Sivagurunathan Sutharsan

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 found that epithelial cell transforming 2 like (ECT2L) and double zinc ribbon and ankyrin repeat-containing protein 1 (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.

Background/Objectives: Krebs von den Lungen-6 (KL-6) is a mucin-like glycoprotein that is elevated in a variety of lung diseases and used as a diagnostic and prognostic biomarker in people with cystic fibrosis (pwCF). Single nucleotide polymorphisms (SNPs) in mucin-1 (MUC1) influence KL-6 serum concentration. This study investigated the relationship between serum KL-6 concentrations in pwCF and a MUC1 SNP and its longitudinal dynamics. Methods: The study included pwCF (n = 174) and healthy controls (n = 30). In pwCF, 365 samples were collected for longitudinal analyses; KL-6 levels were measured and the MUC1 SNP rs4072037 was genotyped in pwCF and controls. Cross-sectional and longitudinal associations between KL-6, genotype, and clinical parameters, such as infectious exacerbation, body mass index, inflammatory values and lung function, were analyzed using linear mixed-effects models. Results: Serum KL-6 was significantly elevated in pwCF compared with controls (458 ± 357 vs. 283 ± 103 U/mL; p < 0.001). Homozygous G/G carriers exhibited higher baseline KL-6 than A/A carriers (627 ± 673 vs. 397 ± 148 U/mL; p < 0.001), while heterozygous individuals showed intermediate levels. Longitudinally, the MUC1 SNP and interindividual differences in vital capacity (ppFVC) primarily determined baseline KL-6 levels, explaining 52.5% of variance. Short-term intraindividual fluctuations were largely driven by infectious exacerbations independent of genotype, accounting for ~10% of within-subject variance. Conclusions: PwCF generally showed elevated serum KL-6 levels and reflected both stable interindividual differences, mainly driven by the MUC1 SNP and ppFVC. Dynamic intraindividualchanges were associated with infectious exacerbations. Given the influence of MUC1 polymorphisms (e.g., rs4072037) on KL-6 concentration, personalized interpretation based on the genotype status may be informative in pwCF.

Bronchiectasis is a chronic, often progressive respiratory disease characterized by irreversible dilation of the bronchi. It is etiologically heterogeneous and frequently associated with a significant symptom burden, multiple complications, and reduced quality of life. In recent years, the global prevalence of bronchiectasis has increased markedly, placing a substantial economic burden on healthcare systems. These consensus-based guidelines are the first German-language guidelines focused on the management of bronchiectasis in adults. They underscore the critical role of thoracic imaging – particularly computed tomography – in diagnosing and distinguishing bronchiectasis and highlight the importance of identifying the underlying etiology in guiding treatment decisions. The guidelines provide comprehensive recommendations for both pharmacological and non-pharmacological treatment strategies. Non-drug interventions include smoking cessation, physiotherapy, physical training, pulmonary rehabilitation, noninvasive ventilation, thoracic surgery, and lung transplantation. Pharmacological therapies emphasize the long-term use of mucolytics, bronchodilators, anti-inflammatory agents, and antibiotics. In addition, the guidelines address the management of upper airway involvement, common comorbidities, and acute exacerbations. They also cover sociomedical issues, disability rights, and the role of patient education and self-management in optimizing care. Special life stages – such as transition from pediatric to adult care, family planning, pregnancy, parenthood, and palliative care – are also considered. The overarching goal was to promote comprehensive, consensus-driven, and patient-centered care that accounts for individual risks and needs.

Objective: To assess whether chronic rhinosinusitis (CRS) severity is associated with obstructive sleep apnea (OSA) in adult people with cystic fibrosis (pwCF). Methods: We conducted a retrospective single-center study of 44 adults with CF who underwent overnight polysomnography (PSG), Epworth Sleepiness Scale (ESS) assessment, and sinus computed tomography (CT). CRS severity was quantified using the Lund–Mackay score (LMS) and the main nasal cavity score (MNCS). OSA was defined by Apnea–Hypopnea Index (AHI) thresholds per American Academy of Sleep Medicine criteria. Results: Participants had a mean age of 31.1 ± 8.4 years and a mean percent predicted FEV1 of 51.8 ± 15.7. Sinus CT showed radiological evidence of CRS in all participants. Mean AHI was 5.3 ± 4.4/h; 48% had AHI ≥ 5/h. There were no significant differences between pwCF with and without OSA in age, sex, BMI, lung function, total sleep time, sleep efficiency, or ESS score (all p > 0.05). Mean LMS and MNCS did not differ between OSA and non-OSA groups (both p > 0.05), and neither score correlated with PSG parameters or ESS (all p > 0.05). Receiver operating characteristic (ROC) analysis demonstrated low discriminative ability of LMS and MNCS for predicting OSA (AUCs < 0.70, p < 0.05). Conclusions: In this cohort of adults with CF, CT-based CRS severity was not associated with OSA. Given the substantial prevalence of OSA observed, PSG screening should be considered irrespective of CRS severity.

Objective: Chest computed tomography (CT) is a key component of the diagnostic assessment of people with cystic fibrosis (PwCF) and is increasingly replacing chest radiography. Due to improvements in life expectancy, radiation exposure has become a growing concern in PwCF. Photon-counting CT (PCCT) has the potential to reduce the risk of radiation-induced malignancies while maintaining diagnostic accuracy. This study aimed to compare the radiation dose and image quality of low-dose high-resolution (LD-HR) and ultra-low-dose high-resolution (ULD-HR) CT protocols using PCCT in PwCF. Methods: This retrospective study included 72 PwCF, with 36 undergoing a LD-HR chest CT protocol and 36 receiving an ULD-HR protocol on a PCCT. The radiation dose and image quality were assessed by comparing the effective dose and signal-to-noise ratio (SNR). Three blinded radiologists evaluated the overall image quality, sharpness, noise, and assessability of the bronchi, bronchial wall thickening, and bronchiolitis using a five-point Likert scale. Results: The ULD-HR PCCT protocol reduced radiation exposure by approximately 65% compared with the LD-HR PCCT protocol (median effective dose: 0.19 vs. 0.55 mSv, p < 0.001). While LD-HR images were consistently rated higher than ULD-HR images (p < 0.001), both protocols maintained diagnostic significance (median image quality rating of “4-good”). The average SNR of the lung parenchyma was significantly lower with ULD-HR PCCT compared to LD-HR PCCT (p < 0.001). Conclusions: ULD-HR PCCT significantly reduced radiation exposure while maintaining good diagnostic image quality in PwCF. The effective dose of ULD-HR PCCT is only twice that of a two-plane chest X-ray, making it a viable low-radiation alternative for routine imaging in PwCF.

Background: This study aimed to investigate longitudinal changes in muscle mass, quality, and composition (sarcopenia and myosteatosis) in adult people with cystic fibrosis (pwCF) using artificial intelligence (AI)-assisted body composition analysis (BCA) with chest computed tomography (CT) at the T12 level and to examine the influence of CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI). Methods: A retrospective observational study was conducted on 102 adult pwCF (42 females (41%), mean age 33.9 ± 11.1 years) who underwent routine chest CT scans with a minimum of six months between scans. PwCF were categorized into ETI and no ETI groups. AI-assisted BCA was performed on chest CT images at the T12 level to measure skeletal muscle area (SMA), inter- and intramuscular adipose tissue (IMAT), and low-attenuation muscle area (LAMA). IMAT/SMA ratio and height- and weight-related skeletal muscle indices (SMI) were calculated. Results: The ETI group showed a significant increase in SMA over time (p < 0.001), whereas the IMAT, LAMA, and IMAT/SMA ratio increased in both groups (all p < 0.05). SMI showed alterations only in the ETI group, with an increase in SMA/m² (p < 0.001) and a decrease in SMA/kg (p = 0.003) and SMA/BMI (p = 0.006). Sex-specific analysis showed that SMA and myosteatosis increased regardless of sex (all p < 0.05). Weight-adjusted SMI decreased only in females receiving ETI therapy (p < 0.05). Conclusions: Adult pwCF, particularly those undergoing ETI therapy, experience significant changes in body composition, including increased muscle mass and myosteatosis. Trends in the development of sarcopenic obesity have been observed, particularly in female pwCF. These findings emphasize the importance of comprehensive body composition assessments and targeted interventions in pwCF treated with ETI to optimize muscle mass and quality while managing adipose tissue accumulation.

Rationale: The mucoid phenotype of Staphylococcus aureus is caused by adaptation. Excessive biofilm formation associated with a protective effect for mucoid S. aureus was observed in isolates from respiratory samples of people with cystic fibrosis (pwCF). Objectives: There is little knowledge about the prevalence of mucoid S. aureus in pwCF and a potential association with CF lung disease. Methods: A prospective multicenter study was conducted (cross-sectional and longitudinal). Specimens and case report forms were sent to the central study laboratory for characterization of S. aureus and analysis of clinical parameters. Measurements and Main Results: In the cross-sectional study, in 41 (9.1%) of 451 S. aureus–positive pwCF from 13 CF centers, mucoid S. aureus was cultured. In the longitudinal study, the distribution of CFTR genotypes and the number of pwCF with highly effective modulator therapy and coinfection with Pseudomonas aeruginosa were equivalent in the mucoid group (35 pwCF) versus the control group (only nonmucoid S. aureus; 36 pwCF). Although lung function did not differ between groups as a whole, a subgroup analysis revealed significantly worse lung function for female pwCF with mucoid S. aureus as well as for pwCF if P. aeruginosa coinfection was excluded. Conclusions: In the era of highly effective modulator therapy, worse lung function was associated with female and P. aeruginosa–negative pwCF with mucoid S. aureus compared with pwCF with only nonmucoid S. aureus. Therefore, appropriate culture conditions should be established to detect mucoid S. aureus. Further investigations are needed to elucidate the relationship between mucoid S. aureus and CF lung disease. Clinical trial registered with www.clinicaltrials.gov (NCT04171583).

Background/Objectives: Recent studies indicate that sleep and sleep disorders differ between men and women, but corresponding data in people with chronic lung diseases are lacking. This study aims to answer the question of what the sex-specific differences in sleep profiles and responses to elexacaftor/tezacaftor/ivacaftor (ETI) therapy in people with cystic fibrosis (pwCF) are. Methods: Adult pwCF and a matched control group (adults with suspected sleep-disordered breathing undergoing in-laboratory polysomnography (PSG)) were included. PSG data at baseline and after 6 months’ ETI therapy were compared between men (mwCF) and women (wwCF) with cystic fibrosis. PSG data at baseline and 6-month follow-up for mwCF/wwCF were compared with baseline PSG data for men/women in the control group. Daytime sleepiness was evaluated using the Epworth Sleepiness Scale (ESS). Correlations between change in percentage predicted forced expiratory volume in 1 s from baseline to 6 months were correlated with corresponding changes in key sleep parameters. Changes in transferrin during ETI therapy were also documented. Results: Twenty-eight pwCF (12 wwCF, 16 mwCF) and 28 matched controls were included. Both mwCF (4 ± 5 vs. 9 ± 20 events/h, p = 0.028) and wwCF (3 ± 3 vs. 8 ± 9 events/h, p = 0.004) had fewer respiratory events during sleep versus male and female controls, but worse sleep efficiency (75 ± 11% vs. 84 ± 11%; p = 0.004 and 76 ± 10% vs. 83 ± 11%; p = 0.011. The baseline ESS score was significantly higher in wwCF versus female controls (8 ± 4 vs. 14 ± 8; p = 0.040). Although some sleep parameters normalized during ETI therapy in pwCF, sleep quality remained poor. The transferrin levels at baseline (2.7 ± 0.4 vs. 2.2 ± 0.5; p = 0.049) and 6 months (3.8 ± 0.4 vs. 2.6 ± 0.5; p < 0.001) were significantly higher in the wwCF versus the mwCF, and the change from baseline during ETI therapy was significantly greater in women versus men (1.1 ± 0.6 vs. 0.4 ± 0.4; p < 0.001). Conclusions: These data suggest that wwCF and mwCF should be managed differently with respect to their sleep.

Background: Cystic fibrosis bone disease (CFBD) is a common comorbidity in adult people with cystic fibrosis (pwCF), resulting in an increased risk of bone fractures. This study evaluated the capacity of artificial intelligence (AI)-assisted low-dose chest CT (LDCT) opportunistic screening for detecting low bone mineral density (BMD) in adult pwCF. Methods: In this retrospective single-center study, 65 adult pwCF (mean age 30.1 ± 7.5 years) underwent dual-energy X-ray absorptiometry (DXA) of the lumbar vertebrae L1 to L4 to determine BMD and corresponding z-scores and completed LDCTs of the chest within three months as part of routine clinical care. A fully automated CT-based AI algorithm measured the attenuation values (Hounsfield units [HU]) of the thoracic vertebrae Th9–Th12 and first lumbar vertebra L1. The ability of the algorithm to diagnose CFBD was assessed using receiver operating characteristic (ROC) curves. Results: HU values of Th9 to L1 and DXA-derived BMD and the corresponding z-scores of L1 to L4 showed a strong correlation (all p < 0.05). The area under the curve (AUC) for diagnosing low BMD was highest for L1 (0.796; p = 0.001) and Th11 (0.835; p < 0.001), resulting in a specificity of 84.9% at a sensitivity level of 75%. The HU threshold values for distinguishing normal from low BMD were <197 (L1) and <212 (Th11), respectively. Conclusions: Routine LDCT of the chest with the fully automated AI-guided determination of thoracic and lumbar vertebral attenuation values is a valuable tool for predicting low BMD in adult pwCF, with the best results for Th11 and L1. However, further studies are required to define clear threshold values.

Background: CF is an important cause of bronchiectasis (BE) with specific highly effective modulator treatments available for the majority of patients. Patients with CF may not be detected by screening and may therefore present for the first time in adult non-CF BE clinics. Aim: To describe the frequency of testing for CF within European non-CF BE clinics. Methods: EMBARC is a prospective observational registry of patients with CT confirmed BE from 31 countries. Data on CF testing by sweat test and CF genetics were recorded if they were performed at any time prior to the baseline visit. Patients with a diagnosis of CF were not included. A multiple logistic regression model was used to identify independent predictors of being tested for CF. Results: Among 19,324 patients, 1,749 underwent sweat tests: 1,512 negative, 216 intermediate, and 21 positive for potential CF. Genetic testing in 1,213 patients revealed CFTR mutations in 121 cases. Factors influencing testing included younger age (OR 0.96, 95% CI 0.95-0.96, p < 0.001), longer diagnosis duration (p < 0.0001), presence of P. aeruginosa (OR 1.35, 95% CI 1.18-1.54, p < 0.0001) and S. aureus (OR 1.25, 95% CI 1.04-1.50, p = 0.02), poorer lung function (p < 0.0001), nasal polyposis, rhinosinusitis (OR 1.67, 95% CI 1.48-1.88, p < 0.0001), and severe radiological findings. Conversely, patients with asthma and COPD were less likely to be tested. Testing rates were highest in Northern and Western Europe (23.6%) and Southern Europe (16.3%), lowest in Eastern Europe. Conclusion: The findings underscore a significant proportion of adult BE patients remaining untested for CF.