Search Results (99)

Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous disorder that impairs mucociliary clearance and leads to progressive lung disease. This study aimed to characterize lung function decline in a genetically homogeneous cohort of Puerto Rican patients with RSPH4A-associated PCD and to develop a clinical tool to predict lung function decline and support transplant referral decisions. We conducted a retrospective chart review of patients (n = 25) with a confirmed RSPH4A [c.921+3_6delAAGT] genetic variant, collecting longitudinal spirometry data and applying linear regressions to calculate each patient’s individual FEV₁ decline. The median FEV₁ at diagnosis was 55%, with a median annual decline of −0.75% predicted. Adults exhibited significantly lower lung function compared to pediatric patients, while no difference was seen between males and females. Based on this observed decline, we developed the Predicted Capacity Decline Index (PCDx), an index that estimates the age and time until a patient reaches the 30% FEV₁ threshold, the point at which lung transplant referral is typically considered. Our findings underscore the need for early intervention and suggest that genotype-specific tools like the PCDx may enhance clinical decision-making in managing progressive lung disease in PCD. Full article

Objectives: Although patients with bronchiectasis tend to have obstructive nonreversible lung functions, some have bronchodilator response (BDR), and a relatively large number are treated with bronchodilators. We assessed BDR in patients with cystic fibrosis (CF) and other bronchiectatic diseases and healthy controls (HCs) in a randomized controlled setup. Methods: Patients with cystic fibrosis (CF), primary ciliary dyskinesia (PCD) and non-CF non-PCD bronchiectasis (non-CF/PCD), as well as HCs, were recruited. Participants were randomly assigned to receive salbutamol (four puffs) and then a placebo or a placebo and then salbutamol. BDR was calculated using the American Thoracic Society (ATS)/European Respiratory Society (ERS) standard, defined as the change related to the individual’s predicted value (new method) or to the initial value (old method). Results: Sixty-nine patients (CF = 30, PCD = 20, non-CF/PCD = 19) and 20 HCs were included. Patients with CF and PCD (but not non-CF/PCD) had a statistically greater mean response to salbutamol compared with the placebo, (CF–salbutamol first: 2.82 vs. 0.85%, p = 0.01; placebo first: 2.39 vs. −0.27%, p = 0.02; PCD–salbutamol first: 5.32 vs. 1.88%, p = 0.01; placebo first: 2.24 vs. 0.77%, p = 0.05). Few patients had significant BDR (new method, >10%)—CF (0), PCD (2), non-CF/PCD (0) and HCs (2)): using the old method, an additional PCD patient and three non-CF/PCD had significant BDR (>12%). Conclusions: Significant BDR seems to be rare in patients with bronchiectasis. In CF and PCD, the response was greater than the placebo; the clinical significance of this difference and its therapeutic implications, as well as the best method to determine BDR, have yet to be determined. Full article

Background: Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by recurrent sinopulmonary infections due to motile cilia defects. The disease is genetically heterogeneous, with abnormalities in structural ciliary proteins. Zinc finger MYND-type containing 10 (ZMYND10) is essential for the assembly of outer dynein arms (ODA), with chaperones like Glucose-regulated protein 78 (GRP78) facilitating protein folding. This study investigates ZMYND10 and Dynein axonemal heavy chain 5 (DNAH5) mutations in individuals with PCD. Methods: Eight individuals aged 14–22 with clinical PCD symptoms and confirmed DNAH5 mutations were included. We analyzed the correlation between DNAH5 abnormalities and preassembly/chaperone proteins using immunofluorescence labeling. Nasal swabs were double-labeled (DNAH5–β-tubulin, β-tubulin–ZMYND10, β-tubulin–GRP78) and examined via fluorescence microscopy. Serum metabolomics and proteomics were also assessed. Results: The corrected total cell fluorescence (CTCF) levels of DNAH5, ZMYND10, and GRP78 were significantly different between PCD individuals and controls. Metabolomic analysis showed reduced valine, leucine, and isoleucine biosynthesis, with increased malate and triacylglycerol biosynthesis, malate-aspartate and glycerol phosphate shuttles, and arginine/proline metabolism, suggesting mitochondrial and ER stress. Conclusions: The altered expression of DNAH5, ZMYND10, and GRP78, along with metabolic shifts, points to a complex link between ciliary dysfunction and cellular stress in PCD. Further studies are needed to clarify the underlying mechanisms. Full article

Background: Primary ciliary dyskinesia (PCD) is a rare hereditary disorder caused by defective motile cilia, predominantly affecting the respiratory system. Conductive hearing loss (CHL) due to chronic otitis media with effusion (OME) is a typical feature of PCD, particularly in childhood. However, the underlying mechanisms contributing to sensorineural hearing loss (SNHL) in patients with PCD remain unclear. Methods: We present the case of a 52-year-old male with a clinical diagnosis of PCD, confirmed by the presence of situs inversus, chronic respiratory symptoms, and ultrastructural ciliary defects. Results: Despite a history of recurrent acute otitis media (AOM), the patient developed severe bilateral SNHL, a relatively uncommon and poorly understood manifestation of PCD. Genetic testing revealed a pathogenic SH3TC2 variant, a gene classically associated with Charcot–Marie–Tooth disease type 4C (CMT4C), raising the possibility of an alternative or contributory genetic etiology for the patient’s auditory dysfunction. Conclusions: This case highlights the importance of comprehensive audiological and genetic evaluations in PCD patients, particularly those presenting with progressive or atypical HL. The presence of a pathogenic SH3TC2 mutation suggests a potential neuropathic component to the patient’s HL, underscoring the need for further research into the intersection between ciliary dysfunction and genetic neuropathies. Early identification and intervention are critical to optimizing auditory outcomes and quality of life in affected individuals. Full article

Background/Objectives: Primary Ciliary Dyskinesia (PCD) is a rare genetic condition characterized by compromised mucociliary clearance and chronic respiratory manifestations. Anosmia, or the loss of smell, is a lesser-known but clinically relevant symptom that can significantly impact patient safety, nutritional status, and the overall quality of life. The RSPH4A (c.921+3_921+6delAAGT) founder mutation is highly prevalent among Puerto Rican individuals with PCD and may carry distinct phenotypic implications. This study aimed to evaluate olfactory function in Puerto Rican PCD patients with this mutation using the Brief Smell Identification Test (BSIT^®) and to assess associations with age and sex. Methods: We conducted a case–control study involving 30 participants, including 15 PCD patients with genetically confirmed RSPH4A mutations and 15 age- and sex-matched healthy controls. All participants completed the BSIT, and BSIT scores were compared by diagnosis, sex, and age. Results: PCD patients had significantly lower BSIT scores than controls (p = 0.0015). When stratified by sex, both male (p = 0.0289) and female (p = 0.0178) PCD patients demonstrated significantly lower BSIT scores compared to their respective healthy counterparts. Regression analysis showed a significant inverse correlation between age and BSIT score in the PCD group (r² = 0.2873; p = 0.0395), while no such relationship was observed in controls (r² = 0.0096; p = 0.7283). Among PCD patients, age-related decline in olfactory function was more pronounced in females (r² = 0.71; p = 0.005) than in males (r² = 0.31; p = 0.25). Conclusions: These findings demonstrate that the RSPH4A founder mutation is associated with measurable olfactory impairment in PCD patients, particularly in females and with advancing age. The routine assessment of olfactory function should be considered in the clinical evaluation of patients with PCD, as anosmia may represent a key phenotypic feature and contribute to disease burden. Full article

Background and Objective: Primary ciliary dyskinesia (PCD) is a rare genetic disorder that affects the mucociliary system, leading to progressive lung damage. This deterioration can result in bronchiectasis, atelectasis, and respiratory failure, necessitating lung transplantation in severe cases. This study aims to assess ciliary motility and ultrastructure in the bronchial epithelium of transplanted lungs in patients with PCD to determine whether mucociliary function is preserved post-transplantation. The findings seek to enhance scientific understanding and provide prognostic insights for these patients. Materials and Methods: A prospective observational study was conducted on two patients with PCD and advanced lung disease who underwent bilateral lung transplantation. Nasal and bronchial cilia samples were analyzed using high-speed videomicroscopy and transmission electron microscopy. Follow-up assessments included ciliary function analysis, lung rejection monitoring, and quality-of-life evaluations, with follow-up extending up to 30 months post-transplant. Results: Post-transplant evaluations demonstrated normal ciliary motility and ultrastructure in the transplanted lungs throughout the study period (up to 30 months), indicating the long-term preservation of mucociliary function. Conclusions: Transplanted lungs in patients with PCD maintain normal bronchial ciliary motility and structure in the long term, suggesting a favorable prognosis for both the graft and the recipient. These findings support the feasibility and long-term effectiveness of lung transplantation in patients with PCD. Full article

Background: Nocardia species are an emergent pathogen in people with CF (pwCF) or bronchiectasis. Their clinical role and management remain unclear, and their isolation is a challenge. In this paper, we describe four cases of Nocardia detection, in two pwCF and two patients with non-CF bronchiectasis or primary ciliary dyskinesia (PCD). Methods: We conducted a multicenter retrospective study, involving pwCF and non-CF people with bronchiectasis who presented with a Nocardia detection and were followed at three CF Italian centers (Florence, Verona, and Cerignola). Results: Nocardia detection was associated with clinical and radiological respiratory exacerbation and decline in lung function. In one CF patient, Nocardia was not detected in sputum cultures after starting Elexacaftor-Tezacaftor-Ivacaftor therapy. Conclusions: Managing Nocardia detection in patients with underlying lung diseases such as CF, PCD, or bronchiectasis presents significant challenges for clinicians. Full article

Background/Objectives: Primary ciliary dyskinesia (PCD) (OMIM: 244400) is a hereditary, rare disorder with a high prevalence in Turkey due to a high rate of consanguinity. The disorder is caused by malfunctioning motile cilia and is characterized by a variety of clinical symptoms including sinusitis, otitis media and chronic obstructive pulmonary disease. This study presents the first assessment of the efficacy of immunofluorescence (IF) labeling for diagnosing PCD in Turkey by correlating IF with clinical observations when genetic data are scarce. Methods: We have a cohort of 54 PCD-suspected individuals with an age range of 5–27 years classified into two groups: group A with available genomic data (8 individuals) and group B with no available genomic data (46 individuals). We performed immunofluorescence analysis to confirm the pathogenicity of the variants in individuals with a prior genetic diagnosis and to confirm a PCD diagnosis in individuals with typical PCD symptoms and no genetic diagnosis. Results: All individuals had airway infections and displayed clinical symptoms of PCD. Our data revealed an absence of outer dynein arm dynein heavy chain DNAH5 in individuals with pathogenic variants in DNAH5 and DNAAF1 and in 17 other PCD-suspected individuals, an absence of nexin–dynein regulatory complex component GAS8 in 8 PCD-suspected individuals, an absence of outer dynein arm dynein heavy chain DNAH11 in 6 PCD-suspected individuals and an absence of radial spoke head component RSPH9 in 2 PCD-suspected individuals. Furthermore, the pathogenicity of ARMC4 variants was confirmed by the absence of the outer dynein arm docking complex component ARMC4 and the proximal localization of DNAH5. Conclusions: Immunofluorescence analysis, owing to its lower cost and quicker turnaround time, proves to be a powerful tool for diagnosing PCD even in the absence of genetic data or electron microscopy results. Full article

Sleep disorders are characterized by impaired quality, timing, and amount of sleep, resulting in daytime distress and functioning. Primary ciliary dyskinesia (PCD) is a rare genetic condition characterized by oto-sino-pulmonary manifestations with multiple comorbidities, including sleep disorders. Background/Objectives: This pilot study aims to assess sleep disorders and neuropsychiatric comorbidities in Puerto Rican patients with the RSPH4A (c.921+3_921+6delAAGT) PCD founder mutation. However, the literature on sleep-related disorders and their neuropsychiatric comorbidities in PCD is limited. Methods: A cohort of fifteen patients with the RSPH4A (c.921+3_921+6delAAGT) founder mutation (six pediatric, nine adults) were evaluated for sleep quality, cognitive, neurodevelopmental history, and mood-related manifestations, followed by diagnostic polysomnography for sleep-disordered breathing and other sleep-related disorder detection. Results: Twelve out of fifteen (12/15, 80%) patients presented with sleep-related disorders, particularly obstructive sleep apnea where the median Pediatric AHI was 1.25/h (IQR: 1.1–1.75/h), T < 90: 0.1 min (IQR: 0–1.9 min) and adult AHI 1.3 (IQR: 0.9–8), T < 90: 0.2 min (IQR: 0–3.5 min). PCD patients also presented complex sleep behaviors, and more than half had sleep-related movement manifestations such as sleep-related Bruxism, PLMS, among others. All pediatric patients with OSA met criteria for an anxiety disorder, with a GAD-7 of 13 (IQR: 10.5–15.8); this association was not clearly seen in adults. Conclusions: Patients with PCD RSPH4A exhibited multiple sleep and neuropsychiatric manifestations, particularly OSA, sleep-related movement disorders and complex sleep behaviors. Further studies are needed to determine if these manifestations result from obstructive breathing, sleep mechanism disruption, or other neurodevelopmental impairment associated with this ciliopathy. Full article

Macrophage (Mph) polarization and functional activity play an important role in the development of inflammatory lung conditions. The previously widely used bimodal classification of Mph into M1 and M2 does not adequately reflect the full range of changes in polarization and functional diversity observed in Mph in response to various stimuli and disease states. Here, we have developed a model for the direct assessment of Mph from bronchial alveolar lavage fluid (BALF) functional alterations, in terms of phagocytosis activity, depending on external stimuli, such as exposure to a range of bacteria (E. coli, B. subtilis and L. fermentum). We have employed polymeric mannosylated ligands (the “trapping ligand”) specifically targeting the CD206 receptor to selectively isolate activated Mph from the BALF of patients with pulmonary inflammatory conditions: primary ciliary dyskinesia (PCD), pneumonia and bronchial asthma. An “imaging ligand” allows for the subsequent visualization of the isolated cells using a sandwich technique. Five model strains of E. coli, MH-1, JM109, BL21, W3110 and ATCC25922, as well as B. subtilis and L. fermentum strains, each exhibiting distinct properties and expressing red fluorescent protein (RFP), were used as a phagocytosis substrate. Fluorometric, FTIR- and confocal laser scanning microscopy (CLSM) assessments of the phagocytic response of Mph to these bacterial cells were performed. Mph absorbed different strains of E. coli with different activities due to the difference in the surface villosity of bacterial cells (pili and fimbriae, as well as signal patterns). In the presence of other competitor cells (like those of Lactobacilli), the phagocytic activity of Mph is changed between two and five times and strongly dependent on the bacterial strain. The relative phagocytic activity indexes obtained for BALF-Mph in comparison with that obtained for model human CD206+ Mph in the M1 polarization state (derived from THP-1 monocyte cultures) were considered as a set of parameters to define the Mph polarization profile from the BALF of patients. Mannan as a marker determining the selectivity of the binding to the CD 206 mannose receptor of Mph significantly inhibited the phagocytosis of E. coli and B. subtilis in cases of pneumonia, suggesting an important role of CD206 overexpression in acute inflammation. Conversely, L. fermentum binding was enhanced in PCD, possibly reflecting altered macrophage responsiveness in chronic lung diseases. Our approach based on the profiling of Mph from patient BALF samples in terms of phagocytosis for a range of model bacterial strains is important for the subsequent detailed study of the factors determining dangerous conditions and resistance to existing therapeutic options. Full article

Primary ciliary dyskinesia (PCD) is a rare genetic disorder that affects the structure and function of cilia, primarily impacting the respiratory system. Kartagener syndrome, a subset of PCD, is characterized by situs inversus, bronchiectasis, and chronic sinusitis. Patients with PCD are prone to recurrent respiratory infections due to impaired ciliary function, which hinders effective mucus clearance and promotes pathogen colonization. This case report describes a 24-year-old woman with congenital Kartagener syndrome who developed eosinophilic pneumonia caused by Toxocara canis, a rare parasitic infection that less commonly affects the lungs. Despite initial treatment for a presumed bacterial infection, the patient’s symptoms persisted. Further diagnostics revealed elevated eosinophil counts, total IgE, and the presence of Toxocara canis antibodies. The patient was treated with albendazole, resulting in significant symptom improvement and a reduction in inflammatory markers. This case underscores the diagnostic challenges in treating PCD patients, where atypical infections must be considered, particularly when standard treatments prove ineffective. The complexity of the patient’s condition required interdisciplinary management, integrating parasitological, immunological, and respiratory expertise to ensure appropriate treatment. The case highlights the need for further research into the interactions between congenital respiratory disorders such as Kartagener syndrome and parasitic infections. It also emphasizes the importance of a comprehensive diagnostic approach in managing rare genetic diseases complicated by opportunistic infections. Early detection of parasitic infections in PCD patients is crucial to preventing severe complications, and this case reinforces the necessity of considering parasitic causes in atypical pneumonia cases. Full article

Digital high-speed videomicroscopy (DHSV) is a crucial tool for evaluating ciliary function in children suspected of primary ciliary dyskinesia (PCD). However, until now, samples are taken without anesthesia due to uncertainty about its effect on ciliary function and DHSV interpretation. This study aimed to investigate the impact of general anesthesia on ciliary functional analysis by DHSV in a series of three patients listed for ENT surgeries, which could improve diagnostic procedures for pediatric patients. Patient 1 (7-year-old girl) underwent adenotonsillectomy and tympanostomy placement tube, while patients 2 (17-month-old boy) and 3 (15-month-old girl) underwent adenoidectomy and tympanostomy placement tube. All patients underwent nasal brushing before general anesthesia (control sample). Experimental samples were taken in the contralateral nostril at the time of equilibration of the anesthetic agents (sevoflurane, propofol, sufentanil). Ciliary beat frequency and pattern were measured using digital high-speed videomicroscopy. Our findings highlighted the variability of respiratory ciliary function under general anesthesia among individuals. Our results emphasize the need for caution when interpreting ciliary function data obtained during general anesthesia. Further research with larger cohorts is warranted for validation. Full article

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. Full article

Primary Ciliary Dyskinesia (PCD) is a rare genetic disorder characterized by alterations in motile cilia function. The diagnosis of PCD is challenging due to the lack of standardized methods in clinical practice. High-speed video microscopy analysis (HSVA) directly evaluates ciliary beat frequency (CBF) in PCD. Recently, open-source ciliary analysis software applications have shown promise in measuring CBF accurately. However, there is limited knowledge about the performance of different software applications, creating a gap in understanding their comparative effectiveness in measuring CBF in PCD. We compared two open-source software applications, CiliarMove (v219) and Cilialyzer (v1.2.1-b3098cb), against the manual count method. We used high-speed videos of nasal ciliary brush samples from PCD RSPH4A-positive (PCD (RSPH4A)) patients and healthy controls. All three methods showed lower median CBF values for patients with PCD (RSPH4A) than in healthy controls. CiliarMove and Cilialyzer identified lower CBF in patients with PCD (RSPH4A), similarly to the manual count. Cilialyzer, CiliarMove, and manual count methods demonstrated statistical significance (p-value < 0.0001) in the difference of median CBF values between patients with PCD (RSPH4A) and healthy controls. Correlation coefficients between the manual count values against both software methods demonstrated positive linear relationships. These findings support the utility of open-source software-based analysis tools. Further studies are needed to validate these findings with other genetic variants and identify the optimal software for accurate CBF measurement in patients with PCD. Full article

Several chronic respiratory diseases could be risk factors for acquiring SARS-CoV-2 infection: among them, Primary Ciliary Dyskinesia (PCD) is a rare (about 1:10.000) inherited ciliopathy (MIM 242650) characterized by recurrent upper and lower respiratory tract infections due to a dysfunction of the respiratory cilia. In this study, we aimed to investigate whether PCD subjects are more susceptible to infection by SARS-CoV-2 and whether some polymorphisms of the TAS2R38 bitter taste receptor correlate with an increased prevalence of SARS-CoV-2 infection and severity of symptoms. Patients answered several questions about possible SARS-CoV-2 infection, experienced symptoms, and vaccinations; in the case of infection, they also filled out a SNOT-22 questionnaire and ARTIQ. Forty PCD adult patients (mean age, 36.6 ± 16.7 years; 23 females, 17 males) participated in this study, out of which 30% had tested positive for COVID-19 during the last four years; most of them reported a mildly symptomatic disease. We found no differences in age or sex, but a statistically significant difference (p = 0.03) was observed in body mass index (BMI), which was higher in the COVID-acquired group (23.2 ± 3.3 vs. 20.1 ± 4.1 kg/m²). Genotyping for TAS2R38 polymorphisms showed a prevalence of 28.6% PAV/PAV, 48.6% PAV/AVI, and 22.8% AVI/AVI individuals in our cohort. In contrast to our hypothesis, we did not observe a protective role of the PAV allele towards SARS-CoV-2 infection. Conclusions: Our findings suggest that subjects with PCD may not be at increased risk of severe outcomes from COVID-19 and the TAS2R38 bitter taste receptor genotype does not affect SARS-CoV-2 infection. Full article