Primary Ciliary Dyskinesia: A Clinical Review.

Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous, motile ciliopathy, characterized by neonatal respiratory distress, recurrent upper and lower respiratory tract infections, subfertility, and laterality defects. Diagnosis relies on a combination of tests for confirmation, including nasal nitric oxide (nNO) measurements, high-speed videomicroscopy analysis (HSVMA), immunofluorescent staining, axonemal ultrastructure analysis via transmission electron microscopy (TEM), and genetic testing. Notably, there is no single gold standard confirmatory or exclusionary test. Currently, 54 causative genes involved in cilia assembly, structure, and function have been linked to PCD; this rare disease has a spectrum of clinical manifestations and emerging genotype-phenotype relationships. In this review, we provide an overview of the structure and function of motile cilia, the emerging genetics and pathophysiology of this rare disease, as well as clinical features associated with motile ciliopathies, novel diagnostic tools, and updates on genotype-phenotype relationships in PCD.

Initiatives to improve lung and sleep health in children: Delphi consensus from the pediatrics, pulmonary, and sleep conference.

BACKGROUND AND OBJECTIVES: The lung and sleep health of adults is heavily influenced by early factors, both genetic and environmental; therefore, optimizing respiratory health begins in childhood. Multiple barriers impede improvements in lung and sleep health for children. First, the traditional siloing between general pediatric care in the community, pediatric pulmonary and sleep subspecialty care, and the research community limits the translation of knowledge into practice. Additionally, identifying and addressing health disparities remains a challenge. The 2021 NHLBI-sponsored workshop "Defining and Promoting Pediatric Pulmonary Health (DAP3H)" was a first step in defining critical gaps in our current healthcare system in identifying and optimizing lung and sleep health in children. The workshop identified key opportunities including measuring pulmonary function in young children, sleep-focused outcomes, developing biomarkers, and longitudinal research cohorts. To expand on the work of DAP3H and continue initiatives to improve childhood lung and sleep health, the Pediatrics & Pulmonary Network: Improving Health Together conference was held in 2023. STUDY DESIGN: A modified Delphi process was applied to form consensus surrounding gaps, barriers, and action items, with the goal of identifying the most urgent opportnities for improving childhood lung and sleep health. RESULTS: Cross-cutting foundational principles were identified as: (1) Authentic Stakeholder Collaboration & Engagement, (2) Reach & Implementation in Real World Settings, (3) Understanding Current Landscape & Resources and (4) Purposeful Diversity, Equity, & Inclusion Initiatives. CONCLUSIONS: To improve lung and sleep health in children, these principles should be the foundation for research design, development, and implementation.

The association between gynecologic healthcare providers' sexual health and their comfort discussing their patients' sexual function.

OBJECTIVE: Stigma surrounding discussions of sexuality can prevent patients from discussing sexual health issues with their healthcare providers. Clinicians may also experience similar stigma, compounding the problem if also reticent to assess their patients' sexual health. We explored the association of healthcare providers' personal sexual experience and health with their comfort with and frequency of optimizing their patients' sexual function and satisfaction. METHODS: We conducted an anonymous online survey of gynecologic care providers and their comfort with and frequency of addressing their patients' sexual function. Covariates examined via bivariate analysis included: socio-demographics, training level, prior sexual experiences and education, history of sexual trauma, and current sexual problems and satisfaction. RESULTS: Most respondents (N = 189) identified as sexually active (82.5 %), heterosexual (90.5 %), female (85.7 %) medical trainees (63.5 %). A quarter (23.8 %) reported currently having at least 1 sexual problem and 27.0 % reported a history of sexual trauma. Notably, 91.0 % of respondents had never been asked about their own sexual health by a healthcare provider. Less than half (43.9 %) reported frequently bringing up sexual health issues with their patients, while about half (50.8 %) reported being comfortable optimizing patients' sexual function, which was significantly correlated (p < 0.05) with practicing at the attending level, being comfortable talking about their own sexuality, the absence of sexual problems, reported sexual satisfaction, and prior education in a greater number of sexual healthcare topics. CONCLUSION: Variation in how gynecologic healthcare providers manage their patients' sexual function may be linked to their own sexual experiences and well-being.

Primary Ciliary Dyskinesia.

Primary ciliary dyskinesia (PCD) is a rare, genetic disease characterized by dysfunctional motile cilia and abnormal mucociliary clearance, resulting in chronic sino-oto-pulmonary disease, neonatal respiratory distress, subfertility, and organ laterality defects. Over the past 2 decades, research and international collaborations have led to an improved understanding of disease prevalence, classic and variable phenotypes, novel diagnostics, genotype-phenotype correlations, long term morbidity, and innovative therapeutics. However, PCD is often underrecognized in clinical settings and the recent analyses of genetic databases suggest that only a fraction of these patients are being accurately diagnosed. Knowledge of significant advancements, from pathophysiology to the expanded range of clinical manifestations, will have important clinical impacts. These may include increasing disease recognition, improving diagnostic testing and management, and establishing an adequate pool of affected patients to enroll in upcoming clinical therapeutic trials. The objective of this state-of-the-art review is for readers to gain a greater understanding of the clinical spectrum of motile ciliopathies, cutting-edge diagnostic practices, emerging genotype-phenotype associations, and currently accepted management of people with PCD.

Child Health and the Pediatric Pulmonology Workforce: 2020-2040.

There is concern as to whether the supply of pediatric pulmonology (PULM) subspecialists will be adequate to meet future demand. As part of an American Board of Pediatrics (ABP) Foundation-sponsored supplement investigating the future of the pediatric subspecialty workforce, this article assesses the current PULM clinical workforce and estimates the clinical workforce supply in the United States through 2040. The current workforce was assessed using ABP certification and Maintenance of Certification data, and a workforce supply model evaluating population growth, clinical effort, and geographic trends was developed after incorporating ABP data. Findings demonstrate that the number of pediatric pulmonologists has gradually increased over the past decade, and the ratio of subspecialists to children is likely to increase another 20% to 40% over the next 2 decades, although absolute numbers remain small. Geographic variation in access will persist in some regions. The proportion of women in the discipline has increased, but the proportion of pediatric pulmonologists from underrepresented in medicine backgrounds still lags behind the general population. Based on current trends, the PULM clinical workforce appears equipped to meet both population growth and the modest increase in demand for clinical services speculated to occur because of changes in the subspecialty's clinical portfolio. However, several factors could inhibit growth, and geographic maldistribution may continue to impact care access. Efforts to address variation in access and demographic diversity in the field are warranted. This article concludes by discussing the training, clinical practice, policy, and future workforce research implications of the data presented.

Situs Ambiguus Is Associated With Adverse Clinical Outcomes in Children With Primary Ciliary Dyskinesia.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare disorder of motile cilia associated with situs abnormalities. At least 12% of patients with PCD have situs ambiguus (SA), including organ laterality defects falling outside normal arrangement (situs solitus [SS]) or mirror image inversion (situs inversus totalis [SIT]). RESEARCH QUESTION: Do patients with PCD and SA achieve worse clinical outcomes compared with those with SS or SIT? STUDY DESIGN AND METHODS: This cross-sectional, multicenter study evaluated participants aged 21 years or younger with PCD. Participants were classified as having SA, including heterotaxy, or not having SA (SS or SIT). Markers of disease severity were compared between situs groups, adjusting for age at enrollment and severe CCDC39 or CCDC40 genotype, using generalized linear models and logistic and Poisson regression. RESULTS: In 397 participants with PCD (mean age, 8.4 years; range, 0.1-21), 42 patients were classified as having SA, including 16 patients (38%) with complex cardiovascular malformations or atrial isomerism, 13 patients (31%) with simple CVM, and 13 patients (31%) without cardiovascular malformations. Of these, 15 patients (36%) underwent cardiac surgery, 24 patients (57%) showed an anatomic spleen abnormality, and seven patients (17%) showed both. The remaining 355 participants did not have SA, including 152 with SIT and 203 with SS. Overall, 70 participants (17%) harbored the severe CCDC39 or CCDC40 genotype. Compared with participants without SA, those with SA showed lower median BMI z scores (P = .03), lower FVC z scores (P = .01), and more hospitalizations and IV antibiotic courses for acute respiratory infections during the 5 years before enrollment (P < .01). Participants with cardiovascular malformations requiring surgery or with anatomic spleen abnormalities showed lower median BMI z scores and more hospitalizations and IV therapies for respiratory illnesses compared with participants without SA. INTERPRETATION: Children with PCD and SA achieve worse nutritional and pulmonary outcomes with more hospitalizations for acute respiratory illnesses than those with SS or SIT combined. Poor nutrition and increased hospitalizations for respiratory infections in participants with SA and PCD are associated with cardiovascular malformations requiring cardiac surgery, splenic anomalies, or both. TRIAL REGISTRY: ClinicalTrials.gov; Nos.: NCT02389049 and NCT00323167; URL: www. CLINICALTRIALS: gov.

Defining and Promoting Pediatric Pulmonary Health: Assessing Lung Function and Structure.

Lifelong respiratory health is rooted in the structural and functional development of the respiratory system in early life. Exposures and interventions antenatally through childhood can influence lung development into young adulthood, the life stage with the highest achievable lung function. Because early respiratory health sets the stage for adult lung function trajectories and risk of developing chronic obstructive pulmonary disease, understanding how to promote lung health in children will have far reaching personal and population benefits. To achieve this, it is critical to have accurate and precise measures of structural and functional lung development that track throughout life stages. From this foundation, evaluation of environmental, genetic, metabolic, and immune mechanisms involved in healthy lung development can be investigated. These goals require the involvement of general pediatricians, pediatric subspecialists, patients, and researchers to design and implement studies that are broadly generalizable and applicable to otherwise healthy and chronic disease populations. This National Institutes of Health workshop report details the key gaps and opportunities regarding lung function and structure.

Automatic bronchus and artery analysis on chest computed tomography to evaluate the effect of inhaled hypertonic saline in children aged 3-6 years with cystic fibrosis in a randomized clinical trial.

BACKGROUND: SHIP-CT showed that 48-week treatment with inhaled 7% hypertonic saline (HS) reduced airway abnormalities on chest CT using the manual PRAGMA-CF method relative to isotonic saline (IS) in children aged 3-6 years with cystic fibrosis (CF). An algorithm was developed and validated to automatically measure bronchus and artery (BA) dimensions of BA-pairs on chest CT. Aim of the study was to assess the effect of HS on bronchial wall thickening and bronchial widening using the BA-analysis. METHODS: The BA-analysis (LungQ, version 2.1.0.1, Thirona, Netherlands) automatically segments the bronchial tree and identifies the segmental bronchi (G0) and distal generations (G1-G10). Dimensions of each BA-pair are measured: diameters of bronchial outer wall (Bout), bronchial inner wall (Bin), bronchial wall thickness (Bwt), and artery (A). BA-ratios are computed: Bout/A and Bin/A to detect bronchial widening and Bwt/A and Bwa/Boa (=bronchial wall area/bronchial outer area) to detect bronchial wall thickening. RESULTS: 113 baseline and 102 48-week scans of 115 SHIP-CT participants were analysed. LungQ measured at baseline and 48-weeks respectively 6,073 and 7,407 BA-pairs in the IS-group and 6,363 and 6,840 BA-pairs in the HS-group. At 48 weeks, Bwt/A (mean difference 0.011; 95%CI, 0.0017 to 0.020) and Bwa/Boa (mean difference 0.030; 95% 0.009 to 0.052) was significantly higher (worse) in the IS-group compared to the HS-group representing more severe bronchial wall thickening in the IS-group (p=0.025 and p=0.019 respectively). Bwt/A and Bwa/Boa decreased and Bin/A remained stable from baseline to 48 weeks in the HS while it declined in the IS-group (all p<0.001). There was no difference in progression of Bout/A between two treatment groups. CONCLUSION: The automatic BA-analysis showed a positive impact of inhaled HS on bronchial lumen and wall thickness, but no treatment effect on progression of bronchial widening over 48 weeks.

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.

Evaluation of clinically relevant changes in the lung clearance index in children with cystic fibrosis and healthy controls.

BACKGROUND: The limits of reproducibility of the lung clearance index (LCI) are higher in children with cystic fibrosis (CF) compared with healthy children, and it is currently unclear what defines a clinically meaningful change. METHODS: In a prospective multisite observational study of children with CF and healthy controls (HCs), we measured LCI, FEV1% predicted and symptom scores at quarterly visits over 2 years. Two reviewers performed a detailed review of visits to evaluate the frequency that between visit LCI changes outside ±10%, ±15%, ±20% represented a clinically relevant signal. In the setting of acute respiratory symptoms, we used a generalised estimating equation model, with a logit link function to determine the ability of LCI worsening at different thresholds to predict failure of lung function recovery at follow-up. RESULTS: Clinically relevant LCI changes outside ±10%, ±15% and ±20% were observed at 25.7%, 15.0% and 8.3% of CF visits (n=744), respectively. The proportions of LCI changes categorised as noise, reflecting biological variability, were comparable between CF and HC at the 10% (CF 9.9% vs HC 13.0%), 15% (CF 4.3% vs HC 3.1%) and 20% (CF 2.4% vs HC 1.0%) thresholds. Compared with symptomatic CF visits without a worsening in LCI, events with ≥10% LCI increase were more likely to fail to recover baseline LCI at follow-up. CONCLUSION: The limits of reproducibility of the LCI in healthy children can be used to detect clinically relevant changes and thus inform clinical care in children with CF.

Comparative analysis of respiratory symptom scores to detect acute respiratory events in children with cystic fibrosis.

BACKGROUND: Patient-reported outcomes (PROs) are important outcome measures in research and clinical practice. This study describes the longitudinal variability the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory score and the Chronic Respiratory Infection Symptom Score (CRISS), as well as their ability to identify acute respiratory events in children with CF. METHODS: In this prospective observational study, the parent-proxy (6 -13 years) and self-reported (6-18 years) CFQ-R Respiratory score and CRISS (6-18 years) were measured every 3 months over 2 years. The lung clearance index (LCI) and FEV1 were also measured. We compared the diagnostic accuracy of the PROs in distinguishing acute respiratory events and clinically stable visits, using the minimal important difference of each PRO as the threshold. RESULTS: A total of 98 children with CF were included. On average, the symptom scores did not change between clinically stable visits. The positive predictive value (PPV) and negative predictive value (NPV) of a ≥8.5-point worsening in the parent-proxy CFQ-R score to identify acute respiratory events (n=119) (PPV 70.2% and NPV 87.0%) were higher than for the self-reported CFQ-R score (PPV 58.9% and NPV 72.2%). The PPV and NPV of an ≥11-point change in the CRISS for acute respiratory events (n=137) was 56.5% and 79.6%, respectively. The PPV and NPV of all PROs were increased when combined with the LCI and/or FEV1pp. CONCLUSION: Symptoms scores differ in their ability to identify acute respiratory events in children with CF; PPV and NPV of all PROs were improved when combined with lung function outcomes.

Airway Inflammation in Children with Primary Ciliary Dyskinesia.

Rationale: The role of airway inflammation in disease pathogenesis in children with primary ciliary dyskinesia (PCD) is poorly understood. Objectives: We investigated relationships between sputum inflammation measurements, age, lung function, bronchiectasis, airway infection, and ultrastructural defects in children with PCD. Methods: Spontaneously expectorated sputum was collected from clinically stable children and adolescents with PCD ages 6 years and older participating in a multicenter, observational study. Sputum protease and inflammatory cytokine concentrations were correlated with age, lung function, and chest computed tomography measures of structural lung disease, whereas differences in concentrations were compared between ultrastructural defect categories and between those with and without detectable bacterial infection. Results: Sputum from 77 children with PCD (39 females [51%]; mean [standard deviation] age, 13.9 [4.9] yr; mean [standard deviation] forced expiratory volume in 1 second [FEV1]% predicted, 80.8 [20.5]) was analyzed. Sputum inflammatory marker measurements, including neutrophil elastase activity, IL-1ß (interleukin-1ß), IL-8, and TNF-α (tumor necrosis factor α) concentrations, correlated positively with age, percentage of bronchiectasis, and percentage of total structural lung disease on computed tomography, and negatively with lung function. Correlations between neutrophil elastase concentrations and FEV1% predicted and percentage of bronchiectasis were -0.32 (95% confidence interval, -0.51 to -0.10) and 0.46 (0.14 to 0.69), respectively. Sputum neutrophil elastase, IL-1ß, and TNF-α concentrations were higher in those with detectable bacterial pathogens. Participants with absent inner dynein arm and microtubular disorganization had similar inflammatory profiles compared with participants with outer dynein arm defects. Conclusions: In this multicenter pediatric PCD cohort, elevated concentrations of sputum proteases and cytokines were associated with impaired lung function and structural damage as determined by chest computed tomography, suggesting that sputum inflammatory measurements could serve as biomarkers in PCD.

Airway Disease in Children with Primary Ciliary Dyskinesia: Impact of Ciliary Ultrastructure Defect and Genotype.

Rationale: Primary ciliary dyskinesia (PCD) is characterized by impaired mucociliary clearance, recurrent respiratory infections, progressive airway damage, and obstructive lung disease. Although the association of ciliary ultrastructure defect/genotype with the severity of airflow obstruction has been well characterized, their association with airway abnormalities on chest computed tomography (CT) has been minimally evaluated. Objectives: We sought to delineate the association of ciliary defect class/genotype with chest CT scores in children with PCD. Methods: Cross-sectional analysis of children with PCD (N = 146) enrolled in a prospective multicenter observational study, stratified by defect type: outer dynein arm (ODA), ODA/inner dynein arm (IDA), IDA/microtubular disorganization (MTD), and normal/near normal ultrastructure with associated genotypes. CTs were scored using the MERAGMA-PCD (Melbourne-Rotterdam Annotated Grid Morphometric Analysis for PCD), evaluating airway abnormalities in a hierarchical order: atelectasis, bronchiectasis, bronchial wall thickening, and mucus plugging/tree-in-bud opacities. The volume fraction of each component was expressed as the percentage of total lung volume. The percentage of disease was computed as the sum of all components. Regression analyses were used to describe the association between clinical predictors and CT scores. Results: Acceptable chest CTs were obtained in 141 children (71 male): 57 ODA, 20 ODA/IDA, 40 IDA/MTD, and 24 normal/near normal. The mean (standard deviation) age was 8.5 (4.6) years, forced expiratory volume in 1 second (FEV1) percent predicted was 82.4 (19.5), and %Disease was 4.6 (3.5). Children with IDA/MTD defects had a higher %Disease compared with children with ODA defects (2.71% higher [95% confidence interval (CI), 1.37-4.06; P < 0.001]), driven by higher %Mucus plugging (2.35% higher [1.43-3.26; P < 0.001]). Increasing age, lower body mass index, and lower FEV1 were associated with a higher %Disease (0.23%; 95% CI, 0.11-0.35; P < 0.001 and 0.03%; 95% CI, 0.01-0.04; P = 0.008 and 0.05%; 95% CI, 0.01-0.08; P = 0.011, respectively). Conclusions: Children with IDA/MTD defects had significantly greater airway disease on CT, primarily mucus plugging, compared with children with ODA defects.