despite an autosomal recessive inheritance pattern. RNA sequencing revealed reduced SPAG1 transcript levels and exclusive allele specific expression of the known pathogenic allele, suggesting the presence of a non-coding variant on the second allele that impacts transcription. Targeted long-read DNA sequencing identified a heterozygous 3 kilobase deletion of the 5' untranslated region of SPAG1, overlapping the promoter and first non-coding exon. This non-coding deletion was missed by whole exome sequencing and gene-specific deletion/duplication analysis, highlighting the importance of investigating the non-coding genome in patients with "missing" disease-causing variation. This paradigm demonstrates the utility of both RNA and long-read DNA sequencing in identifying pathogenic non-coding variants in patients with unexplained genetic disease.

Pathogenic variants in CFAP46, CFAP54, CFAP74, and CFAP221 cause Primary Ciliary Dyskinesia with a defective C1d projection of the central apparatus.

Primary ciliary dyskinesia (PCD) is a rare genetic disorder caused by insufficient mucociliary clearance leading to chronic airway infections. The diagnostic guideline of the European Respiratory Society (ERS) primarily recommends the evaluation of the clinical history (e. g. by the PICADAR prediction tool), nasal nitric oxide (nNO) production rate measurements, high-speed videomicroscopy analysis (HSVMA) of ciliary beating, and the assessment of ciliary axonemes via transmission electron microscopy (TEM). Genetic testing can be implemented as a last step. In this study, we aimed to characterise PCD with a defective C1d projection of the ciliary central apparatus (CA) and evaluated the applicability of the ERS diagnostic guideline to this PCD type. Using a high-throughput sequencing approach of genes encoding C1d components, we identified pathogenic variants in the novel PCD genes CFAP46 and CFAP54, and the known PCD gene CFAP221. To fully assess this PCD type, we also analysed individuals with pathogenic variants in CFAP74. Careful evaluation revealed that C1d-defective PCD is associated with normal situs composition, normal nNO-production rates, normal ciliary ultrastructure by TEM, and normal ciliary beating by HSVMA. Despite chronic respiratory disease, PICADAR does not reliably detect this PCD type. However, we could show by in-vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance. Overall, this study extends the spectrum of PCD genes and highlights that C1d-defective PCD individuals elude diagnosis in the current diagnostic algorithm. To enable diagnosis, genetic testing should be prioritised in future diagnostic guidelines.

Predominantly antibody deficiencies: An important underlying cause of recurrent pneumonia in adults

RATIONALE Limited information exists concerning the causes of recurrent pneumonia in adults, particularly regarding immunodeficiencies or inborn errors of immunity. OBJECTIVES This study aims to evaluate the etiology of recurrent pneumonia in the adult population, with a focus on humoral deficiency and inborn errors of immunity. METHODS A cross-sectional non-interventional study was conducted in Cali, Colombia, from January 2019 to March 2021. Consecutive patients, aged over 14 years but under 65 years, with a history of recurrent pneumonia, were included after providing consent. The study involved a thorough review of their past medical records and radiological studies. All participants underwent complete blood count and serum immunoglobulin level measurements (IgG, IgA, IgM and IgE). Further testing was carried out based on the evaluation of a clinical immunologist. RESULTS Sixty-six (66) individuals, comprising 34 females and 32 males, were enrolled in the study. The onset of symptoms occurred at an average age of 14 years (ranging from 5 to 36 years). The analysis revealed that the most prevalent cause of recurrent pneumonia was inborn errors of immunity (20 cases, 30.3%), followed by idiopathic (9 cases, 13.7%), bronchiectasis (7 cases, 10.7%), primary ciliary dyskinesia (6 cases, 9.0%), asthma (6 cases, 9.0%), and post-tuberculosis complications (5 cases, 7.6%). CONCLUSION Predominantly antibody deficiencies, along with other inborn errors of immunity, were identified as an important factor contributing to recurrent pneumonia in adults. These findings highlight the importance of these conditions as major etiological factors in the context of recurrent pneumonia in the Colombian adult population.

A range of 30-62% of functioning multiciliated airway cells is sufficient to maintain ciliary airway clearance.

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? 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. 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. 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.

Cardiopulmonary Exercise Testing In Children With Primary Ciliary Dyskinesia And Healthy Controls

Cardiopulmonary Exercise Testing In Children With Primary Ciliary Dyskinesia And Healthy Controls

Primary ciliary dyskinesia: a case report of double DNAH11 mutant alleles

Primary ciliary dyskinesia (PCD), a rare disorder, is genetically varied. Mutations in proteins involved in the structure, function, or assembly of cilia are known to determine situs inversus, male infertility, and chronic destructive airway disease. PCD is inherited by an autosomal recessive pattern of inheritance in most cases. Nonetheless, patterns of autosomal dominant and X-linked inheritance have been mentioned. A history of recurrent upper and lower respiratory tract infections raised clinical suspicion of primary ciliary dyskinesia in a 10-year-old patient. Genetic tests were performed using next-generation sequencing technology (Illumina NextGen) with the multiplex ligation-dependent probe amplification technique for primary ciliopathies and syndromes subject to differential diagnosis. Genetic testing identified two pathogenic variants, not previously associated with a case report in the literature, c.7727A&gt;G (p.Asp2576Gly) and c.8578G&gt;A (p.Gly2860Ser), within the DNAH11 gene, which is associated with autosomal recessive PCD. The result also reported mutations in other genes involved in autosomal recessive PCD (DNAH8, DNAH9 and ZMYND10), which were classified as variants with uncertain clinical significance. Transmission electron microscopy of respiratory cilia and nasal nitric oxide measurement cannot be used to diagnose PCD in patients with DNAH11 mutations because the structure of cilia is normal, and the levels of NO are not constantly low. High-speed video microscopy analysis can be helpful because DNAH11 mutations cause a distinct phenotype of PCD. Nevertheless, the mutation analysis of various PCD-causing genes remains the easiest to conduct and with good results. Genetic research on PCD has identified a number of significant ciliary genes in recent years, offering fresh perspectives on the molecular processes underlying cilia assembly and function. This facilitates the development of new methods for the diagnosis, prevention, and treatment of PCD. However, because it is a highly complex and heterogeneous disease, the field of gene diagnosis and therapy in PCD is still in its infancy.

Inhaled Medications for Maintenance Therapy in Pediatric Noncystic Fibrosis Bronchiectasis.

This review focuses on evaluating literature for the use of inhaled mucolytics (hypertonic saline, mannitol, and dornase alfa), inhaled antibiotics (tobramycin, aztreonam, colistin, and amikacin), and inhaled corticosteroids in pediatric noncystic fibrosis bronchiectasis. A literature search via PubMed was conducted using the search terms "non-cystic fibrosis bronchiectasis," "primary ciliary dyskinesia," and "bronchiectasis" in combination with each inhaled agent of interest. Studies were included if they were specific to patients with a clinical diagnosis of noncystic fibrosis bronchiectasis published from 1998 to July 2024. Several inhaled medications can be considered as maintenance therapies for pediatric patients with noncystic fibrosis bronchiectasis. Hypertonic saline could be considered for its potential airway clearance benefits and low risk of causing harm. Inhaled antipseudomonal antibiotics should be considered in patients who are colonized with Pseudomonas aeruginosa. Inhaled corticosteroid therapy should be reserved for patients with concomitant asthma. Dornase alfa has shown worse outcomes in adults with noncystic fibrosis bronchiectasis and should be used with caution. Risks and benefits should be carefully considered when evaluating these therapies for use in noncystic fibrosis bronchiectasis, and patient-specific treatment regimens should be developed. Chronic management of pediatric noncystic fibrosis bronchiectasis remains challenging due to paucity of applicable literature. Risks and benefits of different agents are discussed in this article with recommendations for application to clinical practice based on studies performed in both adult and pediatric patients with noncystic fibrosis bronchiectasis. Several inhaled medications could be considered as maintenance therapies for pediatric patients with noncystic fibrosis bronchiectasis, with more robust evidence to support use of inhaled antipseudomonal antibiotics and hypertonic saline compared with other available agents. Further investigation is needed to identify a clear place in therapy for inhaled therapies in pediatric noncystic fibrosis bronchiectasis.

HYDIN variants cause primary ciliary dyskinesia in the Finnish population.

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by chronic respiratory tract infections and in some cases laterality defects and infertility. The symptoms of PCD are caused by malfunction of motile cilia, hair-like organelles protruding out of the cell. Thus far, disease causing variants in over 50 genes have been identified and these variants explain around 70% of all known cases. Population specific genetics underlying PCD has been reported highlighting the importance of characterizing gene variants in different populations for development of gene-based diagnostics and management. Whole exome sequencing was used to identify disease causing variants in Finnish PCD cohort. The effect of the identified HYDIN variants on cilia structure and function was confirmed by high-speed video analysis, immunofluorescence and electron tomography. In this study, we identified three Finnish PCD patients carrying homozygous loss-of-function variants and one patient with compound heterozygous variants within HYDIN. The functional studies showed defects in the axonemal central pair complex. All patients had clinical PCD symptoms including chronic wet cough and recurrent airway infections, associated with mostly static airway cilia. Our results are consistent with the previously identified important role of HYDIN in the axonemal central pair complex and improve specific diagnostics of PCD in different national populations.

Ciliary Function, Antigen Stasis and Asthma.

The prevalence of asthma exceeds 3% of the population. Asthma is observed to be more common in children following severe viral lower respiratory illnesses that affect ciliary function, but mechanisms linking ciliary function to asthma pathogenesis have been obscure. Recent data regarding primary ciliary dyskinesia (PCD) may help us to understand the association. Here, I will review what is known about the relationship between ciliary function and asthma. PCD is caused by pathologic variants in over 50 different genes that affect the structure and function of motile cilia. At the cellular level, a characteristic feature shared by most PCD patients is that antigens and other particles are not cleared from the epithelial surface. Poor antigen clearance results in pro-oxidant pathway activation and airway epithelial damage and may predispose PCD patients to DUOX1- and IL33-mediated asthma. Secondary ciliary dysfunction, such as that caused by viruses or by smoking, can also contribute to asthma development. Moreover, variants in genes that affect the function of cilia can be associated with poor lung function, even in the absence of PCD, and with increased asthma severity. The role of antigen stasis on the surface of dysfunctional airway cilia in the pathophysiology of asthma is a novel area for research, because specific airway clearance techniques and other therapeutic interventions, such as antioxidants, could be of value in preventing the development of asthma.