Association of factors with childhood asthma and allergic diseases using latent class analysis.

We hypothesize that children characterized by deprived factors have poorer health outcomes. We aim to identify clustering of determinants and estimate risk of early childhood diseases. This 1993-2019 longitudinal cohort study combines three Canadian pediatric cohorts and their families. Mothers and children are clustered using latent class analysis (LCA) by 16 indicators in three domains (maternal and newborn; socioeconomic status [SES] and neighbourhood; environmental exposures). Hazard ratios (HR) of childhood asthma, allergic rhinitis (AR), and eczema are quantified with Cox proportional hazard (PH) regression. Rate ratios (RR) of children's health services use (HSU) are estimated with Poisson regression. Here we report the inclusion of 15,724 mother-child pairs; our LCA identifies four mother-clusters. Classes 1 and 2 mothers are older (30-40 s), non-immigrants with university education, living in high SES neighbourhoods; Class 2 mothers have poorer air quality and less greenspace. Classes 3 and 4 mothers are younger (20-30 s), likely an immigrant/refugee, with high school-to-college education, living in lower SES neighborhoods with poorer air quality and less greenspace. Children's outcomes differ by Class, in comparison to Class 1. Classes 3 and 4 children have higher risks of asthma (HR 1.24, 95% CI 1.11-1.37 and HR 1.39, 95% CI 1.22-1.59, respectively), and similar higher risks of AR and eczema. Children with AR in Class 3 have 20% higher all-cause physician visits (RR = 1.20, 95% CI 1.10-1.30) and those with eczema have 18% higher all-cause emergency department visits (RR = 1.18, 95% CI 1.09-1.28) and 14% higher all-cause physician visits (RR = 1.14, 95% CI 1.09-1.19). Multifactorial-LCA mother-clusters may characterize associations of children's health outcomes and care, adjusting for interrelationships.

Mortality of Pediatric Surgical Lung Biopsies in Ontario, Canada, 2000-2019.

Rationale: Surgical lung biopsies are often required for the definitive diagnosis of nonmalignant pediatric diffuse lung diseases; however, the literature on mortality after surgical lung biopsy in pediatric patients is sparse. Objectives: To determine the 30-day postoperative mortality rate after surgical lung biopsies for nonmalignant lung disease in pediatric patients in Ontario, Canada, and to identify risk factors associated with mortality. Methods: We performed an observational cohort study using population-based health administrative data available from ICES in Ontario, Canada, from 2000 to 2019. Cases were identified using the Canadian Classification of Health Interventions. Inclusion criteria were first surgical lung biopsies between 2000 and 2019 and age <18 years. Individuals with lung cancer, lung transplant, or missing data were excluded. A multivariable logistic regression model with generalized estimating equation was used to estimate the 30-day odds of mortality after surgical lung biopsy and to identify patient characteristics associated with increased mortality while accounting for clustering by hospital. Results: We identified 1,474 pediatric patients who underwent surgical lung biopsy in Ontario between 2000 and 2019. The overall mortality rates decreased over the study duration from 6.6% (2000-2004) to 3.0% (2015-2019). The study cohort for multivariate analyses consisted of 1,342 patients who had complete data. The pediatric mortality 30 days after surgical lung biopsy was 5.1% but was <1% in elective cases. Risk factors for increased mortality included open surgical lung biopsy (vs. video-assisted) (odds ratio [OR], 13.13; 95% confidence interval [CI], 3.76, 45.87; P < 0.001), nonelective procedure (OR, 11.74; 95% CI, 3.51, 39.27; P < 0.001), younger age (<3 mo) (OR, 6.04; 95% CI, 2.40, 15.22; P < 0.001), and higher comorbidity score (OR, 1.15; 95% CI, 1.05, 1.26; P = 0.003). Conclusions: Pediatric mortality postsurgical lung biopsy is not insignificant, particularly in nonelective procedures. Other important risk factors to consider when pursuing pathologic diagnosis include surgical approach, younger age, and higher comorbidity.

A BEAT-PCD consensus statement: a core outcome set for pulmonary disease interventions in primary ciliary dyskinesia.

Background: Consistent use of reliable and clinically appropriate outcome measures is a priority for clinical trials, with clear definitions to allow comparability. We aimed to develop a core outcome set (COS) for pulmonary disease interventions in primary ciliary dyskinesia (PCD). Methods: A multidisciplinary international PCD expert panel was set up. A list of outcomes was created based on published literature. Using a modified three-round e-Delphi technique, the panel was asked to decide on relevant end-points related to pulmonary disease interventions and how they should be reported. First, inclusion of an outcome in the COS was determined. Second, the minimum information that should be reported per outcome. The third round finalised statements. Consensus was defined as ≥80% agreement among experts. Results: During the first round, experts reached consensus on four out of 24 outcomes to be included in the COS. Five additional outcomes were discussed in subsequent rounds for their use in different subsettings. Consensus on standardised methods of reporting for the COS was reached. Spirometry, health-related quality-of-life scores, microbiology and exacerbations were included in the final COS. Conclusion: This expert consensus resulted in a COS for clinical trials on pulmonary health among people with PCD.

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.

Efficacy of Antibiotic Eradication Therapy of Early Pseudomonas aeruginosa Infection in Children with Primary Ciliary Dyskinesia.

Rationale: Chronic infection with Pseudomonas aeruginosa (PsA) negatively impacts lung disease in patients with primary ciliary dyskinesia (PCD). There is currently limited evidence regarding the efficacy of PsA antibiotic eradication therapy (AET) in children with PCD. Objectives: To assess the effectiveness of AET of early PsA infection in children with PCD. Methods: This retrospective study included pediatric patients with a confirmed PCD diagnosis according to the American Thoracic Society guidelines at the Hospital for Sick Children between 2010 and 2022. Children with newly acquired PsA infection underwent AET using a stepwise protocol. The protocol included the following steps: step 1, 28 days of tobramycin inhalation solution (TIS); step 2, repeat TIS if culture positive after step 1; and step 3, 14 days of intravenous antibiotics followed by 28 days of TIS if culture positive after step 2. Step 3 was also used for patients who presented with pulmonary exacerbation symptoms. The main outcome was a PsA-negative culture result based on the microbiological results of the first culture after completion of each step of treatment. Results: During the study period, 31 children had a new PsA infection and underwent AET. Of the 27 children who had been asymptomatic at the time of the PsA infection, negative PsA culture results were achieved in 20 (74%) of 27, 1 (14%) of 7, and 5 (83%) of 6 after steps 1, 2, and 3 of AET, respectively. All four symptomatic patients who initially were treated with step 3 had successful clearance of PsA. The overall cumulative success rate of the protocol for negative culture results after AET was 97% (30 of 31). For patients in whom AET was successful, the probability of staying PsA free for at least 1 year was 70%. Conclusions: AET for early PsA infection is highly effective in PCD, with sustained efficacy in most individuals. These data suggest that AET should be considered in all children with PCD who have early PsA infection.

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.

Laterality Defects in Primary Ciliary Dyskinesia: Relationship to Ultrastructural Defect or Genotype.

Rationale: The association between organ laterality abnormalities and ciliary ultrastructural defect or genotype in primary ciliary dyskinesia is poorly understood. Objectives: To determine if there is an association between presence and/or type of laterality abnormality and ciliary ultrastructural defect or genotype. Methods: Participants with primary ciliary dyskinesia in a multicenter, prospective study were grouped based on ciliary ultrastructural defect or genotype. In a retrospective analysis of these data, the association of ciliary ultrastructural defect or genotype and likelihood of a laterality abnormality was evaluated by logistic regression adjusted for presence of two loss-of-function versus one or more not-loss-of-function variants. Results: Of 559 participants, 286 (51.2%), 215 (38.5%), and 58 (10.4%) were identified as having situs solitus, situs inversustotalis, and situs ambiguus, respectively; heterotaxy, defined as situs ambiguus with complex cardiovascular defects, was present in 14 (2.5%). Compared with the group with inner dynein arm defects with microtubular disorganization, laterality defects were more likely in the outer dynein arm defects group (odds ratio [OR], 2.07; 95% confidence interval [CI], 1.21-3.54; P < 0.01) and less likely in the normal/near normal ultrastructure group (OR, 0.04; 95% CI, 0.013-0.151; P < 0.01). Heterotaxy was present in 11 of 242 (4.5%) in the outer dynein arm defects group but 0 of 96 in the inner dynein arm defects with microtubular disorganization group (P = 0.038). Conclusion: In primary ciliary dyskinesia, risk of a laterality abnormality differs by ciliary ultrastructural defect. Pathophysiologic mechanisms underlying these differences require further exploration.

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.

Association of Neonatal Hospital Length of Stay with Lung Function in Primary Ciliary Dyskinesia.

Rationale: Primary ciliary dyskinesia (PCD), an inherited lung disease, is characterized by abnormal ciliary function leading to progressive bronchiectasis. There is wide variability in respiratory disease severity at birth and later in life. Objectives: To evaluate the association between neonatal hospital length of stay (neonatal-LOS) and supplemental oxygen duration (SuppO2) with lung function in pediatric PCD. We hypothesized that longer neonatal-LOS and SuppO2 are associated with worse lung function (i.e., forced expiratory volume in 1 second percent predicted [FEV1pp]). Methods: We performed a secondary analysis of the Genetic Disorders of Mucociliary Clearance Consortium prospective longitudinal multicenter cohort study. Participants enrolled, during 2006-2011, were <19 years old with a confirmed PCD diagnosis and followed annually for 5 years. The exposure variables were neonatal-LOS and SuppO2, counted in days since birth. The outcome, FEV1pp, was measured annually by spirometry. The associations of neonatal-LOS and SuppO2 with FEV1pp were evaluated with a linear mixed-effects model with repeated measures and random intercepts, adjusted for age and ciliary ultrastructural defects. Results: Included were 123 participants (male, 47%; mean enrollment age, 8.3 yr [range, 0 to 18 yr]) with 578 visits (median follow-up, 5 yr). The median neonatal-LOS was 9 d (range, 1 to 90 d), and median SuppO2 was 5 d (range, 0 to 180 d). Neonatal-LOS was associated with worse lung function (-0.27 FEV1pp/d [95% confidence interval, -0.53 to -0.01]; P = 0.04). SuppO2 was not associated with lung function. Conclusions: Neonatal-LOS is associated with worse lung function in pediatric PCD, independent of age and ultrastructural defects. Future research on the mechanisms of neonatal respiratory distress and its management may help us understand the variability of lung health outcomes in PCD.

Going beyond the chest X-ray: Investigating laterality defects in primary ciliary dyskinesia.

BACKGROUND: Organ laterality defects in primary ciliary dyskinesia (PCD) are common, ranging from complete mirror image organ arrangement, situs inversus totalis (SIT), to situs ambiguus (SA), which falls along the spectrum of situs solitus (SS) and SIT. Targeted investigations for organ laterality defects are not universally recommended in PCD consensus statements. Without investigations beyond chest radiography (CXR), clinically significant defects may go undetected leading to increased morbidity. We hypothesize that clinically significant SA defects remain undetected on CXR and targeted investigations are needed to detect various laterality defects associated with morbidity. METHODS: This retrospective study collected data from PCD clinics at two Canadian children's hospitals from 2012 to 2020. Participants <30 years old with a confirmed or clinical diagnosis of PCD were enrolled. CXR images were reviewed, and reports of other targeted investigations, including chest computed tomography, abdominal ultrasound, echocardiogram, upper gastrointestinal series, and splenic function studies, were extracted from medical records. Situs classifications from CXR alone versus CXR with add-on targeted investigations were compared using Cochran's q and McNemar tests. RESULTS: One hundred and fifty-nine PCD patients were included, median age at PCD diagnosis of 6.1 years (range: 0-28). The situs classification differed significantly from CXR images alone versus CXR with add-on targeted investigations (p < 0.001); SS 88 (55%) versus 75 (47%), SIT 59 (37%) versus 46 (29%), and SA 12 (8%) versus 38 (24%). Identified SA defects were cardiovascular (21, 13%), intestinal (9, 6%), and/or splenic (16,10%). CONCLUSIONS: In PCD patients, clinically significant SA defects may not be detected by CXR alone. Our results suggest that the routine use of CXR with add-on targeted investigations may be justified.

Hereditary Mucin Deficiency Caused by Biallelic Loss of Function of MUC5B.

Rationale: Mucin homeostasis is fundamental to airway health. Upregulation of airway mucus glycoprotein MUC5B is observed in diverse common lung diseases and represents a potential therapeutic target. In mice, Muc5b is required for mucociliary clearance and for controlling inflammation after microbial exposure. The consequences of its loss in humans are unclear. Objectives: The goal of this study was to identify and characterize a family with congenital absence of MUC5B protein. Methods: We performed whole-genome sequencing in an adult proband with unexplained bronchiectasis, impaired pulmonary function, and repeated Staphylococcus aureus infection. Deep phenotyping over a 12-year period included assessments of pulmonary radioaerosol mucociliary clearance. Genotyping with reverse phenotyping was organized for eight family members. Extensive experiments, including immunofluorescence staining and mass spectrometry for mucins, were performed across accessible sample types. Measurements and Main Results: The proband, and her symptomatic sibling who also had extensive sinus disease with nasal polyps, were homozygous for a novel splicing variant in the MUC5B gene (NM_002458.2: c.1938 + 1G>A). MUC5B was absent from saliva, sputum, and nasal samples. Mucociliary clearance was impaired in the proband, and large numbers of apoptotic macrophages were present in sputum. Three siblings heterozygous for the familial MUC5B variant were asymptomatic but had a shared pattern of mild lung function impairments. Conclusions: Congenital absence of MUC5B defines a new category of genetic respiratory disease. The human phenotype is highly concordant with that of the Muc5b-/- murine model. Further study of individuals with decreased MUC5B production could provide unique mechanistic insights into airway mucus biology.

Development and Validation of an Algorithm for Quality Grading of Pediatric Spirometry: A Quality Improvement Initiative.

Rationale: Current spirometry quality grading for individuals 7 years and older include within-test repeatability thresholds up to 250 ml, which may be inappropriately wide for children. Objectives:1) To develop, internally validate, and implement a quality grading algorithm for forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) for school-aged children and 2) to compare the algorithm with the one proposed by the American Thoracic Society (ATS). Methods: We conducted a review of existing algorithms and obtained expert input. A pediatric quality grading algorithm was drafted and modified in an iterative process until consensus was achieved, with the main difference from current criteria being tighter volume repeatability for the pediatric quality grading. Four pulmonary function technicians evaluated the interrater agreement of the algorithm in a blinded fashion on an unselected consecutive sample of 87 prebronchodilator spirometry tests, and the grades were compared with those from the ATS algorithm in the same sample of spirometry tests. The algorithm was then implemented into the workflow of the pulmonary function laboratory. Results: For FEV1 and FVC, the interrater agreement values for the pediatric algorithm were 92% and 83%, respectively. When the ATS algorithm was used, 75.9% (n = 66) and 63.2% (n = 55) of subjects achieved a grade of A for FEV1 and FVC; when the pediatric algorithm was used, 69.0% (n = 60) and 58.6% (n = 51) met grade A criteria. There was a more uniform distribution of tests for the pediatric algorithm across grades B through F for FEV1 and FVC, and no grade C tests were observed for the ATS grading algorithm. A total of 2,464 tests graded prospectively by using the pediatric algorithm showed a median (interquartile range) FEV1 and FVC repeatability within 29 ml (13-57 ml) and 34 ml (15-66 ml), respectively. Most subjects received a grade of A for FEV1 (81.1%) and FVC (71.6%), performing a repeatable spirometry test to within 100 ml. Conclusions: A quality grading algorithm that uses smaller ranges of expired volumes to define repeatability is feasible and may be more appropriate in a pediatric pulmonary function laboratory.

Super-Resolution Microscopy and FIB-SEM Imaging Reveal Parental Centriole-Derived, Hybrid Cilium in Mammalian Multiciliated Cells.

Motile cilia are cellular beating machines that play a critical role in mucociliary clearance, cerebrospinal fluid movement, and fertility. In the airways, hundreds of motile cilia present on the surface of a multiciliated epithelia cell beat coordinately to protect the epithelium from bacteria, viruses, and harmful particulates. During multiciliated cell differentiation, motile cilia are templated from basal bodies, each extending a basal foot-an appendage linking motile cilia together to ensure coordinated beating. Here, we demonstrate that among the many motile cilia of a multiciliated cell, a hybrid cilium with structural features of both primary and motile cilia is harbored. The hybrid cilium is conserved in mammalian multiciliated cells, originates from parental centrioles, and its cellular position is biased and dependent on ciliary beating. Furthermore, we show that the hybrid cilium emerges independently of other motile cilia and functions in regulating basal body alignment.

A quantitative super-resolution imaging toolbox for diagnosis of motile ciliopathies.

Airway clearance of pathogens and particulates relies on motile cilia. Impaired cilia motility can lead to reduction in lung function, lung transplant, or death in some cases. More than 50 proteins regulating cilia motility are linked to primary ciliary dyskinesia (PCD), a heterogeneous, mainly recessive genetic lung disease. Accurate PCD molecular diagnosis is essential for identifying therapeutic targets and for initiating therapies that can stabilize lung function, thereby reducing socioeconomic impact of the disease. To date, PCD diagnosis has mainly relied on nonquantitative methods that have limited sensitivity or require a priori knowledge of the genes involved. Here, we developed a quantitative super-resolution microscopy workflow: (i) to increase sensitivity and throughput, (ii) to detect structural defects in PCD patients' cells, and (iii) to quantify motility defects caused by yet to be found PCD genes. Toward these goals, we built a localization map of PCD proteins by three-dimensional structured illumination microscopy and implemented quantitative image analysis and machine learning to detect protein mislocalization, we analyzed axonemal structure by stochastic optical reconstruction microscopy, and we developed a high-throughput method for detecting motile cilia uncoordination by rotational polarity. Together, our data show that super-resolution methods are powerful tools for improving diagnosis of motile ciliopathies.

Neuroendocrine Cell Hyperplasia of Infancy. Clinical Score and Comorbidities.

Rationale: Neuroendocrine cell hyperplasia of infancy (NEHI) is an important form of children's interstitial and diffuse lung disease for which the diagnostic strategy has evolved. The prevalence of comorbidities in NEHI that may influence treatment has not been previously assessed.Objectives: To evaluate a previously unpublished NEHI clinical score for assistance in diagnosis of NEHI and to assess comorbidities in NEHI.Methods: We performed a retrospective chart review of 199 deidentified patients with NEHI from 11 centers. Data were collected in a centralized Research Electronic Data Capture registry and we performed descriptive statistics.Results: The majority of patients with NEHI were male (66%). The sensitivity of the NEHI Clinical Score was 87% (95% confidence interval [CI], 0.82-0.91) for all patients from included centers and 93% (95% CI, 0.86-0.97) for those with complete scores (e.g., no missing data). Findings were similar when we limited the population to the 75 patients diagnosed by lung biopsy (87%; 95% CI, 0.77-0.93). Of those patients evaluated for comorbidities, 51% had gastroesophageal reflux, 35% had aspiration or were at risk for aspiration, and 17% had evidence of immune system abnormalities.Conclusions: The NEHI Clinical Score is a sensitive tool for clinically evaluating NEHI; however, its specificity has not yet been addressed. Clinicians should consider evaluating patients with NEHI for comorbidities, including gastroesophageal reflux, aspiration, and immune system abnormalities, because these can contribute to the child's clinical picture and may influence clinical course and treatment.

Nasal Nitric Oxide Measurement in Primary Ciliary Dyskinesia. A Technical Paper on Standardized Testing Protocols.

Nasal nitric oxide concentrations are extremely low in primary ciliary dyskinesia (PCD), and measurement of this nasal gas is recommended as a PCD diagnostic test in cooperative patients aged 5 years and older. However, nasal nitric oxide measurements must be performed with chemiluminescence analyzers using a standardized protocol to ensure proper results, because nasal nitric oxide values can be influenced by various internal and external factors. Repeat nasal nitric oxide testing on separate visits is required to ensure that low diagnostic values are persistent and consistent with PCD. This technical paper presents the standard operating procedures for nasal nitric oxide measurement used by the PCD Foundation Clinical and Research Centers Network at various specialty centers across North America. Adherence to this document ensures reliable nasal nitric oxide testing and high diagnostic accuracy when employed in a population with appropriate clinical phenotypes for PCD.

Validation of pediatric health-related quality of life instruments for primary ciliary dyskinesia (QOL-PCD).

RATIONALE: Having developed the first disease-specific, health-related quality of life (HRQoL) instruments for children with primary ciliary dyskinesia (PCD), we aimed to assess the psychometric performance of quality of life (QOL)-PCD child, adolescent, and parent-proxy versions in terms of reliability and validity across cross-cultural settings and caring for patients with this rare disease. METHODS: Children (n = 71), adolescents (n = 85), and parents (n = 68) from multiple centers in the UK and North America completed age-appropriate QOL-PCD and generic QOL measures: pediatric QOL inventory, COPD assessment test (CAT), and Sino-Nasal Outcome Test 20. Total of 13 children, 13 parents, and 17 adolescents repeated QOL-PCD 10 to 14 days later to assess test-retest reliability. Multitrait analysis evaluated how the items loaded to hypothesized scales: physical, emotional & social functioning, treatment burden, role, vitality, upper and lower respiratory symptoms, and ears and hearing symptoms. Examination of item-to-total correlations led to removal of three, five, and six items, respectively in the prototype child, adolescent and parent-proxy versions; the validated measures now comprise between 34 and 38 items. RESULTS: The QOL-PCD scales had good internal consistency; Cronbach's α for QOL-PCD parent-proxy ranged 0.62 to 0.86. Test-retest reliability demonstrated stability across all scales; for example QOL-PCD adolescent intraclass correlation coefficients ranged 0.71 to 0.89. Significant relationships were found between QOL-PCD scales and similar constructs on generic questionnaires, for example, QOL-PCD adolescent lower respiratory symptoms and the CAT score (r = .64, P < .01); weaker correlations were found between different constructs. CONCLUSION: Age-specific QOL-PCD demonstrated good internal consistency, test-retest reliability, and validity. QOL-PCD offers promising outcome measures for multicenter clinical trials, as well as monitoring symptoms, functioning, and QOL during routine care.

Evaluation of the pulmonary radioaerosol mucociliary clearance scan as an adjunctive test for the diagnosis of primary ciliary dyskinesia in children.

INTRODUCTION: The accuracy of primary ciliary dyskinesia (PCD) diagnosis has improved but no single test is diagnostic and some cases remain unsolved. Data regarding the accuracy of pulmonary radioaerosol mucociliary clearance scan (PRMCC) for the diagnosis of PCD are limited to predominantly adults using a 24-hour test. This study was performed to determine the accuracy of a 60-minute PRMCC test for diagnosing PCD in children. METHODS: Children with suspected PCD and inconclusive clinical diagnostic testing in an expert center were selected for PRMCC testing. Nebulized 99m Tc sulfur colloid was inhaled and dynamic imaging acquired for 60 to 120 minutes. Two independent radiologists blinded to the clinical diagnosis and health records overread PRMCC studies. The PRMCC result was compared with the reference standard diagnosis of PCD made by two physicians using the cumulative health record, blinded to PRMCC results. RESULTS: From 2008 to 2018, 57 patients (6-17 years) participated, of which 16 met criteria for the reference diagnosis of PCD. The PRMCC test was conclusive in 54 patients (94.7%) and had a sensitivity of 100% (95% confidence interval [CI] = 78.2-100), specificity of 85.7% (95% CI = 69.7-95.2), positive predictive value of 75% (95% CI = 57.1-87.1), negative predictive value of 100% (95% CI = 90.2-100), and accuracy of 90% (95% CI = 78.2-96.7). CONCLUSION: The 60-minute PRMCC test is noninvasive and feasible in children with a high negative predictive value for PCD. It may be a helpful adjunctive test to rule out PCD when clinical suspicion remains after guideline recommended first-line clinical testing.

Neighborhood Material Deprivation Is Associated with Childhood Asthma Development: Analysis of Prospective Administrative Data.

Rationale: Material deprivation has been proposed as a more comprehensive measure of socioeconomic status than parental income. Stronger associations between childhood emergency department visits for asthma and air pollution have been demonstrated among children living in neighborhoods with high levels of deprivation, but the associations with asthma development and ongoing asthma are not known. Objectives: We determined the associations between neighborhood material deprivation and the development of new and ongoing childhood asthma. Methods: Prospectively collected administrative data housed at the Institute for Clinical Evaluative Sciences were examined for Toronto children born from 1997 to 2003. Neighborhood material deprivation, comprising no high school graduation, lone parent families, government transfers, unemployment, low income, and homes needing major repairs, was reported in the Ontario Marginalization Index. Incident asthma was defined by the time of entry into the Ontario Asthma Surveillance Information System (OASIS) database. We measured the risk of incident asthma using Cox proportional hazards models and the associations between ongoing asthma visits and deprivation by year of life with generalized linear mixed models. Results: OASIS asthma criteria were met for 21% of the 326,383 children. After adjustment for characteristics strongly associated with asthma, including male sex, prematurity, obesity, and atopic conditions other than asthma, children with high birth neighborhood deprivation were at increased risk of incident asthma (HR 1.11; 95% CI, 1.09-1.13). High deprivation in a given year of life was associated with increased odds of ongoing asthma during that year of life (OR 1.03; 95% CI, 1.02-1.05). Conclusions: Children living in high-deprivation neighborhoods are at increased risk of incident and ongoing asthma. This study suggests that neighborhood material deprivation may represent a helpful tool for evaluating the effects of disparities in health and social advantages on the likelihood of developing and continuing to need healthcare visits for ongoing childhood asthma.