Lung Function in Fontan Patients Over a Ten-Year Period: Is the Fontan Circulation Impairing Lung Development?

Few studies have investigated how the Fontan circulation affects lung function, and no studies have investigated the development of lung function over longer time in these patients. We aimed to describe the development of lung function in Fontan patients over a 10-year period. Pulmonary function tests (PFT), including spirometry and diffusion capacity for Carbon Monoxide (DLCO) and Nitric Oxide (DLNO), were conducted in a Danish Fontan cohort in 2011 (PFT-I). In 2021, re-investigations were performed (PFT-II). We investigated changes in percent predicted (%pred) lung function from PFT-I to PFT-II. Patients were categorized into a pediatric group (age under 18 at PFT-I) and an adult group (age 18 or older at PFT-I). Out of the 81 patients completing PFT-I, 48 completed PFT-II. In the pediatric group (32 patients), there were significant declines in %pred forced expiratory volume in 1s (99.7 (92.4, 104.4)-89.3 (84.9, 97.2), p < 0,001), forced vital capacity (98.3 (87.8, 106.1)-96.7 (86.7, 100.6), p = 0.008), and alveolar volume (95.5 (89.5, 101.6)-89.5 (79.7, 93.2), p < 0.001). The corresponding measurements remained stable in the adult group. However, the median %pred DLNO significantly declined in the adult group (58.4 (53.3, 63.5)-53.7 (44.1, 57.3), p = 0.005). Over a 10-year period, several lung function parameters declined significantly in the younger Fontan patients, suggesting possible impairments in lung development during growth. The decline in %pred DLNO in the adult patient group indicates deterioration of the membrane component of diffusion capacity, implying that the Fontan circulation might negatively affect the alveolar membrane over time.

Automatic analysis of bronchus-artery dimensions to diagnose and monitor airways disease in cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) lung disease is characterised by progressive airway wall thickening and widening. We aimed to validate an artificial intelligence-based algorithm to assess dimensions of all visible bronchus-artery (BA) pairs on chest CT scans from patients with CF. METHODS: The algorithm fully automatically segments the bronchial tree; identifies bronchial generations; matches bronchi with the adjacent arteries; measures for each BA-pair bronchial outer diameter (Bout), bronchial lumen diameter (Bin), bronchial wall thickness (Bwt) and adjacent artery diameter (A); and computes Bout/A, Bin/A and Bwt/A for each BA pair from the segmental bronchi to the last visible generation. Three datasets were used to validate the automatic BA analysis. First BA analysis was executed on 23 manually annotated CT scans (11 CF, 12 control subjects) to compare automatic with manual BA-analysis outcomes. Furthermore, the BA analysis was executed on two longitudinal datasets (Copenhagen 111 CTs, ataluren 347 CTs) to assess longitudinal BA changes and compare them with manual scoring results. RESULTS: The automatic and manual BA analysis showed no significant differences in quantifying bronchi. For the longitudinal datasets the automatic BA analysis detected 247 and 347 BA pairs/CT in the Copenhagen and ataluren dataset, respectively. A significant increase of 0.02 of Bout/A and Bin/A was detected for Copenhagen dataset over an interval of 2 years, and 0.03 of Bout/A and 0.02 of Bin/A for ataluren dataset over an interval of 48 weeks (all p<0.001). The progression of 0.01 of Bwt/A was detected only in the ataluren dataset (p<0.001). BA-analysis outcomes showed weak to strong correlations (correlation coefficient from 0.29 to 0.84) with manual scoring results for airway disease. CONCLUSION: The BA analysis can fully automatically analyse a large number of BA pairs on chest CTs to detect and monitor progression of bronchial wall thickening and bronchial widening in patients with CF.

Nasal nitric oxide measurement in children for the diagnosis of primary ciliary dyskinesia: European Respiratory Society technical standard.

Nasal nitric oxide (nNO) is extremely low in most people with primary ciliary dyskinesia (PCD) and its measurement is an important contributor to making the diagnosis. Existing guidelines and technical standards focus on nNO measurements in older, cooperative children using chemiluminescence analysers. However, measurements of nNO in pre-school-age children (age 2-5 years) may facilitate early diagnosis and electrochemical rather than chemiluminescence analysers are widely used. Pre-schoolers often need different methods to be employed when measuring nNO. Hence, a European Respiratory Society Task Force has developed this technical standard as the first step towards standardising sampling, analysis and reporting of nNO measured as part of the diagnostic testing for PCD in all age groups, including pre-school-age children. Furthermore, we considered both chemiluminescence and electrochemical analysers that are in use worldwide. There was a paucity of quality evidence for electrochemical analysers and sampling methods used in young children, and the Task Force proposes future research priorities to allow updates of this technical standard.

Chronic airway disease in primary ciliary dyskinesia-spiced with geno-phenotype associations.

Primary ciliary dyskinesia (PCD) can be defined as a multiorgan ciliopathy with a dominant element of chronic airway disease affecting the nose, sinuses, middle ear, and in particular, the lower airways. Although most patients with PCD are diagnosed during preschool years, it is obvious that the chronic lung disease starts its course already from birth. The many faces of the clinical picture change, as does lung function, structural lung damage, the burden of infection, and of treatment throughout life. A markedly severe neutrophil inflammation in the respiratory tract seems pervasive and is only to a minimal extent ameliorated by a treatment strategy, which is predominantly aimed at bacterial infections. An ever-increasing understanding of the different aspects, their interrelationships, and possible different age courses conditioned by the underlying genotype is the focus of much attention. The future is likely to offer personalized medicine in the form of mRNA therapy, but to that end, it is of utmost importance that all patients with PCD be carefully characterized and given a genetic diagnosis. In this narrative review, we have concentrated on lower airways and summarized the current understanding of the chronic airway disease in this motile ciliopathy. In addition, we highlight the challenges, gaps, and opportunities in PCD lung disease research.

Lung function from school age to adulthood in primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) presents with symptoms early in life and the disease course may be progressive, but longitudinal data on lung function are scarce. This multinational cohort study describes lung function trajectories in children, adolescents and young adults with PCD. We analysed data from 486 patients with repeated lung function measurements obtained between the age of 6 and 24 years from the International PCD Cohort and calculated z-scores for forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio using the Global Lung Function Initiative 2012 references. We described baseline lung function and change of lung function over time and described their associations with possible determinants in mixed-effects linear regression models. Overall, FEV1, FVC and FEV1/FVC z-scores declined over time (average crude annual FEV1 decline was -0.07 z-scores), but not at the same rate for all patients. FEV1 z-scores improved over time in 21% of patients, remained stable in 40% and declined in 39%. Low body mass index was associated with poor baseline lung function and with further decline. Results differed by country and ultrastructural defect, but we found no evidence of differences by sex, calendar year of diagnosis, age at diagnosis, diagnostic certainty or laterality defect. Our study shows that on average lung function in PCD declines throughout the entire period of lung growth, from childhood to young adult age, even among patients treated in specialised centres. It is essential to develop strategies to reverse this tendency and improve prognosis.

National multi-centre study found a low prevalence of severely impaired lung function in children and adolescents.

AIM: As no data to our knowledge exist, the aim of the study was to describe the national prevalence and characteristics of Danish children and adolescents with severely impaired lung function. METHODS: We performed a descriptive, cross-sectional Danish multi-centre study. Children and adolescents between 6 and 18 years old demonstrating severely impaired lung function from 2015 to 2018, defined by forced expiratory volume in 1 second (FEV1 ) <60% or who had lung transplantation, were eligible for inclusion. RESULTS: This study included 113 children with a mean age (standard deviation) of 12.9 years (3.5 years). The prevalence of severely impaired lung function was approximately 13 in 100,000. The mean (standard deviation) FEV1 was 46.1% (10.1%) of predicted, and z-score was -4.5 (0.8). The most frequent diagnosis was cystic fibrosis (20.4%), followed by asthma (19.5%) and bronchiolitis obliterans (16.8%), while almost 25% had different elements of airway malformations or non-pulmonary conditions. Two adolescents with cystic fibrosis underwent lung transplantation. CONCLUSION: The estimated prevalence of severely impaired lung function in Danish children and adolescents was low, and extremely, few children underwent lung transplantation. The most frequent diagnosis was cystic fibrosis, while almost 25% had different elements of airway malformations or non-pulmonary conditions, which may require clinical attention.

Mutations in C11orf70 Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry Due to Defects of Outer and Inner Dynein Arms.

Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, male infertility, and randomization of the left/right body axis as a result of defects of motile cilia and sperm flagella. We identified loss-of-function mutations in the open-reading frame C11orf70 in PCD individuals from five distinct families. Transmission electron microscopy analyses and high-resolution immunofluorescence microscopy demonstrate that loss-of-function mutations in C11orf70 cause immotility of respiratory cilia and sperm flagella, respectively, as a result of the loss of axonemal outer (ODAs) and inner dynein arms (IDAs), indicating that C11orf70 is involved in cytoplasmic assembly of dynein arms. Expression analyses of C11orf70 showed that C11orf70 is expressed in ciliated respiratory cells and that the expression of C11orf70 is upregulated during ciliogenesis, similar to other previously described cytoplasmic dynein-arm assembly factors. Furthermore, C11orf70 shows an interaction with cytoplasmic ODA/IDA assembly factor DNAAF2, supporting our hypothesis that C11orf70 is a preassembly factor involved in the pathogenesis of PCD. The identification of additional genetic defects that cause PCD and male infertility is of great importance for the clinic as well as for genetic counselling.

Characterizing Cutaneous Drug Delivery Using Open-Flow Microperfusion and Mass Spectrometry Imaging.

Traditionally, cutaneous drug delivery is studied by skin accumulation or skin permeation, while alternative techniques may enable the interactions between the drug and the skin to be studied in more detail. Time-resolved skin profiling for pharmacokinetic monitoring of two Janus Kinase (JAK) inhibitors, tofacitinib and LEO 37319A, was performed using dermal open-flow microperfusion (dOFM) for sampling of perfusate in an ex vivo and in vivo setup in pig skin. Additionally, matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) was performed to investigate depth-resolved skin distributions at defined time points ex vivo in human skin. By dOFM, higher skin concentrations were observed for tofacitinib compared to LEO 37319A, which was supported by the lower molecular weight, higher solubility, lipophilicity, and degree of protein binding. Using MALDI-MSI, the two compounds were observed to show different skin distributions, which was interpreted to be caused by the difference in the ability of the two molecules to interact with the skin compartments. In conclusion, the techniques assessed time- and depth-resolved skin concentrations and were able to show differences in the pharmacokinetic profiles of two JAK inhibitors. Thus, evidence shows that the two techniques can be used as complementary methods to support decision making in drug development.

Current and Future Treatments in Primary Ciliary Dyskinesia.

Primary ciliary dyskinesia (PCD) is a rare genetic ciliopathy in which mucociliary clearance is disturbed by the abnormal motion of cilia or there is a severe reduction in the generation of multiple motile cilia. Lung damage ensues due to recurrent airway infections, sometimes even resulting in respiratory failure. So far, no causative treatment is available and treatment efforts are primarily aimed at improving mucociliary clearance and early treatment of bacterial airway infections. Treatment guidelines are largely based on cystic fibrosis (CF) guidelines, as few studies have been performed on PCD. In this review, we give a detailed overview of the clinical studies performed investigating PCD to date, including three trials and several case reports. In addition, we explore precision medicine approaches in PCD, including gene therapy, mRNA transcript and read-through therapy.

A retrospective review of Achromobacter species and antibiotic treatments in patients with primary ciliary dyskinesia.

Objectives: Primary ciliary dyskinesia (PCD) is a rare congenital disease with defective mucociliary clearance causing frequent and often persistent pulmonary infections. Achromobacter species are opportunistic pathogens renowned for the difficulty of effective treatments and deteriorating effects on lung function. We aimed to describe the occurrence, treatment, and rate of successful eradication of Achromobacter species in patients with PCD. Methods: We retrospectively reviewed 18 years of historical microbiological samples and 10 years of electronic health records for PCD patients in Denmark. Results: We included 136 patients. Twenty-six patients had isolates of Achromobacter species. On average, 5% of the cohort had at least one annual isolate. Infections became persistent in 38% with a median length of 6.6 years leading to a significant number of antibiotic treatments. Resistance toward tobramycin and ciprofloxacin was prevalent. Overall, successful eradication was achieved in 62% of patients. We found the course of lung function significantly worse during persistent Achromobacter species infection than during the two preceding years, but not different to the course in unaffected age-matched controls. Conclusion The prevalence of Achromobacter species in patients with PCD is in line with what has been reported in cystic fibrosis and can occur transiently, intermittently, or develop into a serious persistent lung infection associated with long-term antibiotic treatment.

SPEF2- and HYDIN-Mutant Cilia Lack the Central Pair-associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous chronic destructive airway disease. PCD is traditionally diagnosed by nasal nitric oxide measurement, analysis of ciliary beating, transmission electron microscopy (TEM), and/or genetic testing. In most genetic PCD variants, laterality defects can occur. However, it is difficult to establish a diagnosis in individuals with PCD and central pair (CP) defects, and alternative strategies are required because of very subtle ciliary beating abnormalities, a normal ciliary ultrastructure, and normal situs composition. Mutations in HYDIN are known to cause CP defects, but the genetic analysis of HYDIN variants is confounded by the pseudogene HYDIN2, which is almost identical in terms of intron/exon structure. We have previously shown that several types of PCD can be diagnosed via immunofluorescence (IF) microscopy analyses. Here, using IF microscopy, we demonstrated that in individuals with PCD and CP defects, the CP-associated protein SPEF2 is absent in HYDIN-mutant cells, revealing its dependence on functional HYDIN. Next, we performed IF analyses of SPEF2 in respiratory cells from 189 individuals with suspected PCD and situs solitus. Forty-one of the 189 individuals had undetectable SPEF2 and were subjected to a genetic analysis, which revealed one novel loss-of-function mutation in SPEF2 and three reported and 13 novel HYDIN mutations in 15 individuals. The remaining 25 individuals are good candidates for new, as-yet uncharacterized PCD variants that affect the CP apparatus. SPEF2 mutations have been associated with male infertility but have not previously been identified to cause PCD. We identified a mutation of SPEF2 that is causative for PCD with a CP defect. We conclude that SPEF2 IF analyses can facilitate the detection of CP defects and evaluation of the pathogenicity of HYDIN variants, thus aiding the molecular diagnosis of CP defects.

Prevalence and course of disease after lung resection in primary ciliary dyskinesia: a cohort & nested case-control study.

BACKGROUND: Lung resection is a controversial and understudied therapeutic modality in Primary Ciliary Dyskinesia (PCD). We assessed the prevalence of lung resection in PCD across countries and compared disease course in lobectomised and non-lobectomised patients. METHODS: In the international iPCD cohort, we identified lobectomised and non-lobectomised age and sex-matched PCD patients and compared their characteristics, lung function and BMI cross-sectionally and longitudinally. RESULTS: Among 2896 patients in the iPCD cohort, 163 from 20 centers (15 countries) underwent lung resection (5.6%). Among adult patients, prevalence of lung resection was 8.9%, demonstrating wide variation among countries. Compared to the rest of the iPCD cohort, lobectomised patients were more often females, older at diagnosis, and more often had situs solitus. In about half of the cases (45.6%) lung resection was performed before presentation to specialized PCD centers for diagnostic work-up. Compared to controls (n = 197), lobectomised patients had lower FVC z-scores (- 2.41 vs - 1.35, p = 0.0001) and FEV1 z-scores (- 2.79 vs - 1.99, p = 0.003) at their first post-lung resection assessment. After surgery, lung function continued to decline at a faster rate in lobectomised patients compared to controls (FVC z-score slope: - 0.037/year Vs - 0.009/year, p = 0.047 and FEV1 z-score slope: - 0.052/year Vs - 0.033/year, p = 0.235), although difference did not reach statistical significance for FEV1. Within cases, females and patients with multiple lobe resections had lower lung function. CONCLUSIONS: Prevalence of lung resection in PCD varies widely between countries, is often performed before PCD diagnosis and overall is more frequent in patients with delayed diagnosis. After lung resection, compared to controls most lobectomised patients have poorer and continuing decline of lung function despite lung resection. Further studies benefiting from prospective data collection are needed to confirm these findings.

Exercise-based cardiac rehabilitation for adult patients with an implantable cardioverter defibrillator.

BACKGROUND: An effective way of preventing sudden cardiac death is the use of an implantable cardioverter defibrillator (ICD). In spite of the potential mortality benefits of receiving an ICD device, psychological problems experienced by patients after receiving an ICD may negatively impact their health-related quality of life, and lead to increased readmission to hospital and healthcare needs, loss of productivity and employment earnings, and increased morbidity and mortality. Evidence from other heart conditions suggests that cardiac rehabilitation should consist of both exercise training and psychoeducational interventions; such rehabilitation may benefit patients with an ICD. Prior systematic reviews of cardiac rehabilitation have excluded participants with an ICD. A systematic review was therefore conducted to assess the evidence for the use of exercise-based intervention programmes following implantation of an ICD. OBJECTIVES: To assess the benefits and harms of exercise-based cardiac rehabilitation programmes (exercise-based interventions alone or in combination with psychoeducational components) compared with control (group of no intervention, treatment as usual or another rehabilitation programme with no physical exercise element) in adults with an ICD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase and four other databases on 30 August 2018 and three trials registers on 14 November 2017. We also undertook reference checking, citation searching and contacted study authors for missing data. SELECTION CRITERIA: We included randomised controlled trials (RCTs) if they investigated exercise-based cardiac rehabilitation interventions compared with no intervention, treatment as usual or another rehabilitation programme. The trial participants were adults (aged 18 years or older), who had been treated with an ICD regardless of type or indication. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias. The primary outcomes were all-cause mortality, serious adverse events and health-related quality of life. The secondary outcomes were exercise capacity, antitachycardia pacing, shock, non-serious adverse events, employment or loss of employment and costs and cost-effectiveness. Risk of systematic errors (bias) was assessed by evaluation of predefined bias risk domains. Clinical and statistical heterogeneity were assessed. Meta-analyses were undertaken using both fixed-effect and random-effects models. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: We identified eight trials published from 2004 to 2017 randomising a total of 1730 participants, with mean intervention duration of 12 weeks. All eight trials were judged to be at overall high risk of bias and effect estimates are reported at the end of the intervention with a follow-up range of eight to 24 weeks.Seven trials reported all-cause mortality, but deaths only occurred in one trial with no evidence of a difference between exercise-based cardiac rehabilitation and control (risk ratio (RR) 1.96, 95% confidence interval (CI) 0.18 to 21.26; participants = 196; trials = 1; quality of evidence: low). There was also no evidence of a difference in serious adverse events between exercise-based cardiac rehabilitation and control (RR 1.05, 95% CI 0.77 to 1.44; participants = 356; trials = 2; quality of evidence: low). Due to the variation in reporting of health-related quality of life outcomes, it was not possible to pool data. However, the five trials reporting health-related quality of life at the end of the intervention, each showed little or no evidence of a difference between exercise-based cardiac rehabilitation and control.For secondary outcomes, there was evidence of a higher pooled exercise capacity (peak VO2) at the end of the intervention (mean difference (MD) 0.91 mL/kg/min, 95% CI 0.60 to 1.21; participants = 1485; trials = 7; quality of evidence: very low) favouring exercise-based cardiac rehabilitation, albeit there was evidence of substantial statistical heterogeneity (I2 = 78%). There was no evidence of a difference in the risk of requiring antitachycardia pacing (RR 1.26, 95% CI 0.84 to 1.90; participants = 356; trials = 2; quality of evidence: moderate), appropriate shock (RR 0.56, 95% CI 0.20 to 1.58; participants = 428; studies = 3; quality of evidence: low) or inappropriate shock (RR 0.60, 95% CI 0.10 to 3.51; participants = 160; studies = 1; quality of evidence: moderate). AUTHORS' CONCLUSIONS: Due to a lack of evidence, we were unable to definitively assess the impact of exercise-based cardiac rehabilitation on all-cause mortality, serious adverse events and health-related quality of life in adults with an ICD. However, our findings do provide very low-quality evidence that patients following exercise-based cardiac rehabilitation experience a higher exercise capacity compared with the no exercise control. Further high-quality randomised trials are needed in order to assess the impact of exercise-based cardiac rehabilitation in this population on all-cause mortality, serious adverse events, health-related quality of life, antitachycardia pacing and shock.

Proof of Concept: Very Rapid Tidal Breathing Nasal Nitric Oxide Sampling Discriminates Primary Ciliary Dyskinesia from Healthy Subjects.

INTRODUCTION: Nasal nitric oxide (nNO) is extremely low in individuals with primary ciliary dyskinesia (PCD) and is recommended as part of early workup. We investigated whether tidal breathing sampling for a few seconds was as discriminative between PCD and healthy controls (HC) as conventional tidal breathing sampling (cTB-nNO) for 20-30 s. METHODS: We performed very rapid sampling of tidal breathing (vrTB-nNO) for 2, 4 and 6 s, respectively. Vacuum sampling with applied negative pressure (vrTB-nNOvac; negative pressure was applied by pinching the sampling tube) for < 2 s resulted in enhanced suction of nasal air during measurement. Feasibility, success rate, discriminatory capacity, repeatability and agreement were assessed for all four sampling modalities. RESULTS: We included 13 patients with PCD, median (IQR) age of 21.8 (12.2-27.7) years and 17 HC, 25.3 (14.5-33.4) years. Measurements were highly feasible (96.7% success rate). Measured NO values with vrTB-nNO modalities differed significantly from TB-nNO measurements (HC: p < 0.001, PCD: p < 0.05). All modalities showed excellent discrimination. The vacuum method gave remarkably high values of nNO in both groups (1865 vs. 86 ppb), but retained excellent discrimination. vrTB-nNO4sec, vrTB-nNO6sec and vrTB-nNOvac showed identical specificity to cTB-nNO (all: 1.0, 95% CI 0.77-1.0). CONCLUSION: vrTB-nNO sampling requires only a few seconds of probe-in-nose time, is feasible, and provides excellent discrimination between PCD and HC. Rapid TB-nNO sampling needs standardisation and further investigations in infants, young children and patients referred for PCD workup.

Preschool Multiple-Breath Washout Testing. An Official American Thoracic Society Technical Statement.

BACKGROUND: Obstructive airway disease is nonuniformly distributed throughout the bronchial tree, although the extent to which this occurs can vary among conditions. The multiple-breath washout (MBW) test offers important insights into pediatric lung disease, not available through spirometry or resistance measurements. The European Respiratory Society/American Thoracic Society inert gas washout consensus statement led to the emergence of validated commercial equipment for the age group 6 years and above; specific recommendations for preschool children were beyond the scope of the document. Subsequently, the focus has shifted to MBW applications within preschool subjects (aged 2-6 yr), where a "window of opportunity" exists for early diagnosis of obstructive lung disease and intervention. METHODS: This preschool-specific technical standards document was developed by an international group of experts, with expertise in both custom-built and commercial MBW equipment. A comprehensive review of published evidence was performed. RESULTS: Recommendations were devised across areas that place specific age-related demands on MBW systems. Citing evidence where available in the literature, recommendations are made regarding procedures that should be used to achieve robust MBW results in the preschool age range. The present work also highlights the important unanswered questions that need to be addressed in future work. CONCLUSIONS: Consensus recommendations are outlined to direct interested groups of manufacturers, researchers, and clinicians in preschool device design, test performance, and data analysis for the MBW technique.

Variation in treatment strategies for the eradication of Pseudomonas aeruginosa in primary ciliary dyskinesia across European centers.

Primary ciliary dyskinesia (PCD) is a rare disease causing motile cilia dysfunction, recurrent airway infection, and bronchiectasis. Airway infection management strategies are borrowed from cystic fibrosis. The aim of this study is to describe the management of airway infection with Pseudomonas aeruginosa ( PA) in children and adults with PCD across European centers. An online survey questionnaire was sent electronically using SurveyMonkey® to 55 PCD centers in 36 European countries. Fifty-two responded from 43 centers in 26 countries, a response rate of 70%. Most (89%) countries did not have written guidelines for PCD management. Airway sampling for infection detection at each clinic visit was more likely when follow-up was frequent. Eighty-seven percent of centers chose to treat the first PA isolate, most prescribing combined oral ciprofloxacin and inhaled colistimethate sodium (43%, n = 18). The preferred treatment for chronic infection with PA was nebulized colistimethate in 51% ( n = 22). In summary, considerable variation exists across European centers in the frequency of patient follow-up and airway sampling for infection, treatment goals, and the management of PA infection. Few centers had written guidelines for PCD management. Clinical trials to determine optimal treatment of PA in PCD patients are urgently needed.

Loss-of-Function GAS8 Mutations Cause Primary Ciliary Dyskinesia and Disrupt the Nexin-Dynein Regulatory Complex.

Multiciliated epithelial cells protect the upper and lower airways from chronic bacterial infections by moving mucus and debris outward. Congenital disorders of ciliary beating, referred to as primary ciliary dyskinesia (PCD), are characterized by deficient mucociliary clearance and severe, recurrent respiratory infections. Numerous genetic defects, most of which can be detected by transmission electron microscopy (TEM), are so far known to cause different abnormalities of the ciliary axoneme. However, some defects are not regularly discernable by TEM because the ciliary architecture of the axoneme remains preserved. This applies in particular to isolated defects of the nexin links, also known as the nexin-dynein regulatory complex (N-DRC), connecting the peripheral outer microtubular doublets. Immunofluorescence analyses of respiratory cells from PCD-affected individuals detected a N-DRC defect. Genome-wide exome sequence analyses identified recessive loss-of-function mutations in GAS8 encoding DRC4 in three independent PCD-affected families.

Infant nasal nitric oxide over time: natural evolution and impact of respiratory tract infection.

Nasal nitric oxide (NO) discriminates between patients with primary ciliary dyskinesia (PCD) and healthy individuals. We report feasibility of measurement and natural evolution of nasal NO and upon the impact of respiratory tract infection (RTI) on nasal NO in healthy infants (HI), followed from birth until age 2 years, with comparison to nasal NO in infant PCD.Tidal-breathing nasal NO measurements were performed at scheduled visits at 2 weeks old and at 4, 8, 12, 18 and 24 months old, with extra visits during RTIs. Historical nasal NO measurements for infant PCD were included for comparison.Altogether, 224 nasal NO measurements were performed in 44 enrolled infants. Median newborn nasal NO was 46 ppb (interquartile range (IQR) 29-69 ppb), increasing at a rate of 5.4% per month up to 283 ppb (IQR 203-389 ppb) at the age of 2 years. RTIs in 27 out of 44 infants temporarily suppressed nasal NO by 79%. Values for nasal NO in seven infants with PCD ranged from 6-80 ppb. The success rate to accept nasal NO sampling was 223 out of 224 measurements (99.6%).Tidal-breathing nasal NO measurement was indeed feasible in infancy and nasal NO in HI increased significantly up to 2 years of age, in opposition to nasal NO in PCD cases, which stayed low past 2 years of age. RTI episodes caused marked, temporary reductions in nasal NO in HI indistinguishable from that in infant PCD, suggesting that nasal NO should be measured in RTI-free intervals.

Lung function in patients with primary ciliary dyskinesia: an iPCD Cohort study.

Primary ciliary dyskinesia (PCD) has been considered a relatively mild disease, especially compared to cystic fibrosis (CF), but studies on lung function in PCD patients have been few and small.This study compared lung function from spirometry of PCD patients to normal reference values and to published data from CF patients. We calculated z-scores and % predicted values for forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) using the Global Lung Function Initiative 2012 values for 991 patients from the international PCD Cohort. We then assessed associations with age, sex, country, diagnostic certainty, organ laterality, body mass index and age at diagnosis in linear regression models. Lung function in PCD patients was reduced compared to reference values in both sexes and all age groups. Children aged 6-9 years had the smallest impairment (FEV1 z-score -0.84 (-1.03 to -0.65), FVC z-score -0.31 (-0.51 to -0.11)). Compared to CF patients, FEV1 was similarly reduced in children (age 6-9 years PCD 91% (88-93%); CF 90% (88-91%)), but less impaired in young adults (age 18-21 years PCD 79% (76-82%); CF 66% (65-68%)). The results suggest that PCD affects lung function from early in life, which emphasises the importance of early standardised care for all patients.

MALDI imaging facilitates new topical drug development process by determining quantitative skin distribution profiles.

Generation of skin distribution profiles and reliable determination of drug molecule concentration in the target region are crucial during the development process of topical products for treatment of skin diseases like psoriasis and atopic dermatitis. Imaging techniques like mass spectrometric imaging (MSI) offer sufficient spatial resolution to generate meaningful distribution profiles of a drug molecule across a skin section. In this study, we use matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to generate quantitative skin distribution profiles based on tissue extinction coefficient (TEC) determinations of four different molecules in cross sections of human skin explants after topical administration. The four drug molecules: roflumilast, tofacitinib, ruxolitinib, and LEO 29102 have different physicochemical properties. In addition, tofacitinib was administrated in two different formulations. The study reveals that with MALDI-MSI, we were able to observe differences in penetration profiles for both the four drug molecules and the two formulations and thereby demonstrate its applicability as a screening tool when developing a topical drug product. Furthermore, the study reveals that the sensitivity of the MALDI-MSI techniques appears to be inversely correlated to the drug molecules' ability to bind to the surrounding tissues, which can be estimated by their Log D values. Graphical abstract.